volume 16 - number 1 volume 1 - number 1 may - september...

Volume 1 - Number 1 May - September 1997

Volume 16 - Number 1 January 2012

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in

open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.

It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more

traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology,

and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information,

University Hospital

F-86021 Poitiers, France

tel +33 5 49 44 45 46 or +33 5 49 45 47 67

[email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le

Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski.

Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave

Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times

a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of

the French National Center for Scientific Research (INIST-CNRS) since 2008.

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http://www.atlasgeneticsoncology.org/

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)







Editor

Jean-Loup Huret

(Poitiers, France)

Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section

Alessandro Beghini (Milan, Italy) Genes Section

Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections

Judith Bovée (Leiden, The Netherlands) Solid Tumours Section

Vasantha Brito-Babapulle (London, UK) Leukaemia Section

Charles Buys (Groningen, The Netherlands) Deep Insights Section

Anne Marie Capodano (Marseille, France) Solid Tumours Section

Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections

Antonio Cuneo (Ferrara, Italy) Leukaemia Section

Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section

Louis Dallaire (Montreal, Canada) Education Section

Brigitte Debuire (Villejuif, France) Deep Insights Section

François Desangles (Paris, France) Leukaemia / Solid Tumours Sections

Enric Domingo-Villanueva (London, UK) Solid Tumours Section

Ayse Erson (Ankara, Turkey) Solid Tumours Section

Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections

Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section

Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections

Anne Hagemeijer (Leuven, Belgium) Deep Insights Section

Nyla Heerema (Colombus, Ohio) Leukaemia Section

Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections

Sakari Knuutila (Helsinki, Finland) Deep Insights Section

Lidia Larizza (Milano, Italy) Solid Tumours Section

Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section

Edmond Ma (Hong Kong, China) Leukaemia Section

Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections

Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections

Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section

Fredrik Mertens (Lund, Sweden) Solid Tumours Section

Konstantin Miller (Hannover, Germany) Education Section

Felix Mitelman (Lund, Sweden) Deep Insights Section

Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section

Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections

Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections

Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section

Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section

Mariano Rocchi (Bari, Italy) Genes Section

Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section

Albert Schinzel (Schwerzenbach, Switzerland) Education Section

Clelia Storlazzi (Bari, Italy) Genes Section

Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections

Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections

Dan Van Dyke (Rochester, Minnesota) Education Section

Roberta Vanni (Montserrato, Italy) Solid Tumours Section

Franck Viguié (Paris, France) Leukaemia Section

José Luis Vizmanos (Pamplona, Spain) Leukaemia Section

Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 16, Number 1, January 2012

Table of contents

Gene Section

ADAM10 (ADAM metallopeptidase domain 10) 1 Pascal Gelebart, Hanan Armanious, Raymond Lai

BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) 7 Victor M Bolanos-Garcia, Tom L Blundell

FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) 12 Mark Pickard

GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) 18 Stephanie Schulz, Scott A Waldman

LIN28B (lin-28 homolog B (C. elegans)) 20 Yung-Ming Jeng

PKD1 (polycystic kidney disease 1 (autosomal dominant)) 22 Ying-Cai Tan, Hanna Rennert

AMFR (autocrine motility factor receptor) 25 Yalcin Erzurumlu, Petek Ballar

ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) 30 Paul F South, Scott D Briggs

CD109 (CD109 molecule) 34 Shinji Mii, Yoshiki Murakumo, Masahide Takahashi

CLDN7 (claudin 7) 37 Ana Carolina de Carvalho, Andre Vettore

CSE1L (CSE1 chromosome segregation 1-like (yeast)) 41 Ming-Chung Jiang

DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) 44 Zhi-Ren Liu

Leukaemia Section

t(13;19)(q14;p13) 47 Jean-Loup Huret

t(17;17)(q21;q24), del(17)(q21q24) 48 Jean-Loup Huret

Deep Insight Section

MicroRNAs and Cancer 50 Federica Calore, Muller Fabbri

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




Case Report Section

Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis 69 Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda,

Andrea Montella, Maurizio Longinotti

Educational Items Section

Weird animal genomes and sex chromosome evolution 72 Jenny Graves

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 1



ADAM10 (ADAM metallopeptidase domain 10) Pascal Gelebart, Hanan Armanious, Raymond Lai

Department of Laboratory Medicine and Pathology, University of Alberta, Room 1466, 11560

University Avenue, T6G 1Z2-Edmonton, Alberta, Canada (PG, HA, RL)

Published in Atlas Database: July 2011

Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAM10ID44397ch15q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ADAM10ID44397ch15q21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: AD10, CD156c, HsT18717,

MADM, kuz

HGNC (Hugo): ADAM10

Location: 15q21.3

DNA/RNA

Description

The gene spans a region of 15.36 kb and the coding

part is divided into 16 exons.

Transcription

Only one type of transcript has been described. The

2247-nucleotide transcript encodes a protein of 748

amino acid residues. The first and last exons are

partially untranslated.

Pseudogene

None described so far.

Figure 1. Representation of the ADAM10 gene organization.

ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al.


Protein

Description

ADAM10 is a metalloproteinase composed of 748

residues.

Expression

ADAM10 RNA has been reported to be present in

wide range of human tissue (Yanai et al., 2005).

Data obtained from GeneAtlas have shown that

ADAM10 transcript is the most highly expressed in

myeloid, NK cells and monocytes as well as

cardiomyocytes and smooth muscle cells (figure 3).

At the protein level, ADAM10 has been reported in

epithelials tissue of the heart, liver and kidney (Hall

and Erickson, 2003).

Localisation

ADAM10 is localized at the plasma membrane.

However, nuclear localization of ADAM10 has

been reported in prostate cancer and in mantle cell

lymphoma cells (Armanious et al., 2011).

Function

ADAM10 belongs to the family of

metalloproteinases (Chantry et al., 1989; Chantry

and Glynn, 1990; Edwards et al., 2008). ADAM10

protein is composed of multiple functional domains

that include: a prodomain, a catalytic domain, a

cysteine-rich domain, a transmembraneous domain,

a cytoplasmic domain and a SH3 domain (Seals and

Courtneidge, 2003; Edwards et al., 2008) (see

figure 4). ADAM10 is synthesized as a pro-protein

and therefore needs to be cleaved to be activated

(Anders et al., 2001).

Two proteins, the convertase 7 and the furin, have

been implicated in the activation of ADAM10

(Anders et al., 2001). To date the major function of

ADAM10 appears to be attributed to its enzymatic

activity as a metalloproteinase. In fact, ADAM10 is

involved in the intra-membrane proteolysis process,

whereby it mediates ectodomain shedding of

various membrane bound receptors, adhesion

molecules, growth factors and cytokines like TNF-

alpha (Rosendahl et al., 1997; Lunn et al., 1997;

Hikita et al., 2009; Mezyk-Kopec et al., 2009),

Notch (Hartmann et al., 2002; Gibb et al., 2010), E-

cadherin (Maretzky et al., 2005), Ephrin (Janes et

al., 2005), HER-2 (Liu et al., 2006), CD30

(Eichenauer et al., 2007), CD44 (Anderegg et al.,

2009) and IL-6 receptor to name a few. The

functional role of the SH3 domains of ADAM10

has never been studied. Moreover, the recent

observation that ADAM10 can be found in the

nucleus of some cells raises the possibility of new

and uncovers function of ADAM10 (Arima et al.,

2007).

ADAM10 seems to be detrimental for

embryogenesis as the knockout mice for ADAM10

die at day 9.5 of embryogenesis (Hartmann et al.,

2002). The mice present several developmental

defects in the nervous central system as well in the

cardiovascular system. This latest observation

correlates well with the fact that ADAM10

transcript is highly expressed in cardiomyocyte.

In human, ADAM10 was recently been

demonstrated to be a regulator of the lymphocyte

development (Gibb et al., 2011).

Figure 2. Crystal structure of ADAM10 Disintegrin and cysteine-rich domain at 2.9 A resolution. Adapted from PDB (access number: 2AO7).

http://www.rcsb.org/pdb/explore/jmol.do?structureId=2AO7&bionumber=1



Figure 3. ADAM10 tissue expression profile. Adapted from GeneAtlas U113A.

Figure 4. ADAM10 protein structure organization.

Mutations

Note

No mutation has been reported so far.

Implicated in

Various cancers

Note

ADAM family members have been recently

involved in malignant progression and development

(Mochizuki and Okada, 2007; Rocks et al., 2008;

Wagstaff et al., 2011; Duffy et al., 2009). ADAM10

has been shown to be constitutively active in a

number of solid tumors, and this biochemical defect

is implicated in the pathogenesis of many tumors.

The following paragraphs will summarize what has

been discovered about the function of ADAM10 in

cancer.

Brain tumors

Note

ADAM10 protein has been reported to be highly

expressed in the human central nervous system

(Kärkkäinen et al., 2000). Recently, two different

studies (Kohutek et al., 2009; Formolo et al., 2011)

have uncovered the function of ADAM10 in the

cell migration and invasiveness process of

glioblastoma cells. In fact the authors have shown

that ADAM10 by mediating the cleavage of N-

cadherin was found to regulate the migratory

properties of glioblastoma cells (Kohutek et al.,

2009). On the other hand, the protein expression of

ADAM10 was found to be higher in cell with

strong invasiveness capability.

Prostate cancer

Note

Prostate cancer is one of the most frequent cancers

in men. The cause of prostate cancer development

is unknown but is likely to be arising from several

factors. Development of prostate cancer is

androgen-dependent in early stages of the disease

but cell growth became androgen-independent.

ADAM10 have been found to be expressed in all

prostate tumor samples (Karan et al., 2003).

Interestingly, McCulloch et al. have observed that

ADAM10 expression was up-regulated by

http://biogps.org/#goto=genereport&id=102



androgen stimulation. Those observations were

confirmed in a study published by Arima et al.

However, in this work they reveal that ADAM10

was predominantly localized in the nucleus of

cancer cells and show that ADAM10 can co-

immunoprecipitate with androgen receptor in the

nucleus. Moreover, they also observed that nuclear

expression of ADAM10 was correlating with

several biological parameters like the Gleason score

and prostate specific antigen expression. Inhibition

of ADAM10 expression by a siRNA approach was

able to induce a cell proliferation decrease of

prostate cancer cells. This study suggests for the

first time that ADAM10 may have some function in

the nucleus by regulating androgen receptor

function.

Breast cancer

Note

Expressions of different members of the ADAM

family have been investigated in breast cancer.

Despite that some ADAM family members present

differential expression between non neoplastic and

breast cancer tissue, no difference was observed for

ADAM10 (Lendeckel et al., 2005). Nevertheless,

Liu and co-workers have recently described than

ADAM10 was the principal responsible for HER2

shedding in HER2 over-expressing breast cancer.

The cleavage of HER2 liberates the extracellular

domain of HER2 leaving a p95 fragment containing

the transmembrane domain as well as the

intracellular domain. This p95 fragment presents

constitutive kinase activation and its expression

correlates with a poor prognosis. The author

demonstrated that in conjunction with low amount

of HER2 inhibitor, ADAM10 inhibition was

inducing a decrease in cell proliferation.

Colon and gastric and oral carcinomas

Note

Deregulation of ADAM10 in colon cancer

development has been reported in several studies.

Knösel et al. have reported that ADAM10

expression in colorectal cancer patient samples,

detectable by immunohistochemistry was found to

correlate with higher clinical stage.

Moreover, it has been demonstrated that

xenografting of colorectal cancer cells with

enforced expression of ADAM10 in nude mice

induced formation of liver metastasis compared to

the negative control cells, and this effect can be

attributed to ADAM10-mediated cleavage and

release of L1-CAM, a cell adhesion molecule

(Gavert et al., 2007). Similarly to Knösel et al.,

ADAM10 expression was associated with gastric

cancer progression and correlates with worst

prognostic outcome (Wang et al., 2011). Using

immunohistochemistry, it was also found that

ADAM10 is over-expressed in squamous cell

carcinomas of the oral cavity, as compared to the

benign epithelial cells; knockdown of ADAM10

expression using siRNA in the cell lines derived

from those tumors induces a significant decrease in

cell growth (Ko et al., 2007).

Melanoma, pancreatic cancer and adenoid cystic carcinoma

Note

The expression of ADAM10 has been investigated

in melanoma and Lee et al. have reported that

ADAM10 is over-expressed in melanoma

metastasis in comparison to primary melanoma

cells. Similar findings were made in pancreatic

cancer, where inhibition of ADAM10 expression in

pancreatic carcinoma cell lines also resulted in a

significant decrease in invasiveness and migration

(Gaida et al., 2010).

Hematologic malignancies

Note

Recently, Armanious et al. have described for the

first time the function of ADAM10 in non solid

tumors. They have reported that ADAM10 is

constitutively activated and over-expressed in

different form of B-cell lymphoma like mantle cell

lymphoma and diffuse large B-cell lymphoma.

Moreover, the authors have described that

inhibition of ADAM10 leads to a decrease of cell

proliferation. On the other hand, stimulation of

mantle cells with the recombinant active form of

ADAM10 increases further their proliferation.

Additionally, they also demonstrated, as reported

previously in the literature, that ADAM10 was

responsible for the release of active from of TNF-

alpha that in turn was contributing to the activation

of the NF-kappab pathways.

To be noted

Note

To summarize, the function of ADAM protein

family members emerge as an important player in

the pathobiology of various form of cancers.

Therefore, they represent today a new therapeutic

target of choice for cancer therapy. In particular,

ADAM10 is the object of intense drug development

(Soundararajan et al., 2009; Crawford et al., 2009;

Yavari et al., 1998; Moss et al., 2008).

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Lunn CA, Fan X, Dalie B, Miller K, Zavodny PJ, Narula SK, Lundell D. Purification of ADAM 10 from bovine spleen as a TNFalpha convertase. FEBS Lett. 1997 Jan 6;400(3):333-5



Rosendahl MS, Ko SC, Long DL, Brewer MT, Rosenzweig B, Hedl E, Anderson L, Pyle SM, Moreland J, Meyers MA, Kohno T, Lyons D, Lichenstein HS. Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases. J Biol Chem. 1997 Sep 26;272(39):24588-93

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17 in shedding of tumor necrosis factor-alpha. Biochem Cell Biol. 2009 Aug;87(4):581-93

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Mezyk-Kopeć R, Bzowska M, Stalińska K, Chełmicki T, Podkalicki M, Jucha J, Kowalczyk K, Mak P, Bereta J. Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts. Cytokine. 2009 Jun;46(3):309-15

Soundararajan R, Sayat R, Robertson GS, Marignani PA. Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells. Cancer Biol Ther. 2009 Nov;8(21):2054-62

Gaida MM, Haag N, Günther F, Tschaharganeh DF, Schirmacher P, Friess H, Giese NA, Schmidt J, Wente MN. Expression of A disintegrin and metalloprotease 10 in pancreatic carcinoma. Int J Mol Med. 2010 Aug;26(2):281-8

Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R, Cichy J, Yagita H, Tew JG, Dempsey PJ, Crawford HC, Conrad DH. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J Exp Med. 2010 Mar 15;207(3):623-35

Gutwein P, Schramme A, Abdel-Bakky MS, Doberstein K, Hauser IA, Ludwig A, Altevogt P, Gauer S, Hillmann A, Weide T, Jespersen C, Eberhardt W, Pfeilschifter J. ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases. J Biomed Sci. 2010 Jan 13;17:3

Lee SB, Schramme A, Doberstein K, Dummer R, Abdel-Bakky MS, Keller S, Altevogt P, Oh ST, Reichrath J, Oxmann D, Pfeilschifter J, Mihic-Probst D, Gutwein P.

ADAM10 is upregulated in melanoma metastasis compared with primary melanoma. J Invest Dermatol. 2010 Mar;130(3):763-73

Xu Q, Liu X, Chen W, Zhang Z. Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference. J Transl Med. 2010 Dec 20;8:136

Armanious H, Gelebart P, Anand M, Belch A, Lai R. Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway. Blood. 2011 Jun 9;117(23):6237-46

Formolo CA, Williams R, Gordish-Dressman H, MacDonald TJ, Lee NH, Hathout Y. Secretome signature of invasive glioblastoma multiforme. J Proteome Res. 2011 Jul 1;10(7):3149-59

Gibb DR, Saleem SJ, Chaimowitz NS, Mathews J, Conrad DH. The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity. Mol Immunol. 2011 Jun;48(11):1319-27

Wagstaff L, Kelwick R, Decock J, Edwards DR. The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis. Front Biosci. 2011 Jan 1;16:1861-72

Wang YY, Ye ZY, Li L, Zhao ZS, Shao QS, Tao HQ. ADAM 10 is associated with gastric cancer progression and prognosis of patients. J Surg Oncol. 2011 Feb;103(2):116-23

This article should be referenced as such:

Gelebart P, Armanious H, Lai R. ADAM10 (ADAM metallopeptidase domain 10). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):1-6.

Gene Section Review




BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Victor M Bolanos-Garcia, Tom L Blundell

Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK (VMBG, TLB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/BUB1ID853ch2q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI BUB1ID853ch2q13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: BUB1A, BUB1L, hBUB1

HGNC (Hugo): BUB1

Location: 2q13

Note

The multidomain protein kinase BUB1 is a central

component of the mitotic checkpoint for spindle

assembly (SAC). This evolutionary conserved and

essential self-monitoring system of the eukaryotic

cell cycle ensures the high fidelity of chromosome

segregation by delaying the onset of anaphase until

all chromosomes are properly bi-oriented on the

microtubule spindle.

DNA/RNA

Description

The gene spans 40.2 kb and is composed of 25

exons.

Transcription

NM_004336.3

Protein

Note

Uniprot accession number: NP_004327.1.

ENZYME entry (serine/threonine protein kinase):

EC 2.7.11.1.

Amino acid sequence (FASTA format).

Description

1085 amino acids, 122.37 kDa.

Expression

Ubiquituously expressed.

Localisation

Cytoplasmic in interphase cells. It is localized in

nuclear kinetochores in cells with an unsatisfied

mitotic checkpoint in a process that requires BUB1

binding to Blinkin and BUB3.

Function

BUB1 is required for chromosome congression,

kinetochore localization of BUBR1, CENP-E,

CENP-F and Mad2 in cells with mitotic checkpoint

unsatisfied and for the establishment and/or

maintenance of efficient bipolar attachment to

spindle microtubules (Johnson et al., 2004;

Lampson and Kapoor, 2005; McGuinness et al.,

2009). Deletion of Bub1 from S. pombe increases

the rate of chromosome missegregation (Bernard et

al., 1998) while deletion of Bub1 from S. cerevisiae

results in slow growth and elevated chromosome

loss (Warren et al., 2002).

BUB1 is recruited very early in prophase (Wong

and Fang, 2006) and is essential for assembly of the

functional inner centromere (Taylor et al., 1998;

Boyarchuk et al., 2007).

Figure 1. Schematic representation of the human bub1 gene demonstrating the relative size of each of the 25 exons (introns are

not drawn to scale).

BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))

Bolanos-Garcia VM, Blundell TL


Figure 2. Domain organization of BUB1. Three main regions can be identified in the BUB1 gene product: a conserved N-terminal

region, which contains the kinetochore localization domain; an intermediate, non-conserved region, which is required for Bub3 binding; and a C-terminal region containing a catalytic serine/threonine kinase domain. The main functions associated with the

different BUB1 regions are also indicated.

It accumulates at the kinetochore in SAC-activated

cells and assures the correct kinetochore formation.

The N-terminal region mediates the binding of

BUB1 to the mitotic kinetochore protein Blinkin (a

protein also commonly referred to as

KNL1/Spc105/AF15q14); the interaction is

essential for the kinetochore localization of BUB1

induced in cells with an unsatisfied mitotic

checkpoint (Kiyomitsu et al., 2007). N-terminal

BUB1 is organised as a triple tandem of the TPR

motif (Bolanos-Garcia et al., 2009). In fission yeast,

the Bub1 N-terminal residues 1-179 are required for

targeting the protein Shugoshin 1 (SGO1) to

centromeres (Vaur et al., 2005) while deletion of

residues 28-160 results in a truncated protein

unable to recruit Bub3 and Mad3/BUB1B to

kinetochores (Vanoosthuyse et al., 2004). The C-

terminal region contains a catalytic, serine

threonine kinase domain that resembles the

mechanism of activation of CDKs by cyclins (Kang

et al., 2008).

Homology

The bub1 gene is conserved in chimpanzee, cow,

mouse, rat, chicken, and zebrafish. Homology

exists with the gene encoding for the mitotic

checkpoint kinase BUBR1 (a BUB1 paralogue)

(Bolanos-Garcia and Blundell, 2011).

Mutations The following somatic mutations have been

reported to date: A130->S (Shichiri et al., 2002);

deletion delta76-141 (Cahill et al., 1998); 140,

transition of the splicing donor site (Cahill et al.,

1998); S492->Y (Cahill et al., 1998); deletion

delta827 (Ouyang et al., 2002); G250->N (Ohshima

et al., 2000); S950->G (Imai et al., 1999); Y259->C

(Hempen et al., 2003); H265->N (Hempen et al.,

2003). It could not be determined whether the

R209->Q substitution was the result of a somatic

mutation or due to a rare polymorphism because

constitutional DNA from the patient harbouring this

mutation was not available (Sato et al., 2000). The

clinical condition associated to each mutation is

described in Table 1. The mapping of residues

substitutions onto the BUB1 domains is depicted in

Figure 3.

Bub1 region Mutation Residue Domain Clinical condition Reference

N-terminal

GAG→GAT E36→D

TPR domain

Colorectal cancer Cahill et al., 1999

Deletion Δ76-141,

frameshift Colorectal cancer Cahill et al., 1998

GCT→TCT A130→S Lymph node metastasis Shichiri et al., 2002

G→A

140, transition

of the splicing

donor site

Colorectal cancer Cahill et al., 1998

GLEBS

motif

CGA→CAA R209→Q Lung cancer Sato et al., 2000

GGT→GAT G250→N ATLL Ohshima et al., 2000*

TAT→TGT Y259→C Pancreatic cancer Hempen et al., 2003

CAC→AAC H265→N Pancreatic cancer Hempen et al., 2003

Middle

region of low

structural

complexity

TCC→TTC S375→F Colorectal cancer Saeki et al., 2002

TCT→TAT S492→Y Colorectal cancer Cahill et al., 1998

AAG→AGG K566→R Colorectal cancer Saeki et al., 2002

CCC→CGC P648→R Colorectal cancer Cahill et al., 1999

C-terminal

Deletion Δ827,

frameshift Tyroid follicular adenoma Ouyang et al., 2002

S950→G

Kinase

domain Colorectal cancer Imai et al., 1999

Table 1. Human bub1 mutations associated with cancer. *These authors incorrectly number these residues; the numbering shown here is the correct.




Figure 3. Mapping of cancer associated substitutions onto the amino acid sequence of human BUB1.

Implicated in

Colorectal cancer

Disease

Colorectal cancer, also referred to as bowel cancer,

is characterized by neoplasia in the colon, rectum,

or vermiform appendix. Colorectal cancer is the

third most commonly diagnosed cancer in the world

and fourth most frequent cause of cancer death in

males. More than half of the people who die of

colorectal cancer live in a developed region of the

world.

Cytogenetics

RT-PCR mediated amplification and direct

sequencing of the entire BUB1 coding region in the

colorectal cancer cell line V400 revealed an internal

deletion of 197 bp of this gene (Cahill et al., 1998).

The deletion results in the remotion of codons 76 to

141 and creates a frameshift immediately thereafter.

Sequence analysis of cDNA from another colorectal

cancer cell line, V429, revealed a missense

mutation at codon 492 that resulted in the

substitution of tyrosine for a conserved serine

(Cahill et al., 1998). The V400 and V429 mutations

were heterozygous, somatic and present in primary

tumours but not in normal tissues. Another

heterozygous BUB1 missense mutation (AGT to

GGT) at codon 950 has been identified (Imai et al.,

1999).

Hepatocellular carcinoma (HCC)

Disease

Hepatocellular carcinoma (HCC) is one of the most

common tumors worldwide and it accounts for

most liver cancers. HCC occurs more often in men

than women and is more common in people ages

30-50. Hepatitis virus infection, alcohol

consumption, and dietary exposure to toxins such as

aflatoxin B1 are associated with the occurrence of

HCC.

Cytogenetics

Two BUB1 gene variants have been identified in

HCC specimens (Saeki et al., 2002). The expression

product of one variant has a serine (TCC)

substituted for phenylalanine (TTC) at codon 375

while the other has a lysine (AAG) substituted for

arginine (AGG) at codon 566 (Saeki et al., 2002).

S375F showed a well-differentiated HCC in

cirrhotic liver caused by hepatitis B virus, whereas

K566R showed a moderately differentiated HCC in

hepatitis C virus induced cirrhotic liver. Genomic

DNA extracted from nontumorous liver tissue

revealed the same variants in both cases.

Lung cancer

Disease

Lung cancer is the most frequently diagnosed

cancer among men. The mortality rate is the highest

among men and the second highest among women

worldwide. The main types of lung cancer are

small-cell lung carcinoma and non-small-cell lung

carcinoma. Non-small-cell lung carcinoma is

sometimes treated with surgery, while small-cell

lung carcinoma usually responds better to

chemotherapy and radiation. Lung cancer cells

harbour many cytogenetic abnormalities suggestive

of allele loss, including non-reciprocal

translocations and aneuploidy. The stage of the

disease is a strong predictor of survival, suggesting

that early detection is needed for improvement in

treatment outcomes.

Cytogenetics

A nucleotide change of the BUB1 gene that results

in the substitution of Arginine by Glutamine

R209Q has been identified in the cell line NCI-

H345 (Sato et al., 2000). Unfortunately, it was not

possible to determine whether the change was a

somatic mutation or a rare polymorphism because

constitutional DNA from this patient was not

available.

Adult T-cell leukaemia/lymphoma (ATLL)

Disease

Lymphomas, malignancies of the lymphoid cells,

are divided on the basis of their pathologic features

into Hodgkin lymphoma (HL) and non-Hodgkin

lymphoma (NHL). Adult T-cell

leukemia/lymphoma (ATLL) is usually a highly

aggressive non-Hodgkin's lymphoma of the

patient's own T-cells with no characteristic

histologic appearance except for a diffuse pattern

and a mature T-cell phenotype. The frequent

isolation of HTLV-1 from patients with this disease

and the detection of HTLV-1 proviral genome in




ATLL leukemic cells suggest that HTLV-1 causes

ATLL.

Cytogenetics

A BUB1 missense mutation of G to A at codon 250

(GGT to GAT) has been reported (Ohshima et al.,

2000).

Pancreatic cancer

Disease

The term pancreatic cancer usually refers to

adenocarcinoma that arises within the exocrine

component of the pancreas. Pancreatic cancer is one

of the most aggressive diseases with most cancers

and often has a poor prognosis: for all stages

combined, the 1- and 5-year relative survival rates

are 25% and 6%, respectively; for local disease the

5-year survival is approximately 20% while the

median survival for locally advanced and for

metastatic disease, which collectively represent

over 80% of individuals, is about 10 and 6 months

respectively.

Cytogenetics

Two missense variants in the BUB1 gene have been

identified in the aneuploid pancreatic cell line

Hs766T (Hempen et al., 2003). These mutations are

found in the same allele, accompanied by a wild-

type BUB1 allele. Mutation of nucleotide 776 from

an adenine to a guanine results in an amino acid

change at codon 259 from tyrosine to cysteine

(Y259C). A second mutation at nucleotide 793

changed a cytosine to an adenine (C to A) thus

resulting in the mutant H265N (Hempen et al.,

2003).

Thyroid follicular adenoma

Disease

Almost all thyroid adenomas are follicular

adenomas. Follicular adenomas can be described as

"cold", "warm" or "hot" depending on their level of

function. Histopathologically, follicular adenomas

can be classified according to their cellular

architecture and relative amounts of cellularity and

colloid into the following types:

- fetal (microfollicular), which have the potential

for microinvasion,

- colloid (macrofollicular), which do not have any

potential for microinvasion,

- embryonal (atypical), which have the potential for

microinvasion.

Cytogenetics

A thyroid follicular carcinoma that has a 2-bp

somatic deletion (G2480/A2481) of BUB1 has been

reported by Ouyang and collaborators (2002).

Lymph node metastasis

Disease

Certain cancers spread in a predictable fashion from

where the cancer started. Because the flow of

lymph is directional, if the cancer spreads it will

spread first to lymph nodes close to the tumor

before it spreads to other parts of the body.

Cytogenetics

A BUB1 missense somatic mutation (nucleotide

437 GCT to TCT transition) that replaces Ala to Ser

at codon 130 has been identified in an ascending

colorectal carcinoma (Shichiri et al., 2002).

References Taylor SS, McKeon F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell. 1997 May 30;89(5):727-35

Bernard P, Hardwick K, Javerzat JP. Fission yeast bub1 is a mitotic centromere protein essential for the spindle checkpoint and the preservation of correct ploidy through mitosis. J Cell Biol. 1998 Dec 28;143(7):1775-87

Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998 Mar 19;392(6673):300-3

Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics. 1999 Jun 1;58(2):181-7

Imai Y, Shiratori Y, Kato N, Inoue T, Omata M. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn J Cancer Res. 1999 Aug;90(8):837-40

Ohshima K, Haraoka S, Yoshioka S, Hamasaki M, Fujiki T, Suzumiya J, Kawasaki C, Kanda M, Kikuchi M. Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer Lett. 2000 Oct 1;158(2):141-50

Sato M, Sekido Y, Horio Y, Takahashi M, Saito H, Minna JD, Shimokata K, Hasegawa Y. Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Jpn J Cancer Res. 2000 May;91(5):504-9

Ouyang B, Knauf JA, Ain K, Nacev B, Fagin JA. Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Clin Endocrinol (Oxf). 2002 Mar;56(3):341-50

Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S, Matsuzawa Y. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer. 2002 Apr 1;94(7):2047-54

Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res. 2002 Jan 1;62(1):13-7

Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG, Spencer FA. Distinct chromosome segregation roles for spindle checkpoint proteins. Mol Biol Cell. 2002 Sep;13(9):3029-41

Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE. A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum Mutat. 2003 Apr;21(4):445

Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89




Vanoosthuyse V, Valsdottir R, Javerzat JP, Hardwick KG. Kinetochore targeting of fission yeast Mad and Bub proteins is essential for spindle checkpoint function but not for all chromosome segregation roles of Bub1p. Mol Cell Biol. 2004 Nov;24(22):9786-801

Lampson MA, Kapoor TM. The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat Cell Biol. 2005 Jan;7(1):93-8

Vaur S, Cubizolles F, Plane G, Genier S, Rabitsch PK, Gregan J, Nasmyth K, Vanoosthuyse V, Hardwick KG, Javerzat JP. Control of Shugoshin function during fission-yeast meiosis. Curr Biol. 2005 Dec 20;15(24):2263-70

Wong OK, Fang G. Loading of the 3F3/2 antigen onto kinetochores is dependent on the ordered assembly of the spindle checkpoint proteins. Mol Biol Cell. 2006 Oct;17(10):4390-9

Boyarchuk Y, Salic A, Dasso M, Arnaoutov A. Bub1 is essential for assembly of the functional inner centromere. J Cell Biol. 2007 Mar 26;176(7):919-28

Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell. 2007 Nov;13(5):663-76

Wong OK, Fang G. Cdk1 phosphorylation of BubR1 controls spindle checkpoint arrest and Plk1-mediated

formation of the 3F3/2 epitope. J Cell Biol. 2007 Nov 19;179(4):611-7

Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, Tomchick DR, Machius M, Yu H. Structure and substrate recruitment of the human spindle checkpoint kinase Bub1. Mol Cell. 2008 Nov 7;32(3):394-405

Bolanos-Garcia VM, Kiyomitsu T, D'Arcy S, Chirgadze DY, Grossmann JG, Matak-Vinkovic D, Venkitaraman AR, Yanagida M, Robinson CV, Blundell TL. The crystal structure of the N-terminal region of BUB1 provides insight into the mechanism of BUB1 recruitment to kinetochores. Structure. 2009 Jan 14;17(1):105-16

McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabé AM, Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K. Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol. 2009 Mar 10;19(5):369-80

Bolanos-Garcia VM, Blundell TL. BUB1 and BUBR1: multifaceted kinases of the cell cycle. Trends Biochem Sci. 2011 Mar;36(3):141-50


Bolanos-Garcia VM, Blundell TL. BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):7-11.

Gene Section Review




FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Mark Pickard

Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, ST5

5BG, UK (MP)


Online updated version : http://AtlasGeneticsOncology.org/Genes/FAUID40538ch11q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI FAUID40538ch11q13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: FAU1, FLJ22986, Fub1, Fubi,

MNSFbeta, RPS30, asr1

HGNC (Hugo): FAU

Location: 11q13.1

Local order: FAU is flanked by SYVN1 and

ZNHIT2 on the negative strand.

Note

FAU was originally identified as the cellular

homologue of the fox gene of the retrovirus Finkel-

Biskis-Reilly murine sarcoma virus (FBR-MuSV);

fox is antisense to FAU, and has been shown to

increase the tumorigenicity of FBR-MuSV. FAU

encodes a ubiquitin-like protein fused to ribosomal

protein S30 as a carboxy-terminal extension; the

two products are thought to be cleaved post-

translationally. The S30 protein is a member of the

S30E family of ribosomal proteins and is a

constituent of the 40S subunit of the ribosome;

additionally it is secreted and has anti-microbial

activity ('ubiquicidin'). The function of the

ubiquitin-like protein, termed FUBI, is unclear; in

murine cells, it has been reported to covalently

modify inter alia a T-cell receptor alpha-like protein

and Bcl-G, suggestive of roles in

immunomodulation and apoptosis regulation,

respectively. In human cells, ectopic FAU

expression enhances basal apoptosis, whereas

siRNA-mediated silencing of FAU gene expression

induces resistance to apoptosis induction in

response to a range of stimuli. FAU gene

expression is down-regulated in a number of human

cancers, including breast, prostate and ovarian

cancers.

DNA/RNA

Description

Gene is located on the negative strand at -

64889908: -64887863 (2046 bases). The promoter

contains a number of regulatory elements, including

binding sites for transcription factors such as AP-1,

IRF-1, Max, c-Myc, glucocorticoid receptor

isoforms and ATF.

Transcription

Comprises 5 exons spanning -64888099: -

64889672. The mRNA product length is 579 bases.

Pseudogene

A retropseudogene, FAU1P, has been described in

the human genome and is located on chromosome

18. Retropseudogenes of FAU have also been

described in the mouse genome.

FAU comprises 5 exons - the coding sequence for FUBI is located within exons 2 and 3, whereas the coding sequence for S30 is

located within exons 4 and 5.

FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)

Pickard M


A. Protein products of FAU - FAU encodes a ubiquitin-like protein (FUBI) with ribosomal protein S30 as a C-terminal extension protein (CEP). These are cleaved post-translationally. B. FUBI has 37/57% sequence identity/similarity to ubiquitin (Ub; latter is fused to CEP80/S27a ribosomal protein). The C-terminal G-G dipeptide (shown in orange), which is required for cleavage from

the CEP and for isopeptide bond formation to lysine of targets, is conserved. Note however, that lysine residues (shown in green) which serve as sites for polyubiquitin chain formation are absent. Consequently, FUBI is unlikely to have an analogous role to

ubiquitin in protein degradation.

Protein

Description

The protein product comprises a ubiquitin-like

protein, FUBI, with ribosomal protein S30 as a

carboxy-terminal extension protein (CEP); other

ribosomal proteins are produced as CEPs fused to

ubiquitin. FUBI and S30 are thought to be cleaved

post-translationally, but the enzyme catalyzing this

step has not been identified. Whilst FUBI shows a

high degree of sequence similarity to ubiquitin,

notably retaining the C-terminal G-G dipeptide

motif that is required for isopeptide bond formation

between ubiquitin and lysines of target proteins, it

lacks internal lysine residues (especially lysine-48)

which serve as sites of polyubiquitin chain

formation and usually facilitate proteasomal

degradation of target molecules. Rather,

modification of proteins with monomers of

ubiquitin or ubiquitin-like proteins may influence

the activity, intracellular localisation or inter-

molecular interactions of target proteins. Little

information exists regarding target proteins for

FUBI in human cells. In mouse, four target proteins

have been identified. Covalent modification occurs

for: (i) a T-cell receptor alpha-like protein (resulting

in the production of murine monoclonal non-

specific suppressor factor, which exhibits

immunomodulatory activity); (ii) Bcl-G (a pro-

apoptotic member of the Bcl-2 family; and (iii)

endophilin II (regulates phagocytosis in mouse

macrophages). Non-covalent modification of

histone 2A has also been reported.

Expression

Steady state FAU mRNA levels are highly

abundant and largely invariant in normal tissues

indicative of a house-keeping gene role. However,

physiological variations occur in FAU expression,

notably in endometrium. FAU transcript levels have

been reported to be reduced in a number of human

cancers, including those affecting the breast, the

prostate and the ovary.

Localisation

Cytosolic, ribosomal and nuclear localisations have

been reported for FAU products. In addition,

secretion of FUBI (in association with a T-cell

receptor-alpha-like molecule) has been reported for

some immune system cell types.

Function

FAU regulates apoptosis in human epithelial and T-

cell lines. It also possesses immunomodulatory and

anti-microbial activities, and encodes a constituent

of the ribosome.

Regulation of apoptosis

Functional expression cloning in mouse leukemic

cell lines, with selection (dexamethasone and


Pickard M


gamma-irradiation) for suppression of cell death,

led to the isolation of a sequence which was

antisense to FAU (Mourtada-Maarabouni et al.,

2004). Subcloning experiments confirmed that this

antisense sequence produced resistance to apoptosis

induced by dexamethasone and, additionally, by

cisplatin and by ultraviolet-C irradiation. The

antisense sequence reduced endogenous FAU

expression. Conversely, overexpression of FAU

promoted cell death, and this effect could be

prevented by co-transfection with a plasmid

encoding Bcl-2 (an anti-apoptotic factor) or by

inhibition of caspases. Further work in human T-

cell lines and the epithelial cell line, 293T/17, has

confirmed that ectopic FAU expression increases

basal apoptosis, and that siRNA-mediated silencing

of FAU attenuates apoptosis in response to

ultraviolet-C irradiation (Pickard et al., 2011). FAU

also regulates apoptosis in other human epithelial

cell lines derived from breast (Pickard et al., 2009),

ovarian (Moss et al., 2010) and prostate (Pickard et

al., 2010) tumours (see 'Implicated in'). FUBI has

been shown to covalently modify Bcl-G (a pro-

apoptotic member of the Bcl-2 family) in mouse

cells (Nakamura and Tanigawa, 2003), and it is

feasible therefore, that FAU regulates apoptosis via

Bcl-G. Indeed, prior knockdown of Bcl-G ablated

the stimulation of basal apoptosis by FAU in human

cells (Pickard et al., 2011). This pro-apoptotic

activity may underlie the putative tumour

suppressor role of FAU, since failure of apoptosis is

known to play a central role in the development of

many cancers.

Immunomodulation

Monoclonal non-specific suppressor factor (MNSF)

was first isolated from mouse cells in 1986

(Nakamura et al., 1988) and subsequently, from

ascites fluid of a patient with systemic lupus

erythematosus (Xavier et al., 1994); most studies of

MNSF to-date have focussed on murine cells. This

lymphokine-like molecule, which comprises alpha-

and beta-chains, is secreted by CD8+ T-cells

(Xavier et al., 1995). cDNA encoding MNSF-beta

was first isolated from the mouse in 1995, and it

was shown to be identical to FAU (Nakamura et al.,

1995). MNSF inhibits, inter alia, proliferation of

mitogen-stimulated T- and B-cells,

immunoglobulin secretion by B-cells in an isotype-

specific manner (IgE and IgG3 are especially

affected), TNFalpha production by activated

macrophages and interleukin-4 secretion by bone

marrow-derived mast cells and by a type-2 helper

T-cell clone (Nakamura et al., 1988; Nakamura et

al., 1994; Xavier et al., 1994; Nakamura et al.,

1995; Xavier et al., 1995; Nakamura et al., 1996;

Suzuki et al., 1996). Inhibitory effects on T- and B-

cell proliferation are subject to negative regulation

by interleukin-2 (Nakamura et al., 1988). Many of

these immunosuppresive effects of MNSF can be

ascribed to the MNSFbeta subunit, and specifically

to FUBI (aka Ubi-L) (Nakamura et al., 1996). Cell

surface receptors for MNSF have been described in

target cells (Nakamura et al., 1992), and these

exhibit similarities to cytokine receptors (Nakamura

and Tanigawa, 1999), with tyrosine

phosphorylation being implicated in transmembrane

signalling (Nakamura and Tanigawa, 2000;

Nakamura et al., 2002). Both the expression of cell

surface receptors on target cells and the secretion of

MNSFbeta/FUBI by splenocytes are stimulated by

interferon-gamma (Nakamura et al., 1992;

Nakamura et al., 1996). In splenocytes, FUBI

conjugates to a range of intracellular proteins,

including a T-cell receptor-alpha-like molecule; the

resulting complex, which comprises intact MNSF,

is secreted by cells (Nakamura et al., 1998;

Nakamura et al., 2002). FUBI also covalently

modifies Bcl-G in spleen but not in testis, despite

high levels of Bcl-G expression in the latter tissue

(Nakamura and Tanigawa, 2003). In macrophages,

the FUBI/Bcl-G adduct binds to ERKs and inhibits

ERK activation by MEK1 (Nakamura and

Yamaguchi, 2006). In liver and macrophages, FUBI

also forms an adduct with endophilin II and inhibits

phagocytosis by macrophages (Nakamura and

Shimosaki, 2009; Nakamura and Watanabe, 2010).

Host defence

An anti-microbial protein, termed ubiquicidin, has

been isolated from the cytosol of a mouse

macrophage cell line treated with interferon-

gamma; the protein is active against Listeria

monocytogenes, Salmonella typhimurium,

Escherichia coli, Staphylococcus aureus and

Yersinia enterocolitica (Hiemstra et al., 1999).

Ubiquicidin is identical to FAU-encoded ribosomal

protein S30 (Hiemstra et al., 1999). Ubiquicidin is

also produced by human colonic mucosa (Tollin et

al., 2003) and rainbow trout skin (Fernandes and

Smith, 2002). It is also active against methicillin-

resistant Staphylococcus aureus and accumulates at

sites of infection in mice (Brouwer et al., 2006).

Radiolabelled ubiquicidin has applications in

clinical imaging for microbial infections (Brouwer

et al., 2008).

Homology

At the amino acid level, FUBI has 37/57%

sequence identity/similarity to ubiquitin.

Implicated in

Various cancers

Note

Tumor suppression: The retrovirus, FBR-MuSV,

which contains the transduced genes v-fos and fox,

can induce osteosarcomas in mice. In vitro

experiments have shown that fox increases the

transforming capacity of FBR-MuSV

approximately two-fold (Michiels et al., 1993). Fox

is an antisense sequence to the cellular gene FAU,


Pickard M


indicative of a tumour suppressor role for FAU.

Retropseudogenes of FAU have been identified in

human (Kas et al., 1995) and mouse (Casteels et al.,

1995) genomes, suggesting a possible source for the

viral fox gene (which is antisense to FAU). Further

evidence for a tumour suppressor role for FAU has

come from studies of the human carcinogen

arsenite. Thus, functional cloning approaches in

Chinese hamster V79 cells with selection for

arsenite resistance, resulted in the isolation of the

asr1 gene, which is homologous to FAU (Rossman

and Wang, 1999). Subsequent work by this group

using human osteogenic sarcoma cells, indicated

that the ability to confer arsenite resistance resided

in the S30 domain of FAU (Rossman et al., 2003).

Oncogenesis

Expression of the FUBI domain of FAU has been

shown to transform human osteogenic sarcoma

cells to anchorage-independent growth (Rossman et

al., 2003).

Breast cancer

Note

Serial analysis of gene expression (SAGE)

identified FAU as an underexpressed gene in ductal

carcinoma in situ when compared with normal

breast epithelium (Abba et al., 2004). This was

subsequently confirmed using quantitative RT-PCR

analysis of matched (same patient) samples of

breast cancer tissue and adjacent breast epithelial

tissue (Pickard et al., 2009). Furthermore, in a

separate group of breast cancer patients, expression

levels of FAU (determined by cDNA microarray

analysis) were shown to be related to patient

survival in Kaplan-Meier analyses (Pickard et al.,

2009). This analysis indicated that higher

expression of Fau has a protective effect, consistent

with its candidate tumour suppressor role. Whilst

Bcl-G expression was also shown to be down-

regulated in breast cancer, Bcl-G expression was

not related to patient survival (Pickard et al., 2009),

suggesting that the regulation of Bcl-G activity by

post-translational modification is more important

than Bcl-G expression per se in determining breast

cancer patient survival. Functional studies in the T-

47D breast cancer cell line demonstrated that down-

regulation of either FAU or Bcl-G expression by

siRNA-mediated silencing attenuated apoptosis

induction by ultraviolet-C irradiation (Pickard et al.,

2009). Notably, no additional effect was observed

when the two genes were simultaneously silenced,

consistent with a role for Bcl-G in mediating the

pro-apoptotic activity of FAU.

Ovarian cancer

Note

A reduction in FAU gene expression has been

reported for malignant versus normal ovarian

tissue, and for Type I ovarian tumours (typically

include mucinous, endometrioid, clear cell, and

low-grade serous cancers), in particular (Moss et

al., 2010). Over-expression of FAU in a cisplatin-

resistant ovarian cancer cell sub-line, A2780cis,

resulted in increased sensitivity to carboplatin-

induced apoptosis (Moss et al., 2010). Conversely,

down-regulation of FAU in the A2780 parental cell

line resulted in increased resistance to carboplatin-

induced apoptosis (Moss et al., 2010). These in

vitro findings suggest a role for FAU in the

regulation of platinum-based drug resistance in

ovarian cancer.

Prostate cancer

Note

Steady state FAU mRNA levels are down-regulated

in prostate cancer when compared with normal

tissue and tissue from patients with benign prostate

hyperplasia; a similar trend was found for Bcl-G

(Pickard et al., 2010). siRNA-mediated silencing of

FAU or Bcl-G expression in the prostate cell line,

22Rv1, attenuated apoptosis induction consequent

upon ultraviolet-C irradiation. A similar degree of

apoptosis resistance was observed when the two

genes were simultaneously down-regulated,

consistent with FAU and Bcl-G acting in the same

pathway.

Reproduction (implantation)

Note

FAU is expressed in endometrial stromal cells in

non-pregnant mouse uterus (Salamonsen et al.,

2002) and it is also expressed in human

endometrium (Nie et al., 2005). In the mouse

uterus, differential expression of FAU occurs

during blastocyst implantation, with low expression

levels noted in implantation versus

interimplantation sites (Nie et al., 2000).

Expression levels remain low as implantation

advances (Nie et al., 2000). Administration of

antisera to FAU into the mouse uterine lumen

inhibits implantation in a dose-dependent manner

(Wang et al., 2007), suggesting an essential role for

secreted products in implantation. Trophoblast-

derived interferons have been shown to induce

endometrial FAU expression in pigs (Chwetzoff

and d'Andrea, 1997), also supporting an important

role for FAU in early pregnancy.

Breakpoints

Note

A t(11;14)(q13;q21)-positive B-cell non-Hodgkin's

lymphoma patient has been described with an

additional translocation of t(11;17)(q13;q21). The

chromosome 11 breakpoint in the latter

translocation was reported as a 40 kbp region

around FAU.

References Nakamura M, Ogawa H, Tsunematsu T. Isolation and characterization of a monoclonal nonspecific suppressor


Pickard M


factor (MNSF) produced by a T cell hybridoma. J Immunol. 1986 Apr 15;136(8):2904-9

Nakamura M, Ogawa H, Tsunematsu T. Mode of action of monoclonal-nonspecific suppressor factor (MNSF) produced by murine hybridoma. Cell Immunol. 1988 Oct 1;116(1):230-9

Nakamura M, Ogawa H, Tsunematsu T. Characterization of cell-surface receptors for monoclonal-nonspecific suppressor factor (MNSF). Cell Immunol. 1990 Oct 15;130(2):281-90

Kas K, Michiels L, Merregaert J. Genomic structure and expression of the human fau gene: encoding the ribosomal protein S30 fused to a ubiquitin-like protein. Biochem Biophys Res Commun. 1992 Sep 16;187(2):927-33

Nakamura M, Ogawa H, Tsunematsu T. IFN-gamma enhances the expression of cell surface receptors for monoclonal nonspecific suppressor factor. Cell Immunol. 1992 Jan;139(1):131-8

Kas K, Schoenmakers E, van de Ven W, Weber G, Nordenskjöld M, Michiels L, Merregaert J, Larsson C. Assignment of the human FAU gene to a subregion of chromosome 11q13. Genomics. 1993 Aug;17(2):387-92

Michiels L, Van der Rauwelaert E, Van Hasselt F, Kas K, Merregaert J. fau cDNA encodes a ubiquitin-like-S30 fusion protein and is expressed as an antisense sequence in the Finkel-Biskis-Reilly murine sarcoma virus. Oncogene. 1993 Sep;8(9):2537-46

Olvera J, Wool IG. The carboxyl extension of a ubiquitin-like protein is rat ribosomal protein S30. J Biol Chem. 1993 Aug 25;268(24):17967-74

Wlodarska I, Schoenmakers E, Kas K, Merregaert J, Lemahieu V, Weier U, Van den Berghe H, Van de Ven WJ. Molecular mapping of the chromosome 11 breakpoint of t(11;17)(q13;q21) in a t(11;14)(q13;q32)-positive B non-Hodgkin's lymphoma. Genes Chromosomes Cancer. 1993 Dec;8(4):224-9

Nakamura M, Xavier RM, Tanigawa Y. Monoclonal non-specific suppressor factor (MNSF) inhibits the IL4 secretion by bone marrow-derived mast cell (BMMC). FEBS Lett. 1994 Feb 21;339(3):239-42

Xavier RM, Nakamura M, Tsunematsu T. Isolation and characterization of a human nonspecific suppressor factor from ascitic fluid of systemic lupus erythematosus. Evidence for a human counterpart of the monoclonal nonspecific suppressor factor and relationship to the T cell receptor alpha-chain. J Immunol. 1994 Mar 1;152(5):2624-32

Casteels D, Poirier C, Guénet JL, Merregaert J. The mouse Fau gene: genomic structure, chromosomal localization, and characterization of two retropseudogenes. Genomics. 1995 Jan 1;25(1):291-4

Kas K, Stickens D, Merregaert J. Characterization of a processed pseudogene of human FAU1 on chromosome 18. Gene. 1995 Jul 28;160(2):273-6

Nakamura M, Xavier RM, Tanigawa Y. Monoclonal nonspecific suppressor factor beta inhibits interleukin-4 secretion by a type-2 helper T cell clone. Eur J Immunol. 1995 Aug;25(8):2417-9

Nakamura M, Xavier RM, Tsunematsu T, Tanigawa Y. Molecular cloning and characterization of a cDNA encoding monoclonal nonspecific suppressor factor. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3463-7

Xavier R, Nakamura M, Kobayashi S, Ishikura H, Tanigawa Y. Human nonspecific suppressor factor (hNSF): cell source and effects on T and B lymphocytes. Immunobiology. 1995 Feb;192(3-4):262-71

Nakamura M, Nagata T, Xavier M, Tanigawa Y. Ubiquitin-like polypeptide inhibits the IgE response of lipopolysaccharide-activated B cells. Int Immunol. 1996 Nov;8(11):1659-65

Nakamura M, Xavier RM, Tanigawa Y. Ubiquitin-like moiety of the monoclonal nonspecific suppressor factor beta is responsible for its activity. J Immunol. 1996 Jan 15;156(2):532-8

Suzuki K, Nakamura M, Nariai Y, Dekio S, Tanigawa Y. Monoclonal nonspecific suppressor factor beta (MNSF beta) inhibits the production of TNF-alpha by lipopolysaccharide-activated macrophages. Immunobiology. 1996 Jul;195(2):187-98

Chwetzoff S, d'Andrea S. Ubiquitin is physiologically induced by interferons in luminal epithelium of porcine uterine endometrium in early pregnancy: global RT-PCR cDNA in place of RNA for differential display screening. FEBS Lett. 1997 Mar 24;405(2):148-52

Nagata T, Nakamura M, Kawauchi H, Tanigawa Y. Conjugation of ubiquitin-like polypeptide to intracellular acceptor proteins. Biochim Biophys Acta. 1998 Mar 5;1401(3):319-28

Nakamura M, Tanigawa Y. Ubiquitin-like polypeptide conjugates to acceptor proteins in concanavalin A- and interferon gamma-stimulated T-cells. Biochem J. 1998 Mar 1;330 ( Pt 2):683-8

Nakamura M, Tsunematsu T, Tanigawa Y. TCR-alpha chain-like molecule is involved in the mechanism of antigen-non-specific suppression of a ubiquitin-like protein. Immunology. 1998 Jun;94(2):142-8

Hiemstra PS, van den Barselaar MT, Roest M, Nibbering PH, van Furth R. Ubiquicidin, a novel murine microbicidal protein present in the cytosolic fraction of macrophages. J Leukoc Biol. 1999 Sep;66(3):423-8

Kondoh T, Nakamura M, Nabika T, Yoshimura Y, Tanigawa Y. Ubiquitin-like polypeptide inhibits the proliferative response of T cells in vivo. Immunobiology. 1999 Feb;200(1):140-9

Nakamura M, Tanigawa Y. Biochemical analysis of the receptor for ubiquitin-like polypeptide. J Biol Chem. 1999 Jun 18;274(25):18026-32

Rossman TG, Wang Z. Expression cloning for arsenite-resistance resulted in isolation of tumor-suppressor fau cDNA: possible involvement of the ubiquitin system in arsenic carcinogenesis. Carcinogenesis. 1999 Feb;20(2):311-6

Nakamura M, Tanigawa Y. Protein tyrosine phosphorylation induced by ubiquitin-like polypeptide in murine T helper clone type 2. Biochem Biophys Res Commun. 2000 Aug 2;274(2):565-70

Nie GY, Li Y, Hampton AL, Salamonsen LA, Clements JA, Findlay JK. Identification of monoclonal nonspecific suppressor factor beta (mNSFbeta) as one of the genes differentially expressed at implantation sites compared to interimplantation sites in the mouse uterus. Mol Reprod Dev. 2000 Apr;55(4):351-63

Fernandes JM, Smith VJ. A novel antimicrobial function for a ribosomal peptide from rainbow trout skin. Biochem Biophys Res Commun. 2002 Aug 9;296(1):167-71

Nakamura M, Tsunematsu T, Tanigawa Y. Biochemical analysis of a T cell receptor alpha-like molecule involved in antigen-nonspecific suppression. Biochim Biophys Acta. 2002 Apr 3;1589(2):196-202

Salamonsen LA, Nie G, Findlay JK. Newly identified endometrial genes of importance for implantation. J Reprod Immunol. 2002 Jan;53(1-2):215-25


Pickard M


Nakamura M, Tanigawa Y. Characterization of ubiquitin-like polypeptide acceptor protein, a novel pro-apoptotic member of the Bcl2 family. Eur J Biochem. 2003 Oct;270(20):4052-8

Rossman TG, Visalli MA, Komissarova EV. fau and its ubiquitin-like domain (FUBI) transforms human osteogenic sarcoma (HOS) cells to anchorage-independence. Oncogene. 2003 Mar 27;22(12):1817-21

Salamonsen LA, Dimitriadis E, Jones RL, Nie G. Complex regulation of decidualization: a role for cytokines and proteases--a review. Placenta. 2003 Apr;24 Suppl A:S76-85

Tollin M, Bergman P, Svenberg T, Jörnvall H, Gudmundsson GH, Agerberth B. Antimicrobial peptides in the first line defence of human colon mucosa. Peptides. 2003 Apr;24(4):523-30

Abba MC, Drake JA, Hawkins KA, Hu Y, Sun H, Notcovich C, Gaddis S, Sahin A, Baggerly K, Aldaz CM. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression. Breast Cancer Res. 2004;6(5):R499-513

Mourtada-Maarabouni M, Kirkham L, Farzaneh F, Williams GT. Regulation of apoptosis by fau revealed by functional expression cloning and antisense expression. Oncogene. 2004 Dec 16;23(58):9419-26

Nakamura M, Tanigawa Y. Ubiquitin-like polypeptide inhibits cAMP-induced p38 MAPK activation in Th2 cells. Immunobiology. 2004;208(5):439-44

Nakamura M, Tanigawa Y. Noncovalent interaction of MNSFbeta, a ubiquitin-like protein, with histone 2A. Comp Biochem Physiol B Biochem Mol Biol. 2005 Feb;140(2):207-10

Nie G, Findlay JK, Salamonsen LA. Identification of novel endometrial targets for contraception. Contraception. 2005 Apr;71(4):272-81

Brouwer CP, Bogaards SJ, Wulferink M, Velders MP, Welling MM. Synthetic peptides derived from human antimicrobial peptide ubiquicidin accumulate at sites of infections and eradicate (multi-drug resistant) Staphylococcus aureus in mice. Peptides. 2006 Nov;27(11):2585-91

Nakamura M, Yamaguchi S. The ubiquitin-like protein MNSFbeta regulates ERK-MAPK cascade. J Biol Chem. 2006 Jun 23;281(25):16861-9

Wang J, Huang ZP, Nie GY, Salamonsen LA, Shen QX. Immunoneutralization of endometrial monoclonal nonspecific suppressor factor beta (MNSFbeta) inhibits mouse embryo implantation in vivo. Mol Reprod Dev. 2007 Nov;74(11):1419-27

Brouwer CP, Wulferink M, Welling MM. The pharmacology of radiolabeled cationic antimicrobial peptides. J Pharm Sci. 2008 May;97(5):1633-51

Nakamura M, Omura S. Quercetin regulates the inhibitory effect of monoclonal non-specific suppressor factor beta on tumor necrosis factor-alpha production in LPS-stimulated macrophages. Biosci Biotechnol Biochem. 2008 Jul;72(7):1915-20

Nakamura M, Shimosaki S. The ubiquitin-like protein monoclonal nonspecific suppressor factor beta conjugates to endophilin II and regulates phagocytosis. FEBS J. 2009 Nov;276(21):6355-63

Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mourtada-Maarabouni M, Williams GT. Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res. 2009;11(4):R60

Moss EL, Mourtada-Maarabouni M, Pickard MR, Redman CW, Williams GT. FAU regulates carboplatin resistance in ovarian cancer. Genes Chromosomes Cancer. 2010 Jan;49(1):70-7

Nakamura M, Watanabe N. Ubiquitin-like protein MNSFβ/endophilin II complex regulates Dectin-1-mediated phagocytosis and inflammatory responses in macrophages. Biochem Biophys Res Commun. 2010 Oct 15;401(2):257-61

Pickard MR, Edwards SE, Cooper CS, Williams GT. Apoptosis regulators Fau and Bcl-G are down-regulated in prostate cancer. Prostate. 2010 Oct 1;70(14):1513-23

Pickard MR, Mourtada-Maarabouni M, Williams GT. Candidate tumour suppressor Fau regulates apoptosis in human cells: an essential role for Bcl-G. Biochim Biophys Acta. 2011 Sep;1812(9):1146-53


Pickard M. FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):12-17.

Gene Section Short Communication




GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Stephanie Schulz, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University,

Philadelphia, PA, USA (SS, SAW)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GUCY2CID43303ch12p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI GUCY2CID43303ch12p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: GUC2C, STAR

HGNC (Hugo): GUCY2C

Location: 12p13.1

Local order: ATF7IP - PLBD1 - GUCY2C -

H2AFJ - HIST4H4.

DNA/RNA

Description

The GUCY2C gene is approximately 84 kb in

length and has 27 exons.

Transcription

An approximately 3.8 mRNA is transcribed from

the gene.

Pseudogene

None known.

Protein

Note

GUCY2C encodes a guanylyl cyclase.

Description

1073 amino acid protein with guanylyl cyclase

catalytic activity (4.6.1.2).

Expression

Primarily intestinal epithelial cells.

Localisation

Apical membrane.

Function

In response to binding endogenous hormones

guanylin and uroguanylin, or the exogenous ligand

E. coli heat-stable enterotoxin, GUCY2C

synthesizes cyclic GMP. Cyclic GMP activates

downstream signaling pathways via cGMP-

dependent protein kinases, phosphodiesterases and

cGMP-gated ion channels.

Homology

Adenylyl cyclase.

Image from NCBI.

Image from Ensembl.

http://www.ncbi.nlm.nih.gov/gene/2984#chromosome:%2012;%C2%A0Location:%2012p12%20S

GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))

Schulz S, Waldman SA


SP: signal peptide; ECD: extracellular ligand binding domain; TM: transmembrane domain; KHD: regulatory kinase-homology

domain; CAT: guanylyl cyclase catalytic domain; TAIL: C-terminal tail, interacts with scaffolding proteins.

Implicated in

Colorectal cancer

Note

The endogenous GUCY2C ligands, guanylin and

uroguanylin, are lost early in the neoplastic process.

Targeted deletion of Gucy2c in mice results in a

phenotype of intestinal cancer susceptibility in the

context of predisposing genetic mutations (apcmin

)

or exposure to carcinogen (azoxymethane).

References Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts

the proliferating compartment in intestine. Am J Pathol. 2007 Dec;171(6):1847-58

Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007 Aug;133(2):599-607

Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology. 2010 Jan;138(1):241-54


Schulz S, Waldman SA. GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):18-19.

Gene Section Mini Review




LIN28B (lin-28 homolog B (C. elegans)) Yung-Ming Jeng

Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan

University, Taipei, Taiwan (YMJ)


Online updated version : http://AtlasGeneticsOncology.org/Genes/LIN28BID45723ch6q16.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI LIN28BID45723ch6q16.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: CSDD2, FLJ16517, Lin28.2

HGNC (Hugo): LIN28B

Location: 6q16.3

Note

Size: 146,72 kb. Orientation: plus strand.

DNA/RNA

Description

The gene spans over 125 kb on plus strand; 4

exons.

Transcription

The gene is mainly expressed in fetal tissues and

not expressed in adult tissue and reexpressed in

cancer tissue.

Protein

Description

Lin28B is an oncofetal RNA-binding protein. Lin-

28B protein consists of two domains that contain

RNA-binding motif: the N-terminal cold shock

domain and a pair of retroviral-type CCHC zinc

fingers. It inhibits biosynthesis of let-7 microRNA

through binding to the 5'-GGAG-3' motif in the

terminal loop of pre-let-7 and promoting terminal

uridylation of let-7 precusor by TUTase4.

Uridylated pre-let-7 miRNAs fail to be processed

by Dicer and undergo degradation.

Expression

Cytoplasm.

Function

It inhibits biosynthesis of let-7 microRNA through

promoting terminal uridylation of let-7 precusor by

TUTase4.

Homology

Lin28

Mutations

Note

No somatic mutation of Lin28B was identified in

cancer.

Implicated in

Hepatocellular carcinoma

Note

Lin28B expression is more frequently noted in

high-grade hepatocellular carcinoma with high

alpha-fetoprotein levels. Knockdown of Lin28B by

RNA interference in the HCC cell line suppressed

proliferation in vitro and reduced in vivo tumor

growth in NOD/SCID mice. In contrast,

overexpression of Lin28B in the HCC cell line

enhanced tumorigenicity. Overexpression of

Lin28B also induced epithelial-mesenchymal

transition in HA22T cells and hence, invasion

capacity.

Colorectal cancer

Note

Lin28B is overexpressed in colorectal cancer. It

promotes cell migration, invasion and transforms

immortalized colonic epithelial cells. In addition,

constitutive LIN28B expression increases

LIN28B (lin-28 homolog B (C. elegans)) Jeng YM


expression of intestinal stem cell markers LGR5

and PROM1 in the presence of let-7 restoration.

Ovarian cancer

Note

Lin28B is overexpressed in high grade serous

ovarian cancer. Pleomorphism in Lin28B promoter

region is associated with susceptibility to

epithelium ovarian cancer. Patients with high

Lin28B ovarian cancer had shorter progression-free

and overall survival than those with low Lin28B

ovarian cancer.

Age at menarche

Note

A sequence variation in Lin28B is identified as the

SNP most significant associated with age at

menarche in one genome wide study. Besides, a

meta-analysis of 32 genome-wide association

studies in 87802 women found polymorphism of

Lin28B is strongly associated with age at menarche.

Knockout mice of Lin28B also show delay in

puberty onset.

Body height

Note

A LIN28B SNP, rs314277, is associated with final

body height.

References Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008 Oct 24;32(2):276-84

Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008 Apr 4;320(5872):97-100

He C, Kraft P, Chen C, Buring JE, Paré G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ, Chasman DI. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet. 2009 Jun;41(6):724-8

Lu L, Katsaros D, Shaverdashvili K, Qian B, Wu Y, de la Longrais IA, Preti M, Menato G, Yu H. Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II. Eur J Cancer. 2009 Aug;45(12):2212-8

Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan CG, Golub TR, Sorensen PH, Daley GQ. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009 Jul;41(7):843-8

Helland Å, Anglesio MS, George J, Cowin PA, Johnstone CN, House CM, Sheppard KE, Etemadmoghadam D, Melnyk N, Rustgi AK, Phillips WA, Johnsen H, Holm R, Kristensen GB, Birrer MJ, Pearson RB, Børresen-Dale AL, Huntsman DG, deFazio A, Creighton CJ, Smyth GK, Bowtell DD. Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One. 2011 Apr 13;6(4):e18064

King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. LIN28B promotes colon cancer progression and metastasis. Cancer Res. 2011 Jun 15;71(12):4260-8

King CE, Wang L, Winograd R, Madison BB, Mongroo PS, Johnstone CN, Rustgi AK. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene. 2011 Oct 6;30(40):4185-93


Jeng YM. LIN28B (lin-28 homolog B (C. elegans)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):20-21.





PKD1 (polycystic kidney disease 1 (autosomal dominant)) Ying-Cai Tan, Hanna Rennert

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College 1300 York Street,

F701 New York, NY 10065, USA (YCT, HR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PKD1ID41725ch16p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PKD1ID41725ch16p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: PBP, Pc-1, polycystin-1, TRPP1

HGNC (Hugo): PKD1

Location: 16p13.3

DNA/RNA

Description

This gene has 46 exons that span ~52 kb of

genomic sequence. Exons 1-33 are located in a

genomic region which is duplicated six times on the

same chromosome (~13-16 Mb proximal to PKD1

on the short arm of chromosome 16), resulting in

six pseudogenes. A Mirtron family microRNA

gene, miR-1225, is lying within intron 45 of PKD1,

the function of this microRNA is currently

unknown.

Transcription

The 14,5 kb transcript has two different isoforms as

a result of alternative splicing. The longer variant,

isoform I (NM_001009944), has a 12909 bp open

reading frame. The short variant, isoform II

(NM_000293), uses an alternate acceptor splice

site, 3 nt downstream of that used by isoform I, at

the junction of intron 31 and exon 32. This results

in an isoform (variant II) that is one amino acid

shorter than isoform I.

Pseudogene

The six pseudogenes that result from duplication of

PKD1 exon 1 through 33 are located on

chromosome 16p13.1 and have 97-99% identity to

PKD1. Those pseudogenes are transcripted into

mRNA species with suboptimal start codons, thus

they are not translated.

Ideogram of human chromosome 16, the location of PKD1 gene is indicated by the red vertical line. This graph was generated by

using UCSC genome browser.

Gene structure of PKD1, showing the intron/exon structure. Exons are shown with solid box; introns are shown with thin line arrow heads; 3' and 5' UTR regions are indicated by open boxes. Some exons numbers are labelled above. This graph was

generated by using UCSC genome browser.

http://genome.ucsc.edu/cgi-bin/hgGateway

PKD1 (polycystic kidney disease 1 (autosomal dominant)) Tan YC, Rennert H


Protein structure of polycystin-1 (PC1). The details of the protein domain structures are shown. Abreviation: GPS, GPCR

Proteolystic Site; WSC, cell Wall integrity and Stress response Component; PLAT, (Polycystin-1, Lipoxygenase, Alpha-Toxin); REJ, Receptor for Egg Jelly. This graph was generated by using ExPASY Proteomics Server PROSITE module with some

modifications.

Protein

Description

The longer form of polycystin-1, isoform I, has

4303 aa. It is a 460 kDa membrane protein which

has the structure of a receptor or adhesion molecule.

The large extracellular N-terminal region consisting

of a variety of domains, including 12 PKD domains

(an immunoglobin-like fold), two leucine-rich

repeats, C-type lectin domain, WSC domain, GPS

domain and REJ domain. The short intracellular C-

terminal region has 197 aa, containing a coiled-coil

domain that interact with polycystin-2 and a G-

protein binding domain. Between the N and C-

terminal is a large transmembrane region (1032 aa)

that has 11 transmembrane domains. Polycystin-1 is

cleaved at the G protein-coupled receptor

proteolytic site (GPS) domain, resulting in a 150

kDa C-terminal fragment and a 400 kDa N-terminal

fragment that tether to the membrane. This cleavage

is suggested to be important for protein activation.

Expression

Polycystin-1 is widely expressed in adult tissue,

with high levels in brain and moderate expression

in kidney. In fetal and adult kidney, the expression

was restricted to the epithelial cells with highest

expression in the embryo and downregulation in

adult. In smooth, skeletal and cardiac muscles,

expression is also found.

Localisation

Polycystin-1 is located in the primary cilium, a

single hair-like organelle projecting from the

surface of most mammalian cells. It is also found in

the plasma membrane at focal adhesions,

desmosomes, and adherens junctions. The C-

terminal tail of PC1 has been reported to be cleaved

and migrate to the nucleus, regulating gene

expression.

Function

In the kidney tubule, polycystin-1 was shown to

serve as a mechanoreceptor that senses fluid flow in

the tubular lumen, triggering Ca2+

influx through

polycystin-2, a Ca2+

channel that interact with PC1

in the C-terminal tail, consequently affecting the

intracellular calcium and cyclic AMP (cAMP)

levels. It is also involved in cell-to-cell or cell-to-

matrix interactions.

Homology

The characterized domains of polycystin-1 are

regions highly conserved among species (from

human to fish). A homology and also an interaction

partner in the same signaling passway, polycystin-

2, is located on 4q21.

Mutations

Germinal

Autosomal dominant polycystic kidney disease

(ADPKD) is the most common inherited kidney

disease. Up to 85% of ADPKD cases are caused by

mutations in PKD1 gene. With the current mutation

detection methods, definite pathogenic mutations

(nonsense, truncation and canonical splice defects)

are identified in approximately 60% of the cases.

Large deletions/insertions can be found in ~4% of

cases. Comprehensive analyses, using

bioinformatics analysis tools can identify missense

mutations that may account for the disease in an

additional 22% to 37% of the ADPKD patients.

There are no mutation hot spots for PKD1, which

means mutations are usually private, with 70% of

the mutations unique to a single family, and spread

throughout the entire gene. Mutations on 5' of the

gene are associated with a more sever disease

compared to those occurring in 3' region. The

ADPKD Mutation Database at Mayo Clinic

http://expasy.org/cgi-bin/prosite/PSView.cgi?spac=P98161

PKD1 (polycystic kidney disease 1 (autosomal dominant)) Tan YC, Rennert H


(http://pkdb.mayo.edu/), the most complete one for

ADPKD, documents 416 pathogenic mutations for

PKD1 in a total of 616 families.

Somatic

The pathogenesis of ADPKD has been attributed to

a two-hit mechanism, with somatic and germline

mutations combining to inactivate one of the PKD

genes, leading to loss of function, thus initiating the

disease process. There are significantly less somatic

PKD mutations listed in the ADPKD Mutation

Database, only 9 for PKD1 (http://pkdb.mayo.edu/).

Due to the limited availability of kidney cyst DNA

and the complications associated with PKD1

genotyping, analyzing somatic mutations in

ADPKD was proven to be difficult.

Implicated in

Autosomal dominant polycystic kidney disease (ADPKD)

Disease

ADPKD is a monogenic multi-systemic disorder

characterized by age-dependent development and

progressive enlargement of bilateral, multiple renal

cysts, resulting in chronic renal failure typically in

mid to late adulthood. The cysts are caused by

abnormal proliferation of renal tubule epithelial

cells as a result of inactivation of the PKD genes by

mutations. Mutations in PKD1 gene account for

85% of the ADPKD cases and for the early-onset,

more sever form. Those cysts will increase

gradually in both size and number, leading to

massive kidney enlargement and progressive

decline in renal function. ADPKD has a prevalence

of approximately 1 in 400 to 1 in 1000 live births in

all races, affecting approximately 12,5 million

individuals worldwide. Although ADPKD accounts

for 4,4% of all patients requiring renal replacement

therapy, it is characterized by very large phenotypic

variability, ranging from presentation in-utero with

enlarged, cystic kidneys to incidental diagnosis in

the elderly with adequate renal function. Extra-renal

manifestations include cysts in the liver, pancreas,

seminal vesicles and arachnoid membranes.

Intracranial aneurysm is about five times more

common than in the general population and is

associated with significant morbidity and mortality.

Prognosis

About 50% of patients with ADPKD will progress

to end stage renal disease (ESRD) by the age of 60

years, with hemodialysis or kidney transplant being

the only currently available treatment, though

several potential drugs have been entered into

clinical trials. Hypertension is present in about 50%

of ADPKD patients age 20-30 years with clinically

normal renal function; this is approximately one

decade earlier than the onset of primary

hypertension in the general population.

References Wilson PD. Polycystic kidney disease. N Engl J Med. 2004 Jan 8;350(2):151-64

Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007 Apr 14;369(9569):1287-301

Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R, Balina M, Parker T, Levine D, Leonard DG, Rennert H. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat. 2009 Feb;30(2):264-73

Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009 Jul;76(2):149-68

Harris PC, Rossetti S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2010 Apr;6(4):197-206


Tan YC, Rennert H. PKD1 (polycystic kidney disease 1 (autosomal dominant)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):22-24.

Gene Section Review




AMFR (autocrine motility factor receptor) Yalcin Erzurumlu, Petek Ballar

Ege University, Faculty of Pharmacy, Biochemistry Department, Bornova, 35100, Izmir, Turkey (YE,

PB)

Published in Atlas Database: August 2011

Online updated version : http://AtlasGeneticsOncology.org/Genes/AMFRID627ch16q12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI AMFRID627ch16q12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: GP78, RNF45

HGNC (Hugo): AMFR

Location: 16q12.2

DNA/RNA

Description

The AMFR gene spans 64081 bases on minus

strand. The DNA of AMFR consists of 14 exons

and the coding sequence starts in the first exon.

Transcription

The AMFR gene has two transcripts. One of these

transcripts is 2249 bp long and is a processed

transcript with no protein product. 3598 bp long

second AMFR transcript is a protein coding

transcript (accession number: NM_001144). The

DNA has been cloned in 1999 (Shimizu et al.,

1999).

AMFR gene genomic location at chromosome 16q12.2 (minus strand).

A. The alignment of AMFR mRNA to its genomic sequence. B. AMFR mRNA and its amino acid coding.

AMFR (autocrine motility factor receptor) Erzurumlu Y, Ballar P


A schematic representation of the domain structure.

Protein

Description

AMFR belongs to the family of RING-Finger

ubiquitin ligases. The complete protein contains

643 amino acids. The calculated molecular weight

of AMFR is 73,0 kDa.

AMFR was originally isolated as a membrane

glycoprotein from murine melanoma cells and was

implicated in cell migration (Nabi and Raz, 1987).

Subsequently, gp78/AMFR was identified as the

tumor autocrine motility factor receptor mediating

tumor invasion and metastasis (Nabi et al., 1990). A

monoclonal antibody named 3F3A was generated

against this protein and first sequence reported for

human gp78/AMFR was in 1991 using this

antibody (Watanabe et al., 1991). However, the

protein product was only 321 amino acids

(Watanabe et al., 1991). A sequence giving 643

amino acids protein product was cloned in 1999

(Shimizu et al., 1999).

gp78/AMFR has five to seven transmembrane

domains according to different softwares like SACS

MEMSAT and SOSUI. The protein has a long

cytoplasmic tail composed of around 350 amino

acids (Shimizu et al., 1999). Besides conveying E3

activity the multifunctional cytoplasmic tail is

responsible for interaction with polyubiquitin,

ubiquitin conjugating enzyme, p97/VCP and Ufd1.

The RING finger domain of gp78/AMFR residing

between amino acids 341 and 383 is a RING-H2

type domain containing two His residues in

positions 4 and 5 (Fang et al., 2001). The Cue

domain of gp78/AMFR residing between amino

acids 456 and 497 is responsible for polyubiquitin

binding and has been identified by having

homologous sequences of yeast protein Cue1p

(Ponting, 2000). The p97/VCP-interacting motif of

gp78/AMFR consists of C-terminal amino acid

residues between 614-643 and it is sufficient to

bind to p97/VCP protein (Ballar et al., 2006).

gp78/AMFR binds to its ubiquitin conjugating

enzyme via a region called UBE2G2 binding region

(G2BR) and this region is resides between amino

acids 579 and 600 (Chen et al., 2006). Additionally,

gp78/AMFR interacts directly with Ufd1 through

residues 383-497 (Cao et al., 2007) and with

INSIGs through its transmembrane domains (Song

et al., 2005).

Expression

gp78/AMFR is relatively ubiquitously expressed in

normal human cells, especially highly in liver, heart

and lung. Northern blot analysis detected a 3.5-kb

AMFR transcript in mouse heart, brain, lung, liver,

skeletal muscle, kidney, and testis, but not in spleen

(Shimizu et al., 1999). gp78/AMFR is

overexpressed in certain malignant tumors and

human cancers of the lung, gastrointestinal tract,

breast, liver, thymus, and skin (Chiu et al., 2008;

Sjöblom et al., 2006; Tsai et al., 2007; Joshi et al.,

2010).

Localisation

Endoplasmic reticulum membrane, multi-pass

transmembrane protein (Fang et al., 2001).

Function

In 2001, it has been reported that gp78/AMFR

possesses ubiquitin ligase (E3) activity (Fang et al.,

2001) and can ubiquitinate both itself and other

proteins for proteasomal degradation. gp78/AMFR

is a member of multiprotein complex functioning in

endoplasmic reticulum associated degradation

(ERAD). gp78/AMFR not only functions as an E3

during ERAD but also couples retrotranslocation

and deglycosylation to ubiquitination (Ballar et al.,

2006; Li et al., 2005).

Homology

Homologues have been found in various species

like bovine, chimpanzee (99.8 % homology),

chicken, zebra fish, rat, C. elegans and mouse.

gp78/AMFR shares 94.7 % of homology with

murine gp78/AMFR.

Mutations

Somatic

D605V mutation has been reported in breast cancer

(Sjöblom et al., 2006). Several SNPs have been

found in gp78/AMFR gene both at coding regions

and at UTRs and introns. See SNP database at

NCBI.

Implicated in

Sarcoma metastasis

Note

gp78/AMFR targets KAI1, a known metastasis

http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?showRare=on&chooseRs=coding&go=Go&locusId=267



suppressor protein for ubiquitin mediated

proteasomal degradation (Tsai et al., 2007). Thus

gp78/AMFR has role in metastasis of human

sarcoma. Furthermore, a human sarcoma tissue

microarray study documents that tumors with low

gp78 expression has higher levels of KAI1 and high

gp78 level lower KAI1 expression in tumors (Tsai

et al., 2007).

Breast cancer

Note

gp78/AMFR expression in gp78 transgenic

mammary glands induces mammary gland

hyperplasia, increases duct number and network

density and shows down-regulation of KAI1

metastasis suppressor (Joshi et al., 2010).

Additionally, gp78/AMFR has been identified as

one of the most mutated genes in breast cancer

(Sjöblom et al., 2006). Consistently, gp78/AMFR is

overexpressed in human breast cancer and is

negatively associated with patients' clinical

outcome (Jiang et al., 2006).

Gastric carcinoma

Note

gp78/AMFR expression may be associated with the

progression and invasion of gastric carcinoma as

well as the prognoses of the patients (Hirono et al.,

1996). Furthermore, by using same 3F3A antibody

it was reported that gp78/AMFR expression is

associated with lymph node metastasis and

peritoneal dissemination in gastric carcinoma

(Taniguchi et al., 1998).

Colorectal cancer

Note

gp78/AMFR expression is correlated high

incidence of recurrence of the patients with

colorectal cancer (Nakamori et al., 1994).

Melanoma

Note

It was showed by using 3F3A antibody that

gp78/AMFR protein expression in human

melanoma cell lines correlates to their metastatic

potential. While in thin tumors weak/heterogenous

gp78/AMFR expression predominated, in thick

tumors the strong gp78/AMFR expression profile

was predominant (Tímár et al., 2002).

Lung cancer

Note

Using immunohistochemical staining the

gp78/AMFR expression was showed to be

associated with histologic type of tumor, mainly in

adenocarcinoma (Kara et al., 2001).

Hepatocellular carcinoma

Note

The expression of gp78/AMFR significantly

increased in hepatocellular carcinoma compared

with pericarcinomatous liver tissues. Furthermore,

there is a strong correlation between AMFR

expression and invasion and metastasis of HCC

(Wang et al., 2007).

Bladder carcinoma

Note

While in normal urothelium gp78/AMFR is not

expressed, its expression is increased in bladder

carcinoma specimens (Otto et al., 1994).

Cardiovascular diseases and hypercholesterolemia

Note

Accumulation of sterols in ER membranes triggers

the binding of HMG CoA reductase, the rate

limiting enzyme of cholesterol biosynthesis, to the

Insig1-gp78/AMFR complex which is essential for

the ubiquitination and proteasomal degradation of

HMGCoA-reductase (Goldstein et al., 2006; Jo and

DeBose-Boyd, 2010). gp78/AMFR is also the E3

ligase of apolipoprotein B100, the protein

component of atherogenic lipoproteins,

overproduction of which is a common feature of

human dyslipidemia (Liang et al., 2003).

Cystic fibrosis

Note

gp78/AMFR degrades mutant cystic fibrosis

transmembrane conductance regulator

(CFTRΔF508) associated with cystic fibrosis

(Ballar et al., 2010; Morito et al., 2008).

Metabolism and disposition of drugs

Note

gp78/AMFR participates in proteasomal

degradation of CYP3A4, a dominant human liver

cytochrome P450 enzyme functioning in the

metabolism and disposition of drugs and

responsible for many adverse drug-drug

interactions (Kim et al., 2010; Pabarcus et al.,

2009).

Chronic obstructive pulmonary disease

Note

gp78/AMFR expression is increased with the

severity of emphysema (Min et al., 2011).

Neurodegenerative diseases

Note

gp78/AMFR may play a protective role against

mutant huntingtin toxicity. Mutant huntingtin

hinders polyubiquitin binding to the cue domain of

gp78/AMFR and causes aggregation of ligase

(Yang et al., 2010). gp78/AMFR also enhances

ubiquitination, degradation, suppression of

aggregation of mutant SOD1 associated with

amyotrophic lateral sclerosis (ALS), and mutant

ataxin-3 associated with Machado-Joseph disease.

Furthermore, in spinal cords of ALS mice,



gp78/AMFR expression is significantly is up-

regulated (Ying et al., 2009).

Alpha-1-antitrypsin deficiency

Note

gp78/AMFR targets mutant ATZ (Z-variant alpha-

1-antitrypsin) associated with alpha-1-antitrypsin

deficiency for the proteasomal degradation and

increases its solubility (Shen et al., 2006).

References Nabi IR, Raz A. Cell shape modulation alters glycosylation of a metastatic melanoma cell-surface antigen. Int J Cancer. 1987 Sep 15;40(3):396-402

Nabi IR, Watanabe H, Raz A. Identification of B16-F1 melanoma autocrine motility-like factor receptor. Cancer Res. 1990 Jan 15;50(2):409-14

Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem. 1991 Jul 15;266(20):13442-8

Silletti S, Raz A. Autocrine motility factor is a growth factor. Biochem Biophys Res Commun. 1993 Jul 15;194(1):446-57

Nakamori S, Watanabe H, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Kabuto T, Raz A. Expression of autocrine motility factor receptor in colorectal cancer as a predictor for disease recurrence. Cancer. 1994 Oct 1;74(7):1855-62

Otto T, Birchmeier W, Schmidt U, Hinke A, Schipper J, Rübben H, Raz A. Inverse relation of E-cadherin and autocrine motility factor receptor expression as a prognostic factor in patients with bladder carcinomas. Cancer Res. 1994 Jun 15;54(12):3120-3

Hirono Y, Fushida S, Yonemura Y, Yamamoto H, Watanabe H, Raz A. Expression of autocrine motility factor receptor correlates with disease progression in human gastric cancer. Br J Cancer. 1996 Dec;74(12):2003-7

Taniguchi K, Yonemura Y, Nojima N, Hirono Y, Fushida S, Fujimura T, Miwa K, Endo Y, Yamamoto H, Watanabe H. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer. 1998 Jun 1;82(11):2112-22

Shimizu K, Tani M, Watanabe H, Nagamachi Y, Niinaka Y, Shiroishi T, Ohwada S, Raz A, Yokota J. The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein. FEBS Lett. 1999 Aug 6;456(2):295-300

Ponting CP. Proteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction. Biochem J. 2000 Oct 15;351 Pt 2:527-35

Fang S, Ferrone M, Yang C, Jensen JP, Tiwari S, Weissman AM. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14422-7

Kara M, Ohta Y, Tanaka Y, Oda M, Watanabe Y. Autocrine motility factor receptor expression in patients with stage I non-small cell lung cancer. Ann Thorac Surg. 2001 Mar;71(3):944-8

Tímár J, Rásó E, Döme B, Ladányi A, Bánfalvi T, Gilde K, Raz A. Expression and function of the AMF receptor by human melanoma in experimental and clinical systems. Clin Exp Metastasis. 2002;19(3):225-32

Liang JS, Kim T, Fang S, Yamaguchi J, Weissman AM, Fisher EA, Ginsberg HN. Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem. 2003 Jun 27;278(26):23984-8

Li G, Zhou X, Zhao G, Schindelin H, Lennarz WJ. Multiple modes of interaction of the deglycosylation enzyme, mouse peptide N-glycanase, with the proteasome. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15809-14

Song BL, Sever N, DeBose-Boyd RA. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell. 2005 Sep 16;19(6):829-40

Ballar P, Shen Y, Yang H, Fang S. The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem. 2006 Nov 17;281(46):35359-68

Chen B, Mariano J, Tsai YC, Chan AH, Cohen M, Weissman AM. The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):341-6

Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006 Jan 13;124(1):35-46

Jiang WG, Raz A, Douglas-Jones A, Mansel RE. Expression of autocrine motility factor (AMF) and its receptor, AMFR, in human breast cancer. J Histochem Cytochem. 2006 Feb;54(2):231-41

Shen Y, Ballar P, Fang S. Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1-antitrypsin. Biochem Biophys Res Commun. 2006 Nov 3;349(4):1285-93

Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74

Cao J, Wang J, Qi W, Miao HH, Wang J, Ge L, DeBose-Boyd RA, Tang JJ, Li BL, Song BL. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab. 2007 Aug;6(2):115-28

Tsai YC, Mendoza A, Mariano JM, Zhou M, Kostova Z, Chen B, Veenstra T, Hewitt SM, Helman LJ, Khanna C, Weissman AM. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med. 2007 Dec;13(12):1504-9

Wang W, Yang LY, Yang ZL, Peng JX, Yang JQ. Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma. Dig Dis Sci. 2007 Mar;52(3):770-5

Chiu CG, St-Pierre P, Nabi IR, Wiseman SM. Autocrine motility factor receptor: a clinical review. Expert Rev Anticancer Ther. 2008 Feb;8(2):207-17



Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell. 2008 Apr;19(4):1328-36

Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74

Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E, Wang G. Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet. 2009 Nov 15;18(22):4268-81

Ballar P, Ors AU, Yang H, Fang S. Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. Int J Biochem Cell Biol. 2010 Jan;42(1):167-73

Jo Y, Debose-Boyd RA. Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol. 2010 Jun;45(3):185-98

Joshi B, Li L, Nabi IR. A role for KAI1 in promotion of cell proliferation and mammary gland hyperplasia by the gp78 ubiquitin ligase. J Biol Chem. 2010 Mar 19;285(12):8830-9

Kim SM, Acharya P, Engel JC, Correia MA. Liver cytochrome P450 3A ubiquitination in vivo by gp78/autocrine motility factor receptor and C terminus of Hsp70-interacting protein (CHIP) E3 ubiquitin ligases: physiological and pharmacological relevance. J Biol Chem. 2010 Nov 12;285(46):35866-77

Yang H, Liu C, Zhong Y, Luo S, Monteiro MJ, Fang S. Huntingtin interacts with the cue domain of gp78 and inhibits gp78 binding to ubiquitin and p97/VCP. PLoS One. 2010 Jan 26;5(1):e8905

Min T, Bodas M, Mazur S, Vij N. Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med (Berl). 2011 Jun;89(6):577-93


Erzurumlu Y, Ballar P. AMFR (autocrine motility factor receptor). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):25-29.

Gene Section Review




ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) Paul F South, Scott D Briggs

Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University,

West Lafayette, Indiana 47907, USA (PFS, SDB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ASH2LID44404ch8p11.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ASH2LID44404ch8p11.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: ASH2, ASH2L1, ASH2L2, Bre2

HGNC (Hugo): ASH2L

Location: 8p11.23

DNA/RNA

Description

16 exons spanning over 34218 base pairs.

Transcription

mRNA is 2368 base pairs long.

Protein

Description

There are three known isoforms of ASH2L (Wang

et al., 2001). Isoform 1 is considered the canonical

sequence and consists of 628 amino acids (Wang et

al., 2001). Isoform 2 is missing amino acids 1-94

and 541-573 from isoform 1 (Wang et al., 2001).

Isoform 3 is missing the amino acids 1-94 from

isoform 1 (figure 2) (Wang et al., 2001). There are

four identified domains within ASH2L which

include a N-terminus containing a PHD finger and a

winged helix motif (WH) and the C-terminus

containing a SPRY domain and the Sdc1 DPY-30

Interacting domain (SDI) (figure 2) (Chen et al.,

2011; Roguev et al., 2001; Sarvan et al., 2011;

South et al., 2010; Wang et al., 2001). The largest

of the three identified domains within ASH2L is the

SPRY domain, which is also conserved from yeast

to humans. SPRY domains were originally named

after the SPIa kinase and the RYanodine receptor

proteins in which it was first identified (Rhodes et

al., 2005). Crystal structures of SPRY domain

containing proteins show primarily a beta-sandwich

structure with extending loops (Filippakopoulos et

al., 2010; Kuang et al., 2009; Simonet et al., 2007;

Woo et al., 2006b). The SPRY domain is thought to

be a specific protein-protein interaction domain

Figure 1. Map of chromosome 8 with region 8p11.2 highlighted as the location of the gene ASH2L.

ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) South PF, Briggs SD


Figure 2. Schematic model of the three known isoforms of ASH2L and the amino acid sequence changes compared to the

canonical isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273), SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform 2 and 3 are numbered according to isoform 1.

with specific partners, but instead of recognizing a

particular motif or interaction domain the SPRY

domain binds to interaction partners using non-

conserved binding loops (Filippakopoulos et al.,

2010; Woo et al., 2006a; Woo et al., 2006b). Recent

work has shown that the C-terminus of ASH2L that

contains the SPRY domain and the SDI domain are

able to interact with the other MLL complex

member RBBP5 in vitro (Avdic et al., 2011).

ASH2L also contains a putative Plant Homeo

Domain (PHD) finger in its N-terminus (Wang et

al., 2001). The structure of PHD fingers shows that

conserved cysteine and histidine residues bind to

Zn2+

ions (Champagne et al., 2008; Champagne and

Kutateladze, 2009; van Ingen et al., 2008). There is

no known function attributed to the PHD finger in

ASH2L, though in conjunction with the winged

helix motif it may be necessary for DNA binding.

The N-terminal winged helix (WH) motif was

recently discovered when the crystal structure of the

N-terminus of ASH2L was solved (Chen et al.,

2011; Sarvan et al., 2011). Using in vitro DNA

binding analyses as well as chromatin

immunoprecipitation, it was determined that

ASH2L can bind DNA at the HS2 promoter region

and the beta-globin locus as well as non-specific

DNA sequence (Chen et al., 2011; Sarvan et al.,

2011).

The last identifiable domain within ASH2L is the

SDI domain. There is no structural information on

the SDI domain but the functional importance was

determined biochemically. The function of the SDI

domain was determined using in vitro binding

experiments. ASH2L was shown to directly interact

with DPY-30 without any additional MLL or Set1

complex components (South et al., 2010). The

function of the SDI domain is conserved from yeast

to humans because the yeast ASH2L homolog Bre2

was also shown to interact with the DPY-30

homolog Sdc1 (South et al., 2010). There are

conserved hydrophobic residues in both the SDI

domain of ASH2L and the Dpy-30 domain of DPY-

30 that are important for binding, which suggests

that the interaction between the SDI domain of

ASH2L and the DPY-30 domain of DPY-30 is

through hydrophobic interactions (South et al.,

2010).

Expression

Northern blot analysis from multiple tissues

revealed that ASH2L expression is expressed in 14

different tissue types with the highest expression in

fetal liver and testes (Lüscher-Firzlaff et al., 2008).

ASH2L transcripts were also found to be expressed

higher in various Leukemia cell lines, such as

K562, Hel, and Dami cells (Lüscher-Firzlaff et al.,

2008).

Localisation

Nucleus.

Function

Biochemical data has shown that ASH2L is found

in a methyltransferase core complex composed of

ASH2L, RBBP5, DPY30, WDR5, and the catalytic

SET domain containing protein. This core complex

is highly conserved and similar to the budding yeast

Set1 complex that consists of Set1 (MLL/SET1),

Bre2 (ASH2L), Swd1 (RBBP5), Swd3 (WDR5),

Swd2 (WDR82), Sdc1 (DPY-30), Spp1

(CFP1/CGBP). ASH2L is also known to associate

with numerous additional factors. Many of these

additional factors are thought to associate with

ASH2L and the H3K4 methyltransferase complexes

to target the complex to specific sites within the

genome (Cho et al., 2007; Dou et al., 2006; Hughes

et al., 2004; Steward et al., 2006; Stoller et al.,

2010). Knock-down of ASH2L using siRNA

globally decreases H3K4 trimethylation (Dou et al.,

2006; Steward et al., 2006). ASH2L and H3K4

methylation both appear to play a key role in

oncogenesis (Hess, 2006). ASH2L is found to be

over abundant in many cancer cell lines and knock-

down of ASH2L by siRNA can prevent

tumorigenesis (Lüscher-Firzlaff et al., 2008).

Recent work has suggested that ASH2L in

combination with WDR5 and RBBP5 exhibits

H3K4 methyltransferase activity (Cao et al., 2010;

Patel et al., 2009; Patel et al., 2011). In addition,

this catalytic activity is not dependent on the SET

domain containing proteins such as MLL1 (Cao et

al., 2010; Patel et al., 2009; Patel et al., 2011).



Alternative to ASH2L's function in H3K4

methylation ASH2L may also be playing a role in

endosomal trafficking (Xu et al., 2009). ASH2L,

DPY-30 and WDR5 were originally implicated in

endosomal trafficking when siRNA knock-down of

these genes increased the amount of internalized

CD8-CIMPR and overexpression increased the

amount of cells displaying a altered CIMPR

distribution (Xu et al., 2009).

Homology

ASH2L has homologs in eukaryotes from yeast to

humans.

Implicated in

Various cancers

Note

ASH2L mRNA expression does not appear to be

misregulated in human cancer cell or primary cell

lines. However, expression of ASH2L protein is

increased in many cancer cell lines as well as tumor

samples (Lüscher-Firzlaff et al., 2008). There was

detectable increased staining in the nucleus of

ASH2L protein in a wide array of tumors including

squamous cell carcinoma of the larynx and the

cervix, melanomas, adenocarcinoma of the

pancreas, and acinar and ductal breast cancers

(Lüscher-Firzlaff et al., 2008). ASH2L protein

appears to be more stable in cancer cell lines

compared to the normal cell line counterparts and

knockdown of ASH2L can prevent tumerogenesis

suggesting a role in tumor cell proliferation

(Lüscher-Firzlaff et al., 2008).

References Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R, Stewart AF. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 2001 Dec 17;20(24):7137-48

Wang J, Zhou Y, Yin B, Du G, Huang X, Li G, Shen Y, Yuan J, Qiang B. ASH2L: alternative splicing and downregulation during induced megakaryocytic differentiation of multipotential leukemia cell lines. J Mol Med (Berl). 2001 Jul;79(7):399-405

Hess JL.. MLL: Deep Insight. Atlas Genet Cytogenet Oncol Haematol. August 2003 .

Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M.. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004 Feb 27;13(4):587-97.

Rhodes DA, de Bono B, Trowsdale J.. Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology. 2005 Dec;116(4):411-7. (REVIEW)

Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG.. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30.

Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE, Shilatifard A.. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6.

Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23.

Woo JS, Suh HY, Park SY, Oh BH.. Structural basis for protein recognition by B30.2/SPRY domains. Mol Cell. 2006b Dec 28;24(6):967-76.

Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K.. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007 Jul 13;282(28):20395-406. Epub 2007 May 11.

Simonet T, Dulermo R, Schott S, Palladino F.. Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Dev Biol. 2007 Dec 1;312(1):367-83. Epub 2007 Oct 29.

Champagne KS, Saksouk N, Pena PV, Johnson K, Ullah M, Yang XJ, Cote J, Kutateladze TG.. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins. 2008 Sep;72(4):1371-6.

Luscher-Firzlaff J, Gawlista I, Vervoorts J, Kapelle K, Braunschweig T, Walsemann G, Rodgarkia-Schamberger C, Schuchlautz H, Dreschers S, Kremmer E, Lilischkis R, Cerni C, Wellmann A, Luscher B.. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 2008 Feb 1;68(3):749-58.

van Ingen H, van Schaik FM, Wienk H, Ballering J, Rehmann H, Dechesne AC, Kruijzer JA, Liskamp RM, Timmers HT, Boelens R.. Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure. 2008 Aug 6;16(8):1245-56.

Champagne KS, Kutateladze TG.. Structural insight into histone recognition by the ING PHD fingers. Curr Drug Targets. 2009 May;10(5):432-41. (REVIEW)

Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson TA, Kolesnik TB, Nicholson SE, Garrett TJ, Norton RS.. SPRY domain-containing SOCS box protein 2: crystal structure and residues critical for protein binding. J Mol Biol. 2009 Feb 27;386(3):662-74. Epub 2009 Jan 6.

Patel A, Dharmarajan V, Vought VE, Cosgrove MS.. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25.

Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu D, Matsumoto B, Seaman M, Ma D.. A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking. J Cell Biol. 2009 Aug 10;186(3):343-53. Epub 2009 Aug 3.

Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y.. An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010 Nov 23;5(11):e14102.

Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S, Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS, Bullock AN.. Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. J Mol Biol. 2010 Aug 20;401(3):389-402. Epub 2010 Jun 16.



South PF, Fingerman IM, Mersman DP, Du HN, Briggs SD.. A conserved interaction between the SDI domain of Bre2 and the Dpy-30 domain of Sdc1 is required for histone methylation and gene expression. J Biol Chem. 2010 Jan 1;285(1):595-607. Epub 2009 Nov 6.

Stoller JZ, Huang L, Tan CC, Huang F, Zhou DD, Yang J, Gelb BD, Epstein JA.. Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp Biol Med (Maywood). 2010 May;235(5):569-76.

Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V, Brunzelle J, Couture JF.. Structural and biochemical insights into MLL1 core complex assembly. Structure. 2011 Jan 12;19(1):101-8.

Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y, Chang HY, Lei M.. Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. EMBO Rep. 2011 Jun 10;12(8):797-803. doi: 10.1038/embor.2011.101.

Patel A, Vought VE, Dharmarajan V, Cosgrove MS.. A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2011 Feb 4;286(5):3359-69. Epub 2010 Nov 24.

Sarvan S, Avdic V, Tremblay V, Chaturvedi CP, Zhang P, Lanouette S, Blais A, Brunzelle JS, Brand M, Couture JF.. Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nat Struct Mol Biol. 2011 Jun 5;18(7):857-9. doi: 10.1038/nsmb.2093.


South PF, Briggs SD. ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):30-33.





CD109 (CD109 molecule) Shinji Mii, Yoshiki Murakumo, Masahide Takahashi

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

(SM, YM, MT)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CD109ID42925ch6q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CD109ID42925ch6q13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CPAMD7, DKFZp762L1111,

FLJ38569, FLJ41966, RP11-525G3.1

HGNC (Hugo): CD109

Location: 6q13

Note

CD109 is a glycosylphosphatidylinositol (GPI)-

anchored cell-surface glycoprotein and is a member

of the alpha-2-macroglobulin/C3,C4,C5 family of

thioester-containing proteins.

DNA/RNA

Description

CD109 is a gene of 132.53 kb comprising 33 exons

and 32 introns. The 5' part of exon 1 and the 3' part

of exon 33 are non-coding.

Transcription

Three splice variants are known. The length of the

longest variant is 9464 bp (CDS: 426-4763).

mRNA is mainly expressed in skin and testis.

Pseudogene

Not known.

Protein

Description

CD109 is a GPI-anchored cell-surface glycoprotein

and is a member of the alpha-2-

macroglobulin/C3,C4,C5 family of thioester-

containing proteins (Sutherland et al., 1991;

Haregewoin et al., 1994; Smith et al., 1995; Lin et

al., 2002). The CD109 protein was first identified

as a cell-surface antigen detected by a monoclonal

antibody raised against the primitive

lymphoid/myeloid cell line KG1a (Sutherland et al.,

1991). It was also shown that CD109 carries the

biallelic platelet-specific alloantigen Gov (Kelton et

al., 1990; Smith et al., 1995).

Expression

CD109 is expressed on a subset of fetal and adult

CD34+ bone marrow mononuclear cells,

mesenchymal stem cell subsets,

phytohemagglutinin (PHA)-activated T

lymphoblasts, thrombin-activated platelets,

leukemic megakaryoblasts, endothelial cells, and

some human tumor cell lines, but not on fresh

peripheral leukocytes and normal bone marrow

leukocytes (Kelton et al., 1990; Murray et al., 1999;

Giesert et al., 2003).

Exon-intron structure of CD109 gene. The vertical bars correspond to exons.

CD109 (CD109 molecule) Mii S, et al.


Representation of the CD109 protein with localization of recognized domains. CD109 protein is a GPI-anchored protein having

signal peptide, Gov antigen, thioester region, and furinase cleavage site.

In normal human tissues other than hematopoietic

cells, CD109 is expressed in limited cells including

the myoepithelial cells of the mammary, lacrimal,

salivary and bronchial glands and the basal cells of

the prostate and the bronchial epithelia (Hashimoto

et al., 2004; Zhang et al., 2005; Sato et al., 2007;

Hasegawa et al., 2007; Hasegawa et al., 2008).

Recently, it has been reported that CD109 is highly

expressed in several types of human cancer tissues,

in particular squamous cell carcinomas (Hashimoto

et al., 2004; Zhang et al., 2005; Sato et al., 2007;

Hasegawa et al., 2007; Hasegawa et al., 2008;

Järvinen et al., 2008; Hagiwara et al., 2008;

Ohshima et al., 2010; Hagikura et al., 2010).

Localisation

Plasma membrane.

Function

CD109 negatively regulates TGF-beta signaling in

keratinocytes by directly modulating TGF-beta

receptor activity in vitro (Finnson et al., 2006).

Homology

Orthologs: mouse CD109, rat CD109, cow CD109,

dog CD109, chicken CD109, hagfish CD109,

nematode CD109.

Paralogs: alpha-2-macroglobulin, alpha-2-

macroglobulin-like-1, C3, C4, C5, PZP, CPAMD8.

Mutations

Note

A Tyr703Ser polymorphism of CD109 is associated

with Gova and Gov

b alloantigenic determination

(Schuh et al., 2002).

Implicated in

Various cancer

Note

CD109 is upregulated in squamous cell carcinomas

(SCCs) of lung, esophagus, uterus and oral cavity,

malignant melanoma of skin, and urothelial

carcinoma of urinary bladder (Hashimoto et al.,

2004; Zhang et al., 2005; Sato et al., 2007;

Hasegawa et al., 2007; Hasegawa et al., 2008;

Järvinen et al., 2008; Hagiwara et al., 2008;

Ohshima et al., 2010; Hagikura et al., 2010).

Prognosis

The CD109 expression is significantly higher in

well-differentiated SCCs of the oral cavity and in

low-grade urothelial carcinomas of the urinary

bladder than in moderately- or poorly-differentiated

SCCs and in high-grade urothelial carcinomas,

respectively (Hagiwara et al., 2008; Hagikura et al.,

2010).

Alloimmune thrombocytopenic syndromes

Note

Refractoriness to platelet transfusion, post-

transfusion purpura, and neonatal alloimmune

thrombocytopenia (Smith et al., 1995).

Disease

These diseases are included in alloimmune

thrombocytopenic syndromes. Gova/b

platelet

alloantigens, which reside in the CD109 protein, are

the cause of these 3 diseases.

References Kelton JG, Smith JW, Horsewood P, Humbert JR, Hayward CP, Warkentin TE. Gova/b alloantigen system on human platelets. Blood. 1990 Jun 1;75(11):2172-6

Sutherland DR, Yeo E, Ryan A, Mills GB, Bailey D, Baker MA. Identification of a cell-surface antigen associated with activated T lymphoblasts and activated platelets. Blood. 1991 Jan 1;77(1):84-93

Haregewoin A, Solomon K, Hom RC, Soman G, Bergelson JM, Bhan AK, Finberg RW. Cellular expression of a GPI-linked T cell activation protein. Cell Immunol. 1994 Jul;156(2):357-70

Smith JW, Hayward CP, Horsewood P, Warkentin TE, Denomme GA, Kelton JG. Characterization and localization of the Gova/b alloantigens to the glycosylphosphatidylinositol-anchored protein CDw109 on human platelets. Blood. 1995 Oct 1;86(7):2807-14

Murray LJ, Bruno E, Uchida N, Hoffman R, Nayar R, Yeo EL, Schuh AC, Sutherland DR. CD109 is expressed on a subpopulation of CD34+ cells enriched in hematopoietic stem and progenitor cells. Exp Hematol. 1999 Aug;27(8):1282-94

Lin M, Sutherland DR, Horsfall W, Totty N, Yeo E, Nayar R, Wu XF, Schuh AC. Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood. 2002 Mar 1;99(5):1683-91

Schuh AC, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JY, Campbell K, Sutherland DR, Metcalfe P, Horsfall W, Ouwehand WH. A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood. 2002 Mar 1;99(5):1692-8

Giesert C, Marxer A, Sutherland DR, Schuh AC, Kanz L, Buhring HJ. Antibody W7C5 defines a CD109 epitope expressed on CD34+ and CD34- hematopoietic and mesenchymal stem cell subsets. Ann N Y Acad Sci. 2003 May;996:227-30

Hashimoto M, Ichihara M, Watanabe T, Kawai K, Koshikawa K, Yuasa N, Takahashi T, Yatabe Y, Murakumo Y, Zhang JM, Nimura Y, Takahashi M.

CD109 (CD109 molecule) Mii S, et al.


Expression of CD109 in human cancer. Oncogene. 2004 Apr 29;23(20):3716-20

Zhang JM, Hashimoto M, Kawai K, Murakumo Y, Sato T, Ichihara M, Nakamura S, Takahashi M. CD109 expression in squamous cell carcinoma of the uterine cervix. Pathol Int. 2005 Apr;55(4):165-9

Finnson KW, Tam BY, Liu K, Marcoux A, Lepage P, Roy S, Bizet AA, Philip A. Identification of CD109 as part of the TGF-beta receptor system in human keratinocytes. FASEB J. 2006 Jul;20(9):1525-7

Hasegawa M, Hagiwara S, Sato T, Jijiwa M, Murakumo Y, Maeda M, Moritani S, Ichihara S, Takahashi M. CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells. Pathol Int. 2007 May;57(5):245-50

Sato T, Murakumo Y, Hagiwara S, Jijiwa M, Suzuki C, Yatabe Y, Takahashi M. High-level expression of CD109 is frequently detected in lung squamous cell carcinomas. Pathol Int. 2007 Nov;57(11):719-24

Hasegawa M, Moritani S, Murakumo Y, Sato T, Hagiwara S, Suzuki C, Mii S, Jijiwa M, Enomoto A, Asai N, Ichihara S, Takahashi M. CD109 expression in basal-like breast carcinoma. Pathol Int. 2008 May;58(5):288-94

Hagiwara S, Murakumo Y, Sato T, Shigetomi T, Mitsudo K, Tohnai I, Ueda M, Takahashi M. Up-regulation of CD109

expression is associated with carcinogenesis of the squamous epithelium of the oral cavity. Cancer Sci. 2008 Oct;99(10):1916-23

Järvinen AK, Autio R, Kilpinen S, Saarela M, Leivo I, Grénman R, Mäkitie AA, Monni O. High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer. 2008 Jun;47(6):500-9

Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S, Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai K, Nakamura S, Gotoh M, Takahashi M. Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Pathol Int. 2010 Nov;60(11):735-43

Ohshima Y, Yajima I, Kumasaka MY, Yanagishita T, Watanabe D, Takahashi M, Inoue Y, Ihn H, Matsumoto Y, Kato M. CD109 expression levels in malignant melanoma. J Dermatol Sci. 2010 Feb;57(2):140-2


Mii S, Murakumo Y, Takahashi M. CD109 (CD109 molecule). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):34-36.





CLDN7 (claudin 7) Ana Carolina de Carvalho, Andre Vettore

Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of

Sao Paulo, Diadema, SP, Brazil (ACd, AV)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CLDN7ID40099ch17p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CLDN7ID40099ch17p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CEPTRL2, CLDN-7, CPETRL2,

Hs.84359, claudin-1

HGNC (Hugo): CLDN7

Location: 17p13.1

DNA/RNA

Description

2573 base-pairs, starts at 7163223 and ends at

7165795 bp from pter with minus strand

orientation.

Transcription

This gene contains 4 exons and 3 introns. The

transcription produces 3 alternatively spliced

mRNA variants:

- variant 1 (NM_001307.5) encodes the longer

isoform;

- variant 2 (NM_001185022.1) has an alternate 5'

UTR sequence;

- variant 3 (NM_001185023.1) lacks an exon in the

3' CDS.

Pseudogene

The sequence named LOC100129851 claudin 7

pseudogene is a pseudogene of Claudin 7 located at

Xp11.4.

Figure 1. Schematic representation of the claudin 7 chromosome location, transcript variants and protein isoforms.

CLDN7 (claudin 7) de Carvalho AC, Vettore A


Figure 2. Schematic representation of the claudin 7 protein showing the extracellular loops (EL1 and EL2), the transmembrane

domains (TM1 to TM4) and its amino- and carboxy-terminal tails extending into the cytoplasm.

Protein

Description

The transcription of this gene gives 3 alternatively

spliced mRNA variants that encode 2 different

protein isoforms (variants 1 and 2 encode the same

isoform):

- Isoform 1 is the canonical sequence with 211

amino acids and it weighs 22418 Da.

MANSGLQLLGFSMALLGWVGLVACTAIPQW

QMSSYAGDNIITAQAMYKGLWMDCVTQSTG

MMSCKMYDSVLALSAALQATRALMVVSLVL

GFLAMFVATMGMKCTRCGGDDKVKKARIA

MGGGIIFIVAGLAALVACSWYGHQIVTDFYNP

LIPTNIKYEFGPAIFIGWAGSALVILGGALLSCS

CPGNESKAGYRVPRSYPKSNSSKEYV

- Isoform 2 contains 145 amino acids, with a shorter

C-terminus, lacking amino acids 159 to 211 in

comparison to isoform 1. It weighs 15156 Da.

MANSGLQLLGFSMALLGWVGLVACTAIPQW

QMSSYAGDNIITAQAMYKGLWMDCVTQSTG

MMSCKMYDSVLALSAALQATRALMVVSLVL

GFLAMFVATMGMKCTRCGGDDKVKKARIA

MGGGIIFIVAGMSLALPSLLAGQGLP

CLDN-7 is an integral membrane protein with four

hydrophobic transmembrane domains and two

extracellular loops which appear to be implicated in

tight junction formation and with their amino- and

carboxy-terminal tails extending into the cytoplasm

(figure 2).

Localisation

The protein is localized in the cell membrane as a

constituent of tight junctions.

Function

CLDN-7 encodes a member of the claudin family

of integral transmembrane proteins that are

components of tight junction strands. Claudins

regulate the paracellular transport being essential in

maintaining a functional epithelial barrier, and also

play critical roles in maintaining cell polarity and

signal transductions. Studies have shown that

altered levels of the different claudins may be

related to invasion and progression of carcinoma

cells in several primary neoplasms.

Mutations

Somatic

In the catalogue of Somatic Mutations in Cancer

(Sanger) reports only a heterozygous silent

http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=CLDN7



substitution (339G/T; V113V) in ovarian serous

cystadenocarcinoma is present.

Polymorphisms

According to the Ensembl database 12 variations

could be present in the transcripts (variants 1/2) of

CLDN-7:

Position 963/396 of mRNA a synonymous G/A

polymorphism at position 61 of the amino acid

sequence.

Position 979/412 of mRNA a non-synonymous G/T


sequence. Switching an Ala for an Asp residue.

SIFT deleterious.

Position 1299/732 of mRNA a non-synonymous

C/T polymorphism at position 397 of the amino

acid sequence. Switching an Ala for an Thr residue.

SIFT tolerated.


C/A polymorphism at position 523 of the amino

acid sequence. Switching an Val for an Phe residue.

SIFT deleterious.


A/G polymorphism at position 590 of the amino

acid sequence. Switching an Val for an Ala residue.

SIFT tolerated.

Position 1508/941 of mRNA a synonymous A/C


sequence.

Implicated in

Colorectal carcinoma

Prognosis

Oshima et al. (2008) studied surgical specimens of

cancer tissue and adjacent normal mucosa from

patients with untreated colorectal carcinoma. The

reduced expression of Claudin 7 correlated with

venous invasion and liver metastasis, thus

suggesting that the reduced expression of the

Claudin 7 gene may be a useful predictor of liver

metastasis in patients with colorectal cancer.

Oncogenesis

Bornholdt et al. (2011) observed that Claudin 7

gene was downregulated both at mRNA and protein

levels in biopsies of colorectal tissue from

mild/moderate dysplasia, severe dysplasia and

carcinomas when comparing to biopsies from

healthy individuals. These results suggest that

Claudin 7 downregulation is as an early event in

colorectal carcinogenesis, probably contributing to

the compromised epithelial barrier in adenomas.

Esophageal cancer

Prognosis

Usami et al. (2006) found that reduced expression

of Claudin 7 at the invasive front of the esophageal

cancer was significantly associated with the depth

of invasion, lymphatic vessel invasion, and lymph

node metastasis. Reduced Claudin 7 expression was

also found in the metastatic lymph nodes. They

suggest that the reduced expression of Claudin 7 at

the invasive front of esophageal squamous cell

carcinoma may lead to tumor progression and

subsequent metastatic events.

Epithelial ovarian carcinoma

Prognosis

Kim et al. (2011) described the up-regulation of

Claudin 7 transcripts in patients with epithelial

ovarian carcinoma (EOCs) in comparison to normal

ovarian tissues. The protein Claudin 7 was observed

in the majority of the EOCs but not in normal

ovarian tissues. High Claudin 7 expression in

primary tumor correlated with shorter progression-

free survival and poor sensitivity to platinum-based

chemotherapy. Claudin 7 inhibition in 2774 and

HeyA8 human ovarian cancer cells by siRNA

significantly enhanced the sensitivity of these cells

to cisplatin treatment. These findings suggest

Claudin 7 expression as an independent prognostic

factor for progression-free survival in EOCs

patients and that it may play a role in regulating

response to platinum-based chemotherapy in the

treatment of these tumors.

Oncogenesis

Tassi et al. (2008) found Claudin 7 transcript and

protein significantly overexpressed in both primary

and metastatic EOCs compared to normal ovaries.

Moreover, a strong immunoreactivity for Claudin 7

was detected in EOC cells present in ascites fluids,

whereas ascites-derived inflammatory cells,

histiocytes, and reactive mesothelial cells were

negative. Claudin 7 is significantly overexpressed

in all main histologic types of EOC and in single

neoplastic cells disseminated in peritoneal cavity

and pleural effusions, suggesting its potential role

as novel diagnostic marker in ovarian cancer.

Prostatic carcinoma

Prognosis

Sheehan et al. (2007) reported the pattern of claudin

expression in prostatic adenocarcinomas (PACs)

and found that the decreased expression of Claudin

7 was correlated with high tumor grade.

Oral squamous cell carcinoma

Prognosis

Lourenço et al. (2010) showed that Claudin 7

expression was mostly negative or weakly

expressed in oral squamous cell carcinoma samples.

According their results, the loss of Claudin 7

expression was associated with tumor size, clinical

stage and a worse disease-free survival.

Uterine cervical neoplasia

Oncogenesis

Lee et al. (2005) showed that Claudin 7 expressions

is associated with the progression of uterine

cervical neoplasia since its expression was

undetectable in normal cervical squamous

epithelium and gradually increase in accordance



with the progression from LSIL (low-grade

squamous intraepithelial lesion) to HSIL (high-

grade squamous intraepithelial lesion) and ISCC

(invasive squamous cell carcinoma). Claudin 7

were detected in all cases of ISCC. These authors

suggested that Claudin 7 may play a significant role

in tumor progression of cervical neoplasia.

Breast cancer

Prognosis

Kominsky et al. (2003) conducted RT-PCR and

Western Blot analysis and reported that Claudin 7

expression is lower in breast invasive ductal

carcinomas (IDC) than in normal breast epithelium.

They also reported immunohistochemical (IHC)

analysis of ductal carcinoma in situ (DCIS) and

IDC and showed that the loss of Claudin 7

expression is correlated with histological grade,

occurring predominantly in high-grade lesions.

According to their results, Claudin 7 expression

was lost in the vast majority of in situ lobular

carcinoma cases. In summary, this study provides

insight into the potential role of Claudin 7 in the

breast tumor progression and in the ability of breast

cancer cells to disseminate.

Sauer et al. (2005) evaluated the

immunocytochemical expression of Claudin 7 in

fine needle aspirates of breast carcinomas and

found that reduced Claudin 7 expression was

correlated with grading, locoregional and distant

metastases, nodal involvement and cellular

cohesion in invasive carcinomas.

References Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP, Sukumar S. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene. 2003 Apr 3;22(13):2021-33

Lee JW, Lee SJ, Seo J, Song SY, Ahn G, Park CS, Lee JH, Kim BG, Bae DS. Increased expressions of claudin-1 and claudin-7 during the progression of cervical neoplasia. Gynecol Oncol. 2005 Apr;97(1):53-9

Sauer T, Pedersen MK, Ebeltoft K, Naess O. Reduced expression of Claudin-7 in fine needle aspirates from breast carcinomas correlate with grading and metastatic disease. Cytopathology. 2005 Aug;16(4):193-8

Usami Y, Chiba H, Nakayama F, Ueda J, Matsuda Y, Sawada N, Komori T, Ito A, Yokozaki H. Reduced expression of claudin-7 correlates with invasion and metastasis in squamous cell carcinoma of the esophagus. Hum Pathol. 2006 May;37(5):569-77

Sheehan GM, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP Jr, Ross JS. Loss of claudins-1 and -7 and expression of claudins-3 and -4 correlate with prognostic variables in prostatic adenocarcinomas. Hum Pathol. 2007 Apr;38(4):564-9

Oshima T, Kunisaki C, Yoshihara K, Yamada R, Yamamoto N, Sato T, Makino H, Yamagishi S, Nagano Y, Fujii S, Shiozawa M, Akaike M, Wada N, Rino Y, Masuda M, Tanaka K, Imada T. Reduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancer. Oncol Rep. 2008 Apr;19(4):953-9

Tassi RA, Bignotti E, Falchetti M, Ravanini M, Calza S, Ravaggi A, Bandiera E, Facchetti F, Pecorelli S, Santin AD. Claudin-7 expression in human epithelial ovarian cancer. Int J Gynecol Cancer. 2008 Nov-Dec;18(6):1262-71

Lourenço SV, Coutinho-Camillo CM, Buim ME, de Carvalho AC, Lessa RC, Pereira CM, Vettore AL, Carvalho AL, Fregnani JH, Kowalski LP, Soares FA. Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma. Histopathology. 2010 Nov;57(5):689-98

Bornholdt J, Friis S, Godiksen S, Poulsen SS, Santoni-Rugiu E, Bisgaard HC, Lothe IM, Ikdahl T, Tveit KM, Johnson E, Kure EH, Vogel LK. The level of claudin-7 is reduced as an early event in colorectal carcinogenesis. BMC Cancer. 2011 Feb 10;11:65

Kim CJ, Lee JW, Choi JJ, Choi HY, Park YA, Jeon HK, Sung CO, Song SY, Lee YY, Choi CH, Kim TJ, Lee JH, Kim BG, Bae DS. High claudin-7 expression is associated with a poor response to platinum-based chemotherapy in epithelial ovarian carcinoma. Eur J Cancer. 2011 Apr;47(6):918-25


de Carvalho AC, Vettore A. CLDN7 (claudin 7). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):37-40.

Gene Section Review




CSE1L (CSE1 chromosome segregation 1-like (yeast)) Ming-Chung Jiang

Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University

Hospital, Taipei, Taiwan (MCJ)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CSE1LID40159ch20q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CSE1LID40159ch20q13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: CAS, CSE1, MGC117283,

MGC130036, MGC130037, XPO2

HGNC (Hugo): CSE1L

Location: 20q13.13

DNA/RNA

Note

CDS: 2915 bp.

Description

The CSE1L gene consists of 25 exons (Brinkmann

et al., 1999). The CSE1L gene is high-frequency

amplified in various cancer types (Tai et al., 2010a).

Transcription

Multiple transcript variants encoding several

different isoforms in a tissue-specific manner have

been described for CSE1L gene (Brinkmann et al.,

1999).

Protein

Note

CSE1L is a multiple function protein. The protein is

involved in nuclear protein transport (Lindsay et al.,

2002), cell apoptosis (Brinkmann et al., 1996),

microtubule assembly (Scherf et al., 1996), cell

secretion (Tsao et al., 2009), and cancer cell

invasion (Liao et al., 2008; Tung et al., 2009; Stella

Tsai et al., 2010) etc.

Description

CSE1L gene encodes a 971-amino acid protein with

an approximately 100-kDa molecular mass

(Brinkmann et al., 1995).

Expression

CSE1L is expressed in various tissues, and

particularly it is highly expressed in most cancer

(Tai et al., 2010a; Brinkmann et al., 1995). The

expression level CSE1L is positively correlated

with high tumor stage, high tumor grade, and worse

outcomes of cancer patients (Tai et al., 2010a). The

increased expression of CSE1L in cancer is mainly

due to the amplification of the copy number of the

CSE1L gene in cancer tissue (Tai et al., 2010a).

The association of CSE1L with microtubules is

related with pseudopodia extension and the

migration of cancer cells (Tai et al., 2010b). CSE1L

is also a secretory protein, and it is present is the

sera of cancer patients. The secretion of CSE1L is

related with the invasion of cancer cells (Tung et

al., 2009; Stella Tsai et al., 2010).

Localisation

Nucleus, cytoplasm.

Function

A cell apoptosis susceptibility protein; a

microtubule-associated protein; an export receptor

of importin-a in the nuclear protein import cycle;

involved in tumor cell invasion and metastasis in

cancer progression.

Homology

The yeast chromosome segregation gene CSE1.

CSE1L (CSE1 chromosome segregation 1-like (yeast)) Jiang MC


Implicated in

Breast cancer

Prognosis

Benign breast lesions show weak cytoplasmatic

CSE1L staining, while in ductal and lobular in situ

carcinomas, 70%-90% of breast tumor cells showed

heavy CSE1L staining cytoplasm. Also, in invasive

ductal and lobular carcinomas, 70-90% of the tumor

cells showed heavy CSE1L staining pattern

predominantly in nuclei (Behrens et al., 2001).

Ovarian carcinoma

Prognosis

In serous ovarian carcinoma, moderate to strong

immunostaining of CSE1L was observed in 34 of

41 cases (83%) of serous carcinomas, and CSE1L

immunoreactivity was positively related to the

frequency of apoptotic bodies (p = 0.0170), the

tumor grade (p = 0.0107), and adverse outcomes (p

= 0.0035). CSE1L protein reactivity was present in

100% of 69 ovarian carcinomas, and a significant

reciprocal correlation was observed between high

levels of CSE1L and the histological type, FIGO

(International Federation of Obstetrics and

Gynecology) stage III and grade 3, residual tumors

of > 2 cm, and 20q13.2 (ZNF217 gene)

amplification (> four copies in > 20% cells). A

tissue array study composed of 244 serous ovarian

tumors of different grades (0-3) and stages (I-IV)

showed a higher expression of CSE1L in poorly

compared to highly differentiated invasive ovarian

tumors (Brustmann, 2004; Peiro et al., 2002;

Ouellet et al., 2006).

Melanomas

Prognosis

Analysis of the expression of CSE1L in 27 control

benign and 55 malignant melanocytic lesions

(including 32 primary and 23 metastatic lesions),

and the results showed that only 13 of the 27 benign

melanocytic lesions stained positive for CSE1L.

However, 5 of 7 lentigo maligna melanomas, 11 of

12 superficial spreading melanomas, and all

acrolentiginous (n = 7) and nodular (n = 6)

melanomas showed medium to high intensity

immunoreactivity for CSE1L staining. All

metastatic melanomas (n = 23) showed strong

CSE1L staining. Also, CSE1L detection in clinical

stages according to the International Union Against

Cancer (UICC) showed an increase from 43% ±

34% CSEL-positive cells in stage I, to 53% ± 26%

in stage II, 68% ± 24% in stage III, and 72% ± 24%

in stage IV (Böni et al., 1999).

Lymphomas

Prognosis

In normal lymphoid tissue and malignant

lymphomas, low-grade non-Hodgkin's lymphoma

revealed weak CSE1L staining, with 10% to 60%

of all cells positive. In contrast, highly malignant

non-Hodgkin's lymphoma and malignant cells of

Hodgkin's disease displayed very strong CSE1L

positivity, with staining of up to 80% of atypical

cells (Wellmann et al., 1997).

Endometrial carcinomas

Prognosis

An analysis of 89 endometrial carcinomas and 56

samples of non-neoplastic adjacent endometrium

showed that CSE1L was expressed in 93% of

endometrial carcinomas neoplastic tissues, while

lower levels of CSE1L expression were observed in

the adjacent endometrium compared to the

carcinomas (p = 0.003). Also, CSE1L expression

was higher in grade 3 tumors (p = 0.002) (Peiró et

al., 2001).

Hepatocellular carcinomas

Prognosis

The expression of CSE1L was not detected in

normal hepatocytes, while strong CSE1L

expression was detected in hepatocellular

carcinoma. Study also showed that the

immunohistochemical staining intensity score of

CSE1L was significantly higher in human

hepatocellular carcinoma than in non-tumor tissue

(p < 0.05) (Wellmann et al., 2001; Shiraki et al.,

2006).

Lung cancer

Prognosis

The immunophenotypic profiling of non-small cell

lung cancer progression using tissue microarray

with 59 tissue samples, including 33 primary

tumors without distant metastasis and 26 non-small

cell lung cancer with brain metastases and showed

that elevated expression of CSE1L was

significantly associated with the metastatic

potential of non-small cell lung cancer (Papay et al.,

2007).

Gliomas

Prognosis

The results of array-based comparative genomic

hybridization showed that 57.1% of the

glioblastoma multiforme cases had high-frequency

amplification of the CSE1L gene. Idbaih et al.

investigated a series of 16 low-grade gliomas and

their subsequent progression to higher-grade

malignancies using a one-megabase bacterial

artificial chromosome (BAC)-based array

comparative genomic hybridization technique, and

reported that the CSE1L gene was associated with

the progression of gliomas (Hui et al., 2001; Idbaih

et al., 2008).

Colorectal carcinoma

Prognosis

The expression of CSE1L was also reported to be

higher in the primary and metastatic human

CSE1L (CSE1 chromosome segregation 1-like (yeast)) Jiang MC


colorectal carcinoma compared to the normal colon

mucosa (p < 0.0001). Also, the concentration of

CSE1L in serum is positively correlated with the

stage of colorectal cancer (Stella Tsai et al., 2010;

Seiden-Long et al., 2006).

References Brinkmann U, Brinkmann E, Gallo M, Pastan I. Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10427-31

Brinkmann U, Brinkmann E, Gallo M, Scherf U, Pastan I. Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry. 1996 May 28;35(21):6891-9

Scherf U, Pastan I, Willingham MC, Brinkmann U. The human CAS protein which is homologous to the CSE1 yeast chromosome segregation gene product is associated with microtubules and mitotic spindle. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2670-4

Wellmann A, Krenacs L, Fest T, Scherf U, Pastan I, Raffeld M, Brinkmann U. Localization of the cell proliferation and apoptosis-associated CAS protein in lymphoid neoplasms. Am J Pathol. 1997 Jan;150(1):25-30

Böni R, Wellmann A, Man YG, Hofbauer G, Brinkmann U. Expression of the proliferation and apoptosis-associated CAS protein in benign and malignant cutaneous melanocytic lesions. Am J Dermatopathol. 1999 Apr;21(2):125-8

Brinkmann U, Brinkmann E, Bera TK, Wellmann A, Pastan I. Tissue-specific alternative splicing of the CSE1L/CAS (cellular apoptosis susceptibility) gene. Genomics. 1999 May 15;58(1):41-9

Behrens P, Brinkmann U, Fogt F, Wernert N, Wellmann A. Implication of the proliferation and apoptosis associated CSE1L/CAS gene for breast cancer development. Anticancer Res. 2001 Jul-Aug;21(4A):2413-7

Hui AB, Lo KW, Yin XL, Poon WS, Ng HK. Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. Lab Invest. 2001 May;81(5):717-23

Peiró G, Diebold J, Baretton GB, Kimmig R, Löhrs U. Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome. Int J Gynecol Pathol. 2001 Oct;20(4):359-67

Wellmann A, Flemming P, Behrens P, Wuppermann K, Lang H, Oldhafer K, Pastan I, Brinkmann U. High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: correlation with tumor progression. Int J Mol Med. 2001 May;7(5):489-94

Lindsay ME, Plafker K, Smith AE, Clurman BE, Macara IG. Npap60/Nup50 is a tri-stable switch that stimulates importin-alpha:beta-mediated nuclear protein import. Cell. 2002 Aug 9;110(3):349-60

Peiró G, Diebold J, Löhrs U. CAS (cellular apoptosis susceptibility) gene expression in ovarian carcinoma: Correlation with 20q13.2 copy number and cyclin D1, p53, and Rb protein expression. Am J Clin Pathol. 2002 Dec;118(6):922-9

Brustmann H. Expression of cellular apoptosis susceptibility protein in serous ovarian carcinoma: a clinicopathologic and immunohistochemical study. Gynecol Oncol. 2004 Jan;92(1):268-76

Ouellet V, Guyot MC, Le Page C, Filali-Mouhim A, Lussier C, Tonin PN, Provencher DM, Mes-Masson AM. Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer. 2006 Aug 1;119(3):599-607

Seiden-Long IM, Brown KR, Shih W, Wigle DA, Radulovich N, Jurisica I, Tsao MS. Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. Oncogene. 2006 Jan 5;25(1):91-102

Shiraki K, Fujikawa K, Sugimoto K, Ito T, Yamanaka T, Suzuki M, Yoneda K, Sugimoto K, Takase K, Nakano T. Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma. Int J Mol Med. 2006 Jul;18(1):77-81

Papay J, Krenacs T, Moldvay J, Stelkovics E, Furak J, Molnar B, Kopper L. Immunophenotypic profiling of nonsmall cell lung cancer progression using the tissue microarray approach. Appl Immunohistochem Mol Morphol. 2007 Mar;15(1):19-30

Idbaih A, Carvalho Silva R, Crinière E, Marie Y, Carpentier C, Boisselier B, Taillibert S, Rousseau A, Mokhtari K, Ducray F, Thillet J, Sanson M, Hoang-Xuan K, Delattre JY. Genomic changes in progression of low-grade gliomas. J Neurooncol. 2008 Nov;90(2):133-40

Liao CF, Luo SF, Li LT, Lin CY, Chen YC, Jiang MC. CSE1L/CAS, the cellular apoptosis susceptibility protein, enhances invasion and metastasis but not proliferation of cancer cells. J Exp Clin Cancer Res. 2008 Jul 3;27:15

Tung MC, Tsai CS, Tung JN, Tsao TY, Chen HC, Yeh KT, Liao CF, Jiang MC. Higher prevalence of secretory CSE1L/CAS in sera of patients with metastatic cancer. Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1570-7

Tsao TY, Tsai CS, Tung JN, Chen SL, Yue CH, Liao CF, Wang CC, Jiang MC. Function of CSE1L/CAS in the secretion of HT-29 human colorectal cells and its expression in human colon. Mol Cell Biochem. 2009 Jul;327(1-2):163-70

Stella Tsai CS, Chen HC, Tung JN, Tsou SS, Tsao TY, Liao CF, Chen YC, Yeh CY, Yeh KT, Jiang MC. Serum cellular apoptosis susceptibility protein is a potential prognostic marker for metastatic colorectal cancer. Am J Pathol. 2010 Apr;176(4):1619-28

Tai CJ, Hsu CH, Shen SC, Lee WR, Jiang MC. Cellular apoptosis susceptibility (CSE1L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. J Exp Clin Cancer Res. 2010a Aug 11;29:110

Tai CJ, Shen SC, Lee WR, Liao CF, Deng WP, Chiou HY, Hsieh CI, Tung JN, Chen CS, Chiou JF, Li LT, Lin CY, Hsu CH, Jiang MC. Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells. Exp Cell Res. 2010b Oct 15;316(17):2969-81


Jiang MC. CSE1L (CSE1 chromosome segregation 1-like (yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):41-43.





DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Zhi-Ren Liu

Departments of Biology, Georgia State University, Atlanta, GA 30303, USA (ZRL)


Online updated version : http://AtlasGeneticsOncology.org/Genes/DDX5ID40290ch17q23.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DDX5ID40290ch17q23.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: DKFZp434E109,

DKFZp686J01190, G17P1, HLR1, HUMP68, p68

HGNC (Hugo): DDX5

Location: 17q23.3

Note

DDX5/p68 RNA helicase is a member of DEAD

box RNA helicases. As an example of a cellular

RNA helicase, the ATPase and the RNA unwinding

activities of p68 RNA helicase were documented

with the protein that was purified from human 293

cells (Iggo and Lane, 1989; Ford et al.,1988;

Hirling et al., 1989) and recombinant protein

expressed in E. coli (Huang and Liu, 2002). The

gene is expressed in all dividing cells of different

vertebrates (Lane and Hoeffler, 1980; Stevenson et

al., 1998). p68 RNA helicase is involved in

multiple cellular processes, including gene

transcription (Endoh et al., 1999; Rossow and

Janknecht, 2003), pre-mRNA processing (Liu,

2002; Yang et al., 2006), pre-rRNA processing

(Jalal et al., 2007), pre-miRNA processing (Fukuda

et al., 2007), DNA methylation and de-methylation

(Jost et al., 1999), and chromatin remodeling

(Carter et al., 2010). A number of different post-

translational modifications of p68 are reported,

including phosphorylations, sumoylation, and

ubiquitylation (Causevic et al., 2001; Yang et al.,

2005; Jacobs et al., 2007).

DNA/RNA

Note

DDX5/p68 RNA helicase is expressed in dividing

cells of different vertebrates. Transcription of p68

RNA helicase gene generates a single mRNA

precusor with 13 exons and 12 introns. Alternative

splicing produces two mRNA transcripts, 2.3 kb

and 4.4 kb (Rössler et al., 2000). The 2.3 kb mRNA

transcript codes full length p68, while no

translational product from the 4.4 kb mRNA

transcript is detected in cellular and tissue extracts

(Rössler et al., 2000).

Diagram of pre-mRNA of p68 RNA helicase. The red bars are exons and the blue thin lines are introns.

DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Liu ZR


Domain structure of p68 RNA helicase. Functional sequence motifs are marked.

Protein

Description

Size of p68; 614 amino acids, 69 kDa.

Expression

Expressed in almost all tissue types. Its expression

is increased in cancer cells.

Localisation

Dominately localized in the cell nucleus. It is also

found in the cytoplasm in various physiological

conditions. p68 is a nucleocytoplasm shuttling

protein (Wang et al., 2009).

Function

Pre-mRNA splicing.The protein was demonstrated

to associate with spliceosome by mass-

spectroscopy and an RNA-protein crosslinking

analyses (Hartmuth et al., 2002; Liu et al., 1997;

Neubauer et al., 1998). p68 is functionally involved

in assemble of the splicesome by mediating the U1

snRNP and the 5'ss interaction (Liu, 2002). p68

RNA helicase is also shown to regulate the splice

site selection in the alternative splicing of several

growth related genes, such as c-H-ras and tau (Kar

et al., 2011; Guil et al., 2003).

Transcriptional regulation.The protein is shown

to involve in transcriptional regulation by different

mechanism of actions dependent on each individual

regulated gene and biological processes (Stevenson

et al., 1998; Endoh et al., 1999; Yang et al., 2005;

Kahlina et al., 2004; Wei and Hu, 2001; Warner et

al., 2004). p68 may regulate gene transcription by

direct interaction with transcription factors or

activators, such as p53, ERalpha (Endoh et al.,

1999; Bates et al., 2005), or by mediating

chromatin remodeling, such as modulating

chromatin remodeling complex (Carter et al., 2010).

Epithelial-Mesenchymal-Transition (EMT).p68

becomes phosphorylated at Y593 upon growth

factor stimulation by c-Abl. The tyrosine

phosphorylation of p68 mediates growth factor

stimulated Epithelial-Mesenchymal-Transition

(EMT) (Yang et al., 2006).

Other functions. (1) p68 RNA helicase is shown to

unwind the human let-7 microRNA precursor

duplex. The protein is required for let-7-directed

silencing of gene expression (Salzman et al., 2007).

p68 is an indispensible part of Drosha complex. Its

activity is required for primary miRNA and rRNA

processing (Fukuda et al., 2007). (2) It is also

demonstrated that the RNA helicases p68/p72 and

the noncoding RNA SRA are coregulators of MyoD

and skeletal muscle differentiation (Caretti et al.,

2006). (3) Phosphorylation of p68 at Thr residues

mediates cell apoptosis (Yang et al., 2007).

Homology

Yeast DBP2.

Mutations

Note

Very few mutations of p68 gene were reported. A

recent study shows that a S480A mutation in

hepatic stellate cells is associated with hepatic

fibrosis (Guo et al., 2010).

Implicated in

Colon cancer

Note

p68 expression is significantly increased in colon

cancer (Shin et al., 2007). Phosphorylation of p68

at Tyr correlation with colon cancer metastasis

(Yang et al., 2006; Yang et al., 2005).

Prognosis

Phosphorylation of p68 at tyrosine can be used as a

diagnosis/prognosis marker for cancer.

References Lane DP, Hoeffler WK. SV40 large T shares an antigenic determinant with a cellular protein of molecular weight 68,000. Nature. 1980 Nov 13;288(5787):167-70

Ford MJ, Anton IA, Lane DP. Nuclear protein with sequence homology to translation initiation factor eIF-4A. Nature. 1988 Apr 21;332(6166):736-8

Hirling H, Scheffner M, Restle T, Stahl H. RNA helicase activity associated with the human p68 protein. Nature. 1989 Jun 15;339(6225):562-4

Iggo RD, Lane DP. Nuclear protein p68 is an RNA-dependent ATPase. EMBO J. 1989 Jun;8(6):1827-31

Liu ZR, Laggerbauer B, Lührmann R, Smith CW. Crosslinking of the U5 snRNP-specific 116-kDa protein to

DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Liu ZR


RNA hairpins that block step 2 of splicing. RNA. 1997 Nov;3(11):1207-19

Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M. Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex. Nat Genet. 1998 Sep;20(1):46-50

Stevenson RJ, Hamilton SJ, MacCallum DE, Hall PA, Fuller-Pace FV. Expression of the 'dead box' RNA helicase p68 is developmentally and growth regulated and correlates with organ differentiation/maturation in the fetus. J Pathol. 1998 Apr;184(4):351-9

Endoh H, Maruyama K, Masuhiro Y, Kobayashi Y, Goto M, Tai H, Yanagisawa J, Metzger D, Hashimoto S, Kato S. Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. Mol Cell Biol. 1999 Aug;19(8):5363-72

Jost JP, Schwarz S, Hess D, Angliker H, Fuller-Pace FV, Stahl H, Thiry S, Siegmann M. A chicken embryo protein related to the mammalian DEAD box protein p68 is tightly associated with the highly purified protein-RNA complex of 5-MeC-DNA glycosylase. Nucleic Acids Res. 1999 Aug 15;27(16):3245-52

Rössler OG, Hloch P, Schütz N, Weitzenegger T, Stahl H. Structure and expression of the human p68 RNA helicase gene. Nucleic Acids Res. 2000 Feb 15;28(4):932-9

Causevic M, Hislop RG, Kernohan NM, Carey FA, Kay RA, Steele RJ, Fuller-Pace FV. Overexpression and poly-ubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumours. Oncogene. 2001 Nov 22;20(53):7734-43

Wei Y, Hu MH. [The study of P68 RNA helicase on cell transformation]. Yi Chuan Xue Bao. 2001 Nov;28(11):991-6

Hartmuth K, Urlaub H, Vornlocher HP, Will CL, Gentzel M, Wilm M, Lührmann R. Protein composition of human prespliceosomes isolated by a tobramycin affinity-selection method. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16719-24

Huang Y, Liu ZR. The ATPase, RNA unwinding, and RNA binding activities of recombinant p68 RNA helicase. J Biol Chem. 2002 Apr 12;277(15):12810-5

Liu ZR. p68 RNA helicase is an essential human splicing factor that acts at the U1 snRNA-5' splice site duplex. Mol Cell Biol. 2002 Aug;22(15):5443-50

Guil S, Gattoni R, Carrascal M, Abián J, Stévenin J, Bach-Elias M. Roles of hnRNP A1, SR proteins, and p68 helicase in c-H-ras alternative splicing regulation. Mol Cell Biol. 2003 Apr;23(8):2927-41

Rossow KL, Janknecht R. Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300. Oncogene. 2003 Jan 9;22(1):151-6

Kahlina K, Goren I, Pfeilschifter J, Frank S. p68 DEAD box RNA helicase expression in keratinocytes. Regulation, nucleolar localization, and functional connection to proliferation and vascular endothelial growth factor gene expression. J Biol Chem. 2004 Oct 22;279(43):44872-82

Warner DR, Bhattacherjee V, Yin X, Singh S, Mukhopadhyay P, Pisano MM, Greene RM. Functional interaction between Smad, CREB binding protein, and p68 RNA helicase. Biochem Biophys Res Commun. 2004 Nov 5;324(1):70-6

Bates GJ, Nicol SM, Wilson BJ, Jacobs AM, Bourdon JC, Wardrop J, Gregory DJ, Lane DP, Perkins ND, Fuller-Pace FV. The DEAD box protein p68: a novel transcriptional

coactivator of the p53 tumour suppressor. EMBO J. 2005 Feb 9;24(3):543-53

Yang L, Lin C, Liu ZR. Phosphorylations of DEAD box p68 RNA helicase are associated with cancer development and cell proliferation. Mol Cancer Res. 2005 Jun;3(6):355-63

Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P, Ogryzko V, Fuller-Pace FV, Hoffman EP, Tapscott SJ, Sartorelli V. The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. Dev Cell. 2006 Oct;11(4):547-60

Yang L, Lin C, Liu ZR. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 2006 Oct 6;127(1):139-55

Fukuda T, Yamagata K, Fujiyama S, Matsumoto T, Koshida I, Yoshimura K, Mihara M, Naitou M, Endoh H, Nakamura T, Akimoto C, Yamamoto Y, Katagiri T, Foulds C, Takezawa S, Kitagawa H, Takeyama K, O'Malley BW, Kato S. DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat Cell Biol. 2007 May;9(5):604-11

Jacobs AM, Nicol SM, Hislop RG, Jaffray EG, Hay RT, Fuller-Pace FV.. SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1. Oncogene. 2007 Aug 30;26(40):5866-76. Epub 2007 Mar 19.

Jalal C, Uhlmann-Schiffler H, Stahl H.. Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation. Nucleic Acids Res. 2007;35(11):3590-601. Epub 2007 May 7.

Salzman DW, Shubert-Coleman J, Furneaux H.. P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression. J Biol Chem. 2007 Nov 9;282(45):32773-9. Epub 2007 Aug 27.

Shin S, Rossow KL, Grande JP, Janknecht R.. Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res. 2007 Aug 15;67(16):7572-8.

Yang L, Lin C, Sun SY, Zhao S, Liu ZR.. A double tyrosine phosphorylation of P68 RNA helicase confers resistance to TRAIL-induced apoptosis. Oncogene. 2007 Sep 6;26(41):6082-92. Epub 2007 Mar 26.

Wang H, Gao X, Huang Y, Yang J, Liu ZR.. P68 RNA helicase is a nucleocytoplasmic shuttling protein. Cell Res. 2009 Dec;19(12):1388-400. Epub 2009 Sep 29.

Carter CL, Lin C, Liu CY, Yang L, Liu ZR.. Phosphorylated p68 RNA helicase activates Snail1 transcription by promoting HDAC1 dissociation from the Snail1 promoter. Oncogene. 2010 Sep 30;29(39):5427-36. Epub 2010 Aug 2.

Guo J, Hong F, Loke J, Yea S, Lim CL, Lee U, Mann DA, Walsh MJ, Sninsky JJ, Friedman SL.. A DDX5 S480A polymorphism is associated with increased transcription of fibrogenic genes in hepatic stellate cells. J Biol Chem. 2010 Feb 19;285(8):5428-37. Epub 2009 Dec 17.

Kar A, Fushimi K, Zhou X, Ray P, Shi C, Chen X, Liu Z, Chen S, Wu JY.. RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5' splice site. Mol Cell Biol. 2011 May;31(9):1812-21. Epub 2011 Feb 22.


Liu ZR. DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):44-46.

Leukaemia Section Short Communication




t(13;19)(q14;p13) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,

France (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1319q14p13ID1512.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t1319q14p13ID1512.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology

Disease

B cell acute lymphoblastic leukemia (B-ALL)

Note

An apparently identical t(13;19)(q14;p13) has been

described in 3 cases of chronic lymphocytic

leukemia (CLL) (Finn et al., 1998; Merup et al.,

1998; Brown et al., 1993).

Epidemiology

Only one case to date of ALL with this

translocation, a 19-year-old female patient with pre-

B-ALL; she achieved complete remission and (CR)

was in continuing CR 10 months later, at last follow

up (Barber et al., 2007).

Genes involved and proteins

Note

The translocation involves TCF3 and an unknown

partner.

TCF3

Location

19p13.3

Protein

The E2A gene encodes two distinct basic helix-

loop-helix transcription factors, E12 (ITF1) and

E47 (TCF3) through alternative splicing. It forms

homodimers and heterodimers with other basic

helix-loop-helix transcription factors. Ubiquitously

expressed during development. Role in cell growth,

cell commitment, and differentiation. Role in

epithelial mesenchymal transition (review in

Slattery et al., 2008).

References Brown AG, Ross FM, Dunne EM, Steel CM, Weir-Thompson EM. Evidence for a new tumour suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene. Nat Genet. 1993 Jan;3(1):67-72

Finn WG, Kay NE, Kroft SH, Church S, Peterson LC. Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients. Am J Hematol. 1998 Nov;59(3):223-9

Inukai T, Inaba T, Ikushima S, Look AT. The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Mol Cell Biol. 1998 Oct;18(10):6035-43

Merup M, Jansson M, Corcoran M, Liu Y, Wu X, Rasool O, Stellan B, Hermansson M, Juliusson G, Gahrton G, Einhorn S. A FISH cosmid 'cocktail' for detection of 13q deletions in chronic lymphocytic leukaemia--comparison with cytogenetics and Southern hybridization. Leukemia. 1998 May;12(5):705-9

Barber KE, Harrison CJ, Broadfield ZJ, Stewart AR, Wright SL, Martineau M, Strefford JC, Moorman AV. Molecular cytogenetic characterization of TCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2007 May;46(5):478-86

Slattery C, Ryan MP, McMorrow T. E2A proteins: regulators of cell phenotype in normal physiology and disease. Int J Biochem Cell Biol. 2008;40(8):1431-6


Huret JL. t(13;19)(q14;p13). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):47.

Leukaemia Section Short Communication




t(17;17)(q21;q24), del(17)(q21q24) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,

France (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1717q21q24ID1497.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t1717q21q24ID1497.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology

Disease

Acute myeloid leukaemia, M3 subtype (M3-AML)

Epidemiology

Only one case to date, a 66-year-old male patient

(Catalano et al., 2007).

Cytology

Auer rods and fagot cells were absent.

Evolution

Complete remission was obtained with ATRA, and

the patient remains healthy 2 years after the

diagnosis.

Cytogenetics

Cytogenetics morphological

Cryptic deletion, FISH studies are needed to

uncover the rearrangement.

Genes involved and proteins

RARA

Location

17q21.1

Protein

Contains Zn fingers and a ligand binding region.

Receptor for retinoic acid. Forms heterodimers with

RXR. At the DNA level, binds to retinoic acid

response elements (RARE). Ligand-dependent

transcription factor specifically involved in

hematopoietic cells differentiation and maturation.

PRKAR1A

Location

17q24.2

Protein

Contains two tandem cAMP-binding domains.

Forms heterotetramers with PRKACA (protein

kinase, cAMP-dependent, catalytic, alpha), also

called PKA. Interacts with RARA, and regulates

RARA transcriptional activity.

Result of the chromosomal anomaly

Hybrid gene

Description

5' PRKAR1A - 3' RARA. When we look closely to

the DNA sequences at the fusion breakpoints, they

correspond to the very end of exon 1 in PRKAR1A

(AGAGGTTGGAGAAG) and the very begining of

exon 2 in RARA

(ATTGAGACCCAGAGCAGCAGT, see

sequences in Ensembl), although they were

described in exon 2 and exon 3 in the first and only

report of this rearrangement (Catalano et al., 2007).

Fusion protein

See figure 5' PRKAR1A - 3' RARA.

t(17;17)(q21;q24), del(17)(q21q24) Huret JL


Description

The fusion protein contains the dimerization

domain from PRKAR1A fused to the Zn fingers

and ligand binding regions from RARA.

References Solberg R, Sandberg M, Natarajan V, Torjesen PA, Hansson V, Jahnsen T, Taskén K. The human gene for the regulatory subunit RI alpha of cyclic adenosine 3', 5'-monophosphate-dependent protein kinase: two distinct promoters provide differential regulation of alternately

spliced messenger ribonucleic acids. Endocrinology. 1997 Jan;138(1):169-81

Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, Iland H. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood. 2007 Dec 1;110(12):4073-6


Huret JL. t(17;17)(q21;q24), del(17)(q21q24). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):48-49.

Deep Insight Section




MicroRNAs and Cancer Federica Calore, Muller Fabbri

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University,

Columbus, OH 43210, USA (FC, MF)


Online updated version : http://AtlasGeneticsOncology.org/Deep/MicroRNAandCancerID20101.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI MicroRNAandCancerID20101.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Keywords: microRNAs, non-coding RNAs, cancer, solid tumors, hematological malignancies, oncogene, tumor

suppressor gene, angiogenesis, metastasis, therapy, biomarkers.

Abstract MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with gene expression regulatory functions, whose de-

regulation has been documented in almost all types of human cancer (both solid and hematological

malignancies), with respect to the non-tumoral tissue counterpart. After the initial discovery that the miRNome

(defined as the full spectrum of miRNAs expressed in a specific genome) is de-regulated in cancer, contributes

to human carcinogenesis, and to the mechanisms of angiogenesis and metastases (which are hallmarks of the

malignant phenotype), new pieces of evidence have been provided that miRNAs can be detected in several

human body fluids, and can also be successfully used as tumor biomarkers with diagnostic, prognostic and

theranostic implications. These findings have cast a new “translational” light on the research in the miRNA field,

providing the rationale for a miRNA-based cancer therapy.

Introduction Tumor formation and progression is a complex

multistep process characterized by several

consecutive events: accumulation of genomic

alterations, uncontrolled proliferation, angiogenesis,

invasion and metastasis. Over the past few years an

increasing number of studies have highlighted the

key role that microRNAs have in the regulation of

processes described above.

MicroRNAs (miRNAs) are a family of single-

stranded non-coding RNAs (ncRNAs) between 19-

24 nucleotides in length that regulate the expression

of target mRNAs both at transcriptional and

translational level. In plants such regulation occurs

by perfect base-pairing, usually in the 3'

untranslated region (UTR) of the targeted mRNA,

whereas in mammals the base-pairing is only partial

(Lagos-Quintana et al., 2001; Lee and Ambros,

2001; Hu et al., 2010).

Evolutionarily conserved among distantly related

organisms (Ambros, 2003), miRNA genes represent

approximately 1% of the predicted genes in the

genome of different species. It has been

demonstrated that each miRNA can have hundreds

of different targets and that approximately 30% of

the genes are regulated by at least one miRNA

(Bartel, 2004). MiRNAs are known to be involved

in several biological processes such as cell cycle

regulation, proliferation, apoptosis, differentiation,

development, metabolism, neuronal patterning and

aging (Bartel, 2004; Bagga et al., 2005; Harfe,

2005; Boehm and Slack, 2006; Calin et al., 2006;

Arisawa et al., 2007; Carleton et al., 2007).

The biogenesis of miRNAs starts in the nucleus

(Figure 1), where for the most part an RNA

polymerase II transcribes long primary precursors,

up to several kilobases (pri-miRNAs) (Ambros and

Lee, 2004). Such transcription occurs at the level of

genomic regions located within the introns or exons

of protein-coding genes (70%) or in intergenic areas

(30%) (de Yebenes and Ramiro, 2010).

Long, capped and polyadenylated pri-miRNAs (Cai

et al., 2004) are then processed by a ribonuclease III

(Drosha) and by the double-stranded DNA binding

protein DGCR8/Pasha, which enzymatically cut

MicroRNAs and Cancer Calore F, Fabbri M


Figure 1. MiRNA biogenesis. MiRNA biogenesis begins inside the nucleus, then its processing and maturation take place in the cytoplasm of an eukaryotic cell. MiRNAs are transcribed by RNA polymerase II as long primary transcript (pri-miRNAs)

characterized by hairpin structure and then cleaved by the enzyme Drosha in smaller molecules of nearly 70-nucleotides (pre-miRNAs). These precursors are then exported to the cytoplasm by the Exportin 5/Ran-GTP complex and further processed by

RNAse III Dicer, which generates double-stranded-RNAs called duplex miRNA/miRNA* of 22-24 nucleotides. The strand corresponding to the mature miRNA is incorporated into a large protein complex named RISC (RNA-induced silencing complex)

and they interact with the 3’ UTR of the targeted messenger RNA: if the complementarity between miRNA and the 3’UTR is perfect the latter is cleaved by RISC, whereas if the matching is imperfect then translational repression occurs.

them into smaller fragments of 70-100 nucleotides

(pre-miRNAs) (Ambros, 2004). Precursor

molecules are then exported to the cytoplasm by

Exportin 5 in a Ran-GTP-dependent manner

(Allawi et al., 2004; Bohnsack et al., 2004) and

through an additional step mediated by the RNAse

III Dicer 22 nucleotides double-strand RNAs are

generated (Bartel, 2004; Esquela-Kerscher et al.,

2005). The duplex miR/miR* are finally

incorporated into a large protein complex named

RISC (RNA-induced silencing complex): the strand

of the duplex which represents the mature miRNA

remains stably associated with RISC and drives the

complex to the target mRNA. If the base-pairing

between miRNA and the 3' UTR of the target

mRNA is perfect, the messenger is cleaved and

degraded (as it occurs in plants), if the

complementarity pairing is partial, translational

silencing occurs without mRNA degradation

(mechanism described in animals) (Achard et al.,

2004; Gregory et al., 2006) (Figure 1).

The involvement of miRNAs in cancer arises from

the observation that these small molecules are

differentially expressed in neoplastic tissues in a

tumor-specific manner when compared to normal

tissues (Volinia et al., 2006), and in primary tumors

when compared to metastatic tissues (Tavazoie et

al., 2008).

Moreover the genomic localization of miRNAs

often corresponds to tumor-associated regions,

characterized by chromosomal translocations,

genomic amplifications, fragile sites, breakpoint

regions in proximity to oncogenes (OGs) or tumor

suppressor genes (TSGs) (Calin et al., 2004). In

2002 Calin et al. showed that miR-15a and miR-16-

1 genes are located at a chromosomic region

(13q14) deleted in more than half of B cell chronic

lymphocytic leukemias (B-CLL) and that both

genes are deleted or down-regulated in the majority

of CLL cases (68%) (Calin et al., 2002). Based on

the miRNA profiling analysis the following studies

aimed at investigating the functional role of these

molecules in tumorigenesis by using various

approaches, which have shed light on a more

complex role of miRNAs in cancer development:

depending on the context they can act as OGs or

TSGs, and some of them can even have a dual role

of OG/TSG (Calin et al., 2007) (Table 1).

http://atlasgeneticsoncology.org/Anomalies/CLL.html

http://atlasgeneticsoncology.org/Anomalies/CLL.html



microRNA Dysregulation in cancer miRNA

target Function Reference(s)

miR-155

Upregulated in Burkitt's lymphoma,

Hodgkin disease, primary

mediastinal non Hodgkin's

lymphoma, CLL, AML, lung, breast,

pancreatic cancer

c-maf Oncogene Metzler, Kluiver, Calin,

Garzon, Volinia, Greither

miR-21

Upregulated in glioblastoma, CLL,

AML, prostate, pancreatic, gastric,

colon, breast, lung, liver cancer

PTEN,

PCDC4,

TPM1

Oncogene

Meng, Frankel, Zhu,

Ciafre, Calin, Garzon,

Volinia, Meng

miR-17-92

cluster

Upregulated in breast, colon, lung,

pancreatic, prostate, gastric cancers,

lymphomas

PTEN,

Bim Oncogene Volinia, Venturini

miR-372/373 Upregulated in testicular tumor LATS2 Oncogene Voorhoeve

miR-221/222

Upregulated in thyroid, prostate,

glioblastoma, colon, pancreas,

stomach

P27Kip1 Oncogene Visone, Galardi, le Sage

miR-10b Upregulated in breast cancer HOXD10 Oncogene Ma

miR-15a and

miR-16-1 Downregulated in CLL, prostate

BCL2,

CCND1,

WNT3A

Tumor-

suppressor gene Bullrich, Cimmino, Bonci

miR-29 family

Downregulated in lung cancer, CLL,

AML, breast cancer and

cholangiocarcinoma

TCL1,

MCL1,

DNMT3s

Tumor-

suppressor gene

Calin, Iorio, Garzon, Mott,

Fabbri, Pekarsky

Let-7 family Downregulated in lung and breast

cancer

C-MYC,

HMGA2,

MYCN

Tumor-

suppressor

gene/oncogene

Johnson Sampson, Lee,

Buechner, Brueckner,

Iorio

miR-34 family Downregulated in lung and

pancreatic cancer

BCL2,

MYCN

Tumor-

suppressor gene Gallardo, Cole

miR-143 and -

145 cluster Downregulated in colorectal cancer

ERK5,

C-MYC

Tumor-

suppressor gene Michael, Akao, Ibrahim

Table 1. The main de-regulated miRNAs in cancer. Legend: CLL= chronic lymphocytic leukemia; AML= acute myeloid leukemia.

miRNAs as oncogenes Profiling studies have revealed that several

miRNAs show oncogenic properties. One of the

first oncomiR identified was miR-155 (Metzler et

al., 2004; Kluiver et al., 2005). It is located on

chromosome 21 in a host non-coding RNA called

the B cell integration cluster (BIC) and is highly

expressed in pediatric Burkitt's lymphoma (Metzler

et al., 2004), Hodgkin disease (Kluiver et al., 2005),

primary mediastinal non-Hodgkin's lymphoma

(Calin et al., 2005) , chronic lymphocytic leukemia

(CLL) (Kluiver et al., 2005), acute myelogenous

leukemia (AML) (Calin et al., 2008), lung, breast

and pancreatic cancer (Volinia et al., 2006; Greither

et al., 2010). A study conducted by Costinean et al.

showed that transgenic mice with a B-cell targeted

overexpression of miR-155 develop a

lymphoproliferative disease (polyclonal pre-

leukemic pre-B-cell proliferation followed by full-

blown B-cell malignancy) resembling the human

diseases, indicating that the deregulation mediated

by miR-155 involves both the initiation and

progression of the disease (Costinean et al., 2006).

Moreover the use of miR-155 knock out mouse

model has revealed that miR-155 is strongly

implicated into the induction of Th2 lymphocyte

differentiation and altered cytokine production (de

Yebenes and Ramiro, 2010).

Another miRNA which displays an oncogenic role

is miR-21. Chan et al. demonstrated that

knockdown of miR-21 in multiple glioblastoma

cells induced caspase activation and apoptosis,

indicating that miR-21 could function as an

oncogene by blocking expression of critical

apoptosis-related genes (Abdellatif, 2010). In fact

miR-21 targets TSGs such as PTEN (phosphatase

and tensin homolog) (Choong et al., 2007), PDCD4

(programmed cell death 4) (Dillhoff et al., 2008)

and TPM1 (tropomyosin 1) (Beitzinger et al.,

2007). Similarly to miR-155 it is expressed in a

wide range of tumors such as glioblastoma (Ciafre

et al., 2005), CLL (Calin et al., 2005), AML (Calin

http://atlasgeneticsoncology.org/Anomalies/BurkittID2077.html

http://atlasgeneticsoncology.org/Anomalies/HodgkinID2068.html

http://atlasgeneticsoncology.org/Anomalies/ClassifAMLID1238.html

http://atlasgeneticsoncology.org/Anomalies/ClassifAMLID1238.html

http://atlasgeneticsoncology.org/Genes/MIRN21ID44019ch17q23.html

http://atlasgeneticsoncology.org/Genes/PTENID158.html

http://atlasgeneticsoncology.org/Genes/PDCD4ID41675ch10q24.html



et al., 2008), prostate, pancreatic, gastric, colon,

breast, lung (Costinean et al., 2006) and liver cancer

(Choong et al., 2007).

The miR-17-92 cluster is characterized by six

miRNAs (miR-17, miR-18a, miR-19a, miR-20a,

miR-19b-1 and miR-92-1) highly expressed in

breast, colon, lung, pancreatic, prostate and gastic

cancer, lymphomas (Costinean et al., 2006; Nagel

et al., 2007). It has been demonstrated that the miR-

17-92 cluster induces B cell proliferation.

Moreover, transgenic mice overexpressing miR-17-

92 in lymphocytes developed lymphoproliferative

disease and autoimmunity through the inhibition of

tumor suppressor Pten and the pro-apoptotic protein

Bim (de Yebenes and Ramiro, 2010).

Other miRNAs that have an oncogenic role are

miR-372/373, which are involved in the

development of human testicular germ cell tumors

by neutralizing the TP53 pathway (Voorhoeve et

al., 2006), miR-221/222 which induce proliferation

of thyroid (Iorio et al., 2007), prostate (Galardi et

al., 2007) and glioblastoma (Bai et al., 2007), miR-

10b which promotes cell migration and invasion in

breast cancer (Derby et al., 2007).

miRNAs as tumor suppressor genes If several miRNAs are known for their pro-

oncogenic role, then other miRNAs represent their

counterpart by acting as a TSG. Their silencing due

to mutations, chromosomal rearrangements or to

promoter methylation (Calin et al., 2002; Calin et

al., 2005; Ishii and Saito, 2006; Arisawa et al.,

2007) contributes to the initiation and progression

of cancer.

MiR-15a and miR-16-1 represent a typical example

of TSG miRNA. Encoded as a cluster at the level of

chromosome 13q14.3, a region frequently deleted

in chronic lymphocytic leukemia (CLL) (Bullrich et

al., 2001), miR-15a and -16 display expression

levels inversely correlated to the BCL2 ones. These

miRNAs in fact induce apoptosis in leukemic cells

by directly targeting the anti-apoptotic gene (Calin

et al., 2005). Moreover, it has been demonstrated

that miR-15a and -16 exert a tumor-suppressor role

also in prostate cancer by targeting BCL2, CCND1

(cyclin D1) and WNT3A (encoding a protein which

promotes cell survival, proliferation and invasion)

(Bonci et al., 2008). Taken together, these findings

harbor therapeutic implications and bring new

insights to the comprehension and treatment of

cancer.

Chromosome 7q32 hosts the miR-29 family

(comprising miR-29a, -29b and -29c), which is

downregulated in lung cancer, CLL, AML, breast

cancer and cholangiocarcinoma (Calin et al., 2005;

Mott et al., 2007; Calin et al., 2008). It has been

demonstrated that in lung cancer the expression of

miR-29 family members is inversely correlated

with DNMT3A and -3B (DNA methyltransferases

3A and 3B) and that these miRNAs directly target

these enzymes, inducing global hypomethyation of

tumoral cells (Calin et al., 2007) and reactivation of

methylation-silenced TSGs such as WWOX, FHIT,

MCL1 and TCL1 (Costinean et al., 2006; Mott et

al., 2007).

Among the tumor suppressor miRNAs there is the

let-7 family. Johnson et al. demonstrated an inverse

correlation between the expression of the let-7

family members and the expression of the oncogene

RAS in lung cancer tissue (Adai et al., 2005). Let-7

family targets as well other onco-genes such as C-

MYC (Sampson et al., 2007), HMGA2 (high

mobility group A2) (Barakat et al., 2007) and

MYCN (Buechner et al., 2011). However, not all

the members of this family display a tumor

suppressor role since in lung adenocarcinoma let-

7a-3 has an oncogenic function and promotes tumor

cell proliferation (Brueckner et al., 2007).

The miR-34 family (comprising miR-34a, -34b and

-34c) is downregulated in lung cancer tumor cells

with respect to normal tissue and their re-

expression in pancreatic cancer cell lines inhibits

cell growth and invasion, and induces apoptosis and

cell cycle arrest in G1 and G2/M (Gallardo et al.,

2009). Similarly to the tumor suppressor miRNAs

described above, the miR-34 family exerts its

function by targeting anti apoptotic mRNAs such as

BLC2 and MYCN (Camps et al., 2008).

The list of miRNAs having a tumor suppressor

function ends with the cluster miR-143 and -145.

These miRNAs, downregulated in several tumors

(Akao et al., 2007; Banaudha et al., 2011), have

been found to target ERK5 (extracellular signal-

regulated kinase 5) and c-MYC with consequent

inhibition of tumor proliferation and increased

apoptosis (Akao et al., 2007; Ibrahim et al., 2011).

miRNAs in solid tumors

Lung cancer Lung cancer is the leading cause of cancer death

around the world (Jemal et al., 2009). Gao et al.

performed miRNA microarray expression profiling

in order to compare miRNAs expression in primary

squamous cell lung carcinoma with normal cells

and determine miRNA potential relevance to

clinicopathological factors and patient

postoperative survival times. They found out that

miR-21 was upregulated in nearly 75% of cancer

specimens and that this modulation was

significantly correlated with shortened survival

time (Cheng et al., 2011).

Yanaihara and co-workers used the same approach

and correlated miRNA expression profiles with

survival of lung cancer, finding out that high miR-

155 and low let-7a-2 expression were correlated

with poor survival. Furthermore, they found a

molecular signature for subset of lung cancer: they

identified six miRNAs having a differential

expression in adenocarcinoma and squamous cell

http://atlasgeneticsoncology.org/Tumors/GastricTumOverviewID5410.html

http://atlasgeneticsoncology.org/Tumors/LiverOverviewID5273.html

http://atlasgeneticsoncology.org/Genes/BCL2L11ID772ch2q13.html

http://atlasgeneticsoncology.org/Genes/P53ID88.html

http://atlasgeneticsoncology.org/Genes/MIRN221ID44277chXp11.html

http://atlasgeneticsoncology.org/Genes/MIRN222ID44278chXp11.html

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cancer (mir-205, mir-99b, mir-203, mir-202, mir-

102, and mir-204-Prec). Among these, the

expression of miR-99b and miR-102 was found

higher in adenocarcinoma (Volinia et al., 2006).

Yu et al. found a five-microRNA signature (let-7a,

miR-21, miR-137, miR-372, miR-182*) associated

with survival and cancer relapse in NSCLC (non-

small cell lung cancer) patients (Abdurakhmonov et

al., 2008). Another specific marker for squamous

cell lung carcinoma is miR-205, according to a

microarray study performed by Lebanony et al.,

who found a strong association between the

expression levels of miR-205 and squamous cell

lung carcinoma histology (Barshack et al., 2010).

In addition to the already mentioned miRNAs, miR-

31 is found to act as an oncogenic miRNA by

targeting mRNAs encoding two anti-tumoral

proteins, LATS2 (large tumor-suppressor 2) and

PPP2R2A (PP2A regulatory subunit B alpha

isoform) (Anand et al., 2010). Chou and co-workers

discovered that miR-7 promotes EGFR-mediated

tumorigenesis in lung cancer by targeting ERF (Ets

transcriptional repressor) thus modulating cell

growth (Choudhry and Catto, 2011). However,

miR-7 seems to have a dual function of

oncogene/tumor-suppressor miRNA. Xiong et al.

indeed found that overexpression of miR-7 in

NSCLC A549 cells inhibits cells proliferation and

induces apoptosis by targeting anti-tumoral protein

Bcl-2 (Shao et al., 2011).

Another miRNA that displays a tumor-suppressor

role in lung cancer is miR-451. Wang et al.

demonstrated not only that this miRNA is the most

downregulated in NSCLC tissues, but also that it

regulates survival of cells partially through the

downregulation of the oncogene RAB14 (Ras-

related protein 14) (Bian et al., 2011).

Breast cancer Breast cancer is the second leading cause of cancer

deaths in the developed world and the most

commonly diagnosed cancer in women (Bonev et

al., 2011). A miRNA expression profile study for

breast cancer was conducted by Iorio et al. The

authors found 13 miRNAs differentially expressed

between tumor and normal tissues: among the

upregulated ones there were oncogenic miR-21 and

miR-155, while miR-10b, let-7 miR-125b, miR-145

and miR-205 were found downregulated (Calin et

al., 2005). The latter directly targets HER3 receptor

and blocks the activation of downstream Akt,

inhibiting cell proliferation. Moreover, miR-205

sensitizes cells to Gefitinib and Lapatinib, two

tyrosine-kinase inhibitors, promoting apoptosis

(Iorio et al., 2009).

Shi et al. found that miR-301 has an oncogenic role

in breast tumor by targeting FOXF2, BBC3, PTEN

and COL2A1. Its upregulation promotes

proliferation, migration, invasion and tumor

formation. Moreover, by cooperating with its host

gene SKA2, miR-301 promotes the aggressive

breast cancer phenotype with nodal or distant

relapses (Akao et al., 2011).

Heyn and co-workers identified miR-335 as a

tumor-suppressor gene. It controls different factors

of the upstream BRCA1 regulatory pathway (such

as ERa, IGF1R, SP1), inducing an upregulation of

the tumor suppressor gene BRCA1 (Heyn et al.,

2011).

Colorectal cancer In 2008 a study conducted by Schetter et al. the

authors performed miRNA microarray expression

profiling comparing 84 pairs of tumors (colon

adenocarcinoma) and adjacent non-tumoral tissues

(Schetter et al., 2008). They found 37 differentially

expressed miRNAs; among them miR-20a, -21, -

106, -181b and -203 levels were higher in tumor

specimens. The overexpression of miR-21 and its

role in tumor proliferation in several kind of

cancers has already been described before. Also

miR-20a belongs to the miR-17-92 cluster, whose

overexpression promotes cell proliferation

(Hayashita et al., 2005) and increased tumor size.

One of the most recent tumor suppressor miRNAs

found in colorectal cancer is miR-137. Balaguer et

al. reported that this miRNA is constitutively

expressed in the normal colonic epithelium but

during the early events of colorectal carcinogenesis

it is silenced through promoter hyper-methylation.

Moreover, its re-expression in vitro inhibits cell

proliferation in a cell specific manner. These

findings suggest a prognostic role for miR-137

(Balaguer et al., 2010).

It has been recently demonstrated by Sarver et al.

that miR-183 has an oncogenic role in colon cancer

(but also in synovial sarcoma and

rhabdomyosarcoma) through its regulation of the

expression levels of 2 tumor suppressor genes,

EGR1 and PTEN. The authors also provided

evidence that knockdown of miR-183 affects

cellular migration and they suggest that

pharmaceutical intervention on tumor characterized

by the upregulation of miR-183 may be useful as

anti-cancer therapy (Chen et al., 2010).

Hepatocellular carcinoma One of the most common malignant tumors is

hepatocellular carcinoma. Murakami et al. analysed

the miRNA expression profiles in 25 specimens of

hepatocellular carcinoma compared with adjacent

non-tumoral tissues and nine chronic hepatitis

specimens (Murakami et al., 2006). miR-222, miR-

17-92 and miR-106a exhibited higher expression in

tumor tissues than in the normal ones and were

found associated with the tumor differentiation

status.

Pineau et al. performed profiling studies on 104

hepatocellular carcinoma tissue specimens, 90

cirrhotic, 21 normal and 35 hepatocellular

carcinoma cell lines (Pineau et al., 2010). They

found a 12 miRNA signature that characterizes

tumor progression starting from normal liver, to

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cirrhosis to full blown tumor. Among them, miR-

21, miR-221/222, miR-34a and miR-224 were

found overexpressed in the progression signature.

miR-224 overexpression is connected with the

regulation of cell proliferation, cell migration and

metastasis (Chemistry, 2010).

Su et al. reported that miR-101 is significantly

downregulated in hepatocellular carcinoma and that

its overexpression inhibits tumor development in

nude mice, sensitizes tumor cell lines to serum

starvation and chemotherapeutic treatment (Su et

al., 2009).

Other tumor suppressor miRNAs are: miR-122,

normally downregulated in hepatocellular

carcinoma, whose overexpression induces apoptosis

and cell cycle arrest through targeting of BCLW

(Chemistry, 2010); miR-198, which inhibits

migration and invasion in a c-MET dependent

manner (Akao et al., 2011); miR-125b, which

suppresses tumor cell growth in vitro and in vivo

and induces cell cycle arrest at G1/S acting as a

tumor suppressor gene through the suppression of

LIN28B (Bates et al., 2010), a promoter of cell

proliferation and metastasis through regulation of c-

MYC and E-Cadherin (Ai et al., 2010).

miRNAs in hematological malignancies Similarly to what has been reported in solid tumors,

also in hematological malignancies the miRNome is

frequently de-regulated with respect to the normal

cell counterpart. Physiologic variations in miRNA

expression occur during normal hematopoiesis, and

affect differentiation and commitment of the

multipotent hematologic progenitor (MPP).

Hematologic tumors represent abnormal blocks in

hematopoiesis. Interestingly, the aberrations of the

miRNome occurring in these tumors can be

explained, at least in some instances, as the result of

the block of differentiation leading to the

development of the malignancy. In other cases, the

cause of the observed de-regulation has not been

clarified, but the role of the de-regulated miRNAs

in the acquisition of the malignant phenotype has

been understood, based on the nature of the targeted

genes.

miRNAs in leukemias

Chronic lymphocytic leukemia (CLL) is the most

frequent leukemia of the adult in the Western

world. Chromosomal aberrations recur in human

CLL and harbor diagnostic and prognostic

implications. Occurring in about 65% of cases, the

13q14 deletion is the most frequent chromosomal

aberration observed in human CLL. Based on the

analysis of a large number of CLL cases with

monoallelic 13q14 deletion, a minimal deleted

region (MDR) has been defined. This MDR

includes a long ncRNA, called DLEU2 (deleted in

leukemia 2), strongly conserved among vertebrates,

and the first exon of the DLEU1 gene, another

ncRNA (Migliazza et al., 2001; Chai et al., 2010).

The miR-15a/16-1 cluster is located within intron 4

of DLEU2, and genetic alterations affecting

DLEU2 mRNA expression would also affect miR-

15a/16-1 cluster expression (Calin et al., 2002) .

Therefore, the expression of miR-15a/16-1 is

reduced in the majority of CLL patients carrying

the 13q deletion (Calin et al., 2002). Interestingly,

the same miRNA cluster is involved in cases of

familial CLL, since a germ-line mutation in the

sequence of pre-miR-16-1 (which leads to a

reduced miR-16 expression both in vitro and in

vivo), has been identified associated with the

deletion of the normal allele in leukemic cells of

two CLL patients, one of which with a family

history of CLL and breast cancer (Calin et al.,

2005). A similar point mutation, adjacent to the

miR-16-1 locus has been described in the CLL

prone New Zealand Black mouse strain model

(Raveche et al., 2007). One of the most frequent

molecular hallmarks of the malignant, mostly non-

dividing B-cell of CLL, is the up-regulation of the

antiapoptotic BCL2. It has been demonstrated that

both miR-15a and miR-16 directly target BCL2 in

CLL both in vitro and in vivo (Calin et al., 2005;

Ambs et al., 2008), therefore suggesting that the

miR-15a/16-1 cluster enacts a tumor suppressor

function. Clinicians are aware that CLL is

characterized by recurrent and common

chromosomal aberrations, which harbor prognostic

implications. Some of the most frequent of these

abnormalities are the 13q deletion, the 17p deletion

and the 11q deletion. While CLL patients with the

13q deletion experience the indolent form of the

disease (characterized by IGVH mutated and low

levels of the prognostic surrogate marker ZAP70),

those with the 17p or the 11q deletion (alone or in

association with the 13q), experience an aggressive

form of the disease (characterized by IGVH

unmutated and high levels of ZAP70) (Chiorazzi et

al., 2005). Recently, a new molecular network

explaining the role of these chromosomal

aberrations and their prognostic implications for

human CLL has been described. According to this

model, the miR-15a/16-1 cluster (located at 13q),

directly targets the pro-apoptotic TP53 (located at

17p), which in turn transactivates the miR-34b/34c

cluster (located at 11q), directly targeting ZAP70

(Fabbri et al., 2011). Also, TP53 is able to

transactivate the miR-15a/16-1 cluster, creating a

feed-forward regulatory loop (Fabbri et al., 2011).

These findings identify for the first time some of

the molecular effectors connecting these three

recurrent chromosomal aberrations in CLL and can

explain both their prognostic implications and the

observed levels of ZAP70 according to the degree

of aggressiveness of the disease. Recently, Klein et

al. (Danilov et al., 2010) generated two groups of

transgenic mice models: one mimicking the MDR

and the other containing a specific deletion of the

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miR-15a/16-1 cluster. Although the same spectrum

of clonal lymphoproliferative disorders was

observed in both animal models, the disease was

more aggressive in the MDR group than in the

miR-15a/16-1 group, suggesting that additional

genetic elements in the 13q14 region may affect the

severity of the disease. The oncogene TCL1 (T-cell

leukemia/lymphoma 1A) is over-expressed in the

aggressive CLL (Herling et al., 2006; Barlev et al.,

2010), and is regulated by miR-29b and miR-181b

(Costinean et al., 2006). Furthermore, miR-181a

directly targets BCL2 (Ebert et al., 2007),

suggesting a central role of miR-181 family and of

the miR-15a/16-1 cluster in regulating BCL2

expression in CLL. Stamatopoulos et al.

(Stamatopoulos et al., 2009) found that

downregulation of miR-29c and miR-223 are

predictive of treatment-free survival (TFS) and

overall survival (OS). Low expression of miR-223,

miR-29b, miR-29c, and miR-181 family are

associated with disease progression in CLL cases

harboring the 17p deletion, whereas patients

carrying the trisomy 12 abnormality and high

expression of miR-181a experience a more

aggressive variant of CLL (De Martino et al.,

2009). Interestingly, the miR-29 family has been

demonstrated to control key epigenetic mechanisms

(such as the expression of all three main DNA

methyltranferases) both in solid tumors and in

hematological malignancies (Calin et al., 2007;

Garzon, 2009), therefore suggesting the

involvement also of miRNA-mediated epigenetic

factors in the pathogenesis and prognosis of human

CLL.

Also miR-155 is up-regulated in CLL versus

normal CD19+ B lymphocytes, suggesting that this

miRNA might act as diagnostic biomarker of CLL

(Marton et al., 2008).

The Philadelphia chromosome (reciprocal

translocation t(9;22)) is the hallmark of the chronic

myeloid leukemia (CML), generating the chimeric

protein BCR-ABL1, which is able to activate the

miR-17-92 cluster, together with the oncogene c-

MYC, during the early chronic phase, but not in

blast crisis CML CD34+ cells (Nagel et al., 2007).

These findings suggest that the miR-17-92 cluster

contributes to early phase CML pathogenesis,

harboring CML diagnostic biomarker properties.

ABL1 is also a direct target of miR-203, whose

over-expression inhibits cancer cell proliferation in

an ABL1-dependent manner (Bueno et al., 2008).

Moreover, it has been shown that Philadelphia

positive CMLs, often present a reduced expression

of miR-203 because of its promoter hyper-

methylation, while no methylation can be detected

in other hematological malignancies that do not

carry ABL1 alterations (Bueno et al., 2008).

Finally, down-regulation of miR-10a has been

observed in about 70% of CMLs, with an inverse

correlation with the expression of the oncogene

USF2 (upstream stimulatory factor 2) (Agirre et al.,

2008). Overall, high levels of miR-17-92 cluster

and low expression of miR-203 and miR-10a seem

to be part of the diagnostic signature of human

CML. More recently, miR-451 has emerged as

another key player in CML. Indeed this miRNA can

target BCR-ABL1, which in turn can inhibit miR-

451 expression, creating a regulatory loop, whose

disruption might have therapeutic implications in

the disease (Lopotova et al., 2011). Another gene

which inhibits cell growth and is frequently down-

regulated in CML is CCN3 (also known as NOV or

nephroblastoma overexpressed gene). A possible

mechanism of its down-regulation in CML has been

recently identified and is mediated by miR-130a

and miR-130b, which are up-regulated by BCR-

ABL1 in CML, and directly target CCN3,

contributing to leukemic cell proliferation (Suresh

et al., 2011).

Up-regulation of the miR-17-92 cluster has been

described also in B- and T-cell acute lymphocytic

leukemia (ALL) (Zanette et al., 2007; Nagel et al.,

2009). Recently, the miR-17–92 cluster has been

correlated with the development of mixed lineage

leukemia (MLL)-rearranged acute leukemia

(Chemistry, 2010). Up-regulation of this cluster

was observed not only in MLL-associated AML,

but also in ALL, and is possibly due to both DNA

copy number amplification at 13q31 and to direct

upregulation by MLL fusions (Chemistry, 2010).

Interestingly, a specific miRNA signature of 4

miRNAs is able to distinguish the two forms of

acute leukemias (ALL from AML (acute myeloid

leukemia)) with an accuracy rate of 98%. Indeed,

higher expression of miR-128a and miR-128b was

found in ALL compared to AML, whereas down-

regulation of let-7b, miR-223 indicates ALL vs

AML (Science, 2007). At the moment, the

leukemogenic mechanism of miR-128b is still

poorly understood. Zhang et al., have identified a

miRNA signature in children with ALL

complicated by central nervous system (CNS)

relapse (Ai et al., 2009). The high-risk-of-relapse

signature is composed of over-expression of miR-7,

miR-198, and miR-663, and down-regulation of

miR-126, miR-345, miR-222, and miR-551a. MiR-

16 has a prognostic significance in ALL. Indeed,

Kaddar et al., found that low expression of miR-16

is associated with a better ALL outcome (Kaddar et

al., 2009).

In AML with normal karyotype high levels of miR-

10a, -10b, members of let-7 and miR-29 families,

and down-regulation of miR-204, identify NPM1

(nucleophosmin-1) mutated versus unmutated cases

(Calin et al., 2008). Recently, Ovcharenko et al.,

confirmed that miR-10a expression is highly

characteristic for NPM1 mutated AML, and may

contribute to the intermediate risk of this condition

by interfering with the TP53 machinery, partly

regulated by its target MDM4 (murine double

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minute 4) (Ovcharenko et al., 2011). Over-

expression of miR-155 is associated with FLT3-

ITD+ status, although there is evidence that this up-

regulation is actually independent from FLT3

signaling (Calin et al., 2008). The fusion

oncoprotein AML1/ETO (generated by the t(8;21)

translocation), is the most frequent chromosomal

abnormality in AML, and causes epigenetic

silencing of miR-223, by recruiting chromatin

remodeling enzymes at an AML1-binding site on

the pre-miR-223 gene (Fazi et al., 2007). By

silencing miR-223 expression, the oncoprotein

inhibits the differentiation of myeloid precursors

(promoted by high levels of miR-223), therefore

actively contributing to the pathogenesis of this

myeloproliferative disorder. A central role in the

pathogenesis of AML is also played by miR-29b, a

direct regulator of the expression of all three DNA

methyltransferases (Calin et al., 2007; Garzon et al.,

2009b). Re-expression of miR-29b induces de-

methylation and re-expression of epigenetically

silenced TSGs, such as ESR1 (estrogen-receptor

alpha), and p15 (INK4b) (Garzon et al., 2009b).

Moreover, restoration of miR-29b in AML cell

lines and primary samples, suppresses the

expression of OGs such as MCL1, CXXC6, and

CDK6, which are direct targets of miR-29b (Garzon

et al., 2009a). Abnormal activation of the proto-

oncogene c-KIT contributes to leukemogenesis.

Gao et al., found that miR-193a is silenced by

promoter hyper-methylation in AML, and since this

miRNA directly targets c-KIT, this epigenetic

silencing is responsible, at least in part, for the

aberrant up-regulation of the oncogene in AML

(Cheng et al., 2011). Indeed, restoration of miR-

193a expression by de-methylating agents, reduces

the expression of c-KIT and induces cancer cell

apoptosis and granulocytic differentiation (Cheng et

al., 2011). Similarly, also miR-193b directly targets

c-KIT in AML (Cheng et al., 2011). By using a

novel approach based on the integration of miRNA

and mRNA expression profiles, Havelange et al.,

found a strong positive correlation between miR-10

and miR-20a and HOX-related genes, a significant

inverse correlation between genes involved in

immunity and inflammation (such as IRF7 and

TLR4) and a panel of 4 miRNAs (namely, miR-

181a, -181b, -155, and -146), and a strong direct

correlation between miR-23, -26a, -128a, and -145

and pro-apoptotic genes (such as BIM and PTEN)

(Havelange et al., 2011). Also miR-100 has been

described as an OG in AML, by targeting the TSG

RBSP3 (CTD (carboxy-terminal domain, RNA

polymerase II, polypeptide A) small phosphatase-

like) (Cao et al., 2011). Also in AML, miR-

17/20/93/106 have been shown to promote

hematopoietic cell expansion by targeting

sequestosome 1-regulated pathways in mice

(Meenhuis et al., 2011). Down-regulation of miR-

29a and miR-142-3p has been observed in AML

with respect to controls (Bian et al., 2011), and

miR-29a contributes to counteract leukemic

proliferation by directly targeting the proto-

oncogene SKI (Teichler et al., 2011).

miRNAs in lymphomas

De-regulation of miRNAs has been reported also in

non Hodgkin lymphomas (NHL) and in Hodgkin's

disease (HL). The first evidence of an involvement

of miRNAs in lymphomagenesis was provided by

Eis et al. who observed that the final part of the B-

cell integration cluster (BIC) non-coding RNA

(ncRNA), where miR-155 is located (Chen and

Meister, 2005), was able to accelerate MYC-

mediated lymphomagenesis in a chicken model

(Bashirullah et al., 2003). Subsequently, high levels

of BIC/miR-155 were described also in pediatric

Burkitt's lymphoma (BL) (Metzler et al., 2004), in

diffuse large B-cell lymphoma (DLBCL) (Lawrie,

2007; Hoefiget al., 2008), and in HL (Kluiver et al.,

2005; Abdurakhmonov et al., 2008; Van

Vlierberghe et al., 2009). In a B-cell specific miR-

155 transgenic (TG) mouse model the onset of an

acute lymphoblastic leukemia/high-grade

lymphoma at approximately 9 months of age was

observed (Costinean et al., 2006). In these TG mice,

the B-cell precursors with the highest miR-155

expression were at the origin of the leukemias

(Costinean et al., 2009). Indeed, miR-155 directly

target SHIP (Src homology 2 domain-containing

inositol-5-phosphatase), and C/EBPbeta (CCAAT

enhancer-binding protein beta), two key regulators

of the interleukin-6 signaling pathway, therefore

triggering a chain of events that promotes the

accumulation of large pre-B cells and acute

lymphoblastic leukemia/high-grade lymphoma

(Costinean et al., 2009). Also miR-155 knockout

(KO) mice models have been generated, showing

that the loss of miR-155 switches cytokine

production toward TH2 differentiation (de Yebenes

and Ramiro, 2010), and also compromises the

ability of dendritic cells (DC) to activate T cells,

because of a defective antigen presentation or

abnormal co-stimulatory functions (de Yebenes and

Ramiro, 2010).

As observed in leukemias, also in NHLs, a specific

signature of 4 de-regulated miRNAs (namely miR-

330, -17-5p, -106a, and -210) can differentiate

among reactive lymph nodes, follicular lymphomas

(FL), and DLBCL (Hoefig et al., 2008).

Noteworthy, miR-17-5p, and miR-106a belong to

two paralogous clusters located on chromosome 13

and X, respectively, with a well established

oncogenic role both in solid and hematological

malignancies (Chang et al., 2008). The miR-17-92

cluster is located in a region frequently amplified in

malignant B-cell lymphomas (Abbott et al., 2005),

and is overexpressed in over 60% of B-cell

lymphoma patients (Allawi et al., 2004). In murine

pluripotent cells from MYC-transgenic mice, over-

expression of this miRNA cluster accelerates

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lymphomagenesis (Allawi et al., 2004), whereas in

miR-17-92 TG mice models a higher than expected

rate of lymphoproliferative disorders and

autoimmunity and premature death was observed

(de Yebenes and Ramiro, 2010). These effects are

at least in part due to the direct targeting of the

PTEN and BIM, which controls B-lymphocyte

apoptosis (de Yebenes and Ramiro, 2010). The

miR-106a-363 polycistron is also overexpressed in

46% of acute and chronic human T-cell leukemias

(Landais et al., 2007), claiming a role in

leukemogenesis. Interestingly, both miR-106b-25

and miR-17-92 parologous clusters interfere with

the transforming growth factor-beta (TGF-beta)

signaling (Petrocca et al., 2008), which is inhibited

in several tumors (Derynck et al., 2001). Moreover,

Ventura et al. have shown that the miR-17-92 and

miR-106b-25 double knockout mouse model has a

more severe phenotype than the miR-17-92 single

knockout mouse model (Ventura et al., 2008),

suggesting that both clusters are implicated in the

control of apoptosis in malignant lymphocytes.

Interestingly, miR-17-5p and miR-20a (which

belong to the miR-17-92 cluster) are induced by the

proto-oncogene and transcription factor c-MYC

(Nakamoto et al., 2005), and in turn the cluster

directly targets E2F1, a c-MYC transactivated

transcription factor promoting cell-cycle

progression (Nakamoto et al., 2005). Therefore, the

miR-17-92 cluster tightly regulates c-MYC-driven

cell-cycle progression. From a more translational

perspective, it has been also demonstrated that

over-expression of the miR-17-92 cluster also

significantly increases the resistance to radiotherapy

in human mantle cell lymphoma cells (Ahn et al.,

2010), revealing a role for this cluster as a

theranostic biomarker. MiR-34a is negatively

regulated by c-MYC (Abdurakhmonov et al.,

2008). In c-MYC over-expressing B-lymphocytes

miR-34a confers drug resistance by inhibiting

TP53-dependent bortezomib-induced apoptosis

(Sotillo et al., 2011). Finally, down-regulation of

miR-143 and miR-145 has been described in B-cell

lymphomas and leukemias (Akao et al., 2007), and

re-expression of these miRNAs in a Burkitt

lymphoma cell line demonstrated a dose-dependent

growth inhibitory effect, mediated in part by

miRNA-induced downregulation of the oncogene

ERK5 (Akao et al., 2007).

In HL, Navarro et al. identified a distinctive

signature of 25 miRNAs able to distinguish HL

from reactive lymph nodes, and 36 miRNAs

differentially expressed in the nodular sclerosis and

mixed cellularity subtypes of HL (Navarro et al.,

2007). Interestingly, 3 miRNAs (namely, miR-96, -

128a, and -128b) are selectively downregulated in

HL cells with Epstein–Barr virus (EBV) infection,

but only one of these miRNAs is part of the

signature of 25 de-regulated miRNAs in HL versus

reactive lymph nodes, suggesting that EBV might

not be relevant for HL pathogenesis (Navarro et al.,

2007). Down-regulation of miR-150 and over-

expression of miR-155 frequently occur in HL cell

lines (Gibcus et al., 2009). Since HL develops in

the lymph node germinal center, and high levels of

miR-155 have been described in the germinal center

also during normal lymphopoiesis, it can be

postulated that the observed over-expression of

miR-155 in HL might result from an abnormal

block of lymphocyte differentiation at the germinal

center level. Van Vlierberghe et al., have compared

miRNA profiles of microdissected Reed-Sternberg

cells and Hodgkin cell lines versus CD77+ B-cells

(Van Vlierberghe et al., 2009). In this study a

profile of 12 over and 3 under-expressed miRNAs

was identified (Van Vlierberghe et al., 2009),

showing only a partial overlap with Navarro's

profile. This discrepancy might be due to the

different procedure used to collect HL cells.

Finally, also in HL miRNA expression profile can

predict prognosis. Indeed, low levels of miR-135a

are associated with a higher relapse risk and a

shorter disease-free survival (Gallardo et al., 2009).

A possible molecular explanation for this effect is

that miR-135a directly targets the kinase JAK2

(Janus Kinase 2). Therefore, low levels of miR-

135a are associated with higher expression of

JAK2, which leads to up-regulation of the

antiapoptotic BCL-XL, therefore leading to reduced

apoptosis and increased cell proliferation (Gallardo

et al., 2009).

miRNAs in body fluids as tumor biomarkers MiRNAs have been successfully detected in blood

and other human fluids. It has been shown that they

circulate wrapped in circulating microvescicles

called "exosomes" (Bar et al., 2008), and therefore

are extremely stable and resistant to degradation

(Aumiller and Forstemann, 2008; Kroh et al.,

2010). In 2010, Weber et al. determined miRNA

expression in 12 different types of body fluids

(amniotic fluid, breast milk, bronchial lavage,

cerebrospinal fluid (CSF), colostrum, peritoneal

fluid, plasma, pleural fluid, saliva, seminal fluid,

tears and urine) collected from healthy individuals,

and showed that the highest concentrations of

miRNAs were found in tears and the lowest in CSF,

pleural fluid and urine (Black et al., 2010). The

ability to detect miRNAs in body fluids has

generated interest in their possible role as tumoral

biomarkers. Several studies have demonstrated that

miRNAs can indeed be successfully employed both

as cancer diagnostic and prognostic biomarkers

both in solid and in hematological malignancies.

Table 2 summarizes some of these studies.

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Cancer Expression in

cancer Biomarker property Body fluid miRNA Reference

Solid Tumors

Pancreas High D, D, D Blood 200a, 200b, 210 Ho, Weber

Prostate High (D,P), P Blood 141, 375 Mitchell, Brase

Colorectal High (D,P),D, D Blood 29a, 92, 17-3p Ng, Huang

OSCC High D Blood 31 Liu

Breast High (D,P),D,(D,P) Blood 21, 195, let-7a Asaga, Heneghan

Lung High D,D Blood 25, 223 Lu

HCC Lower ratio D Blood 92a/638 Shigoka

Lung,

Gastric High D,D,D

Pleural

effusion 24, 26a, 30d Xie

Bladder High D,D,D Urine 126, 182, 199a Hanke

OSCC High D Saliva 31 Liu

OSCC Low D Saliva 200a, 125a Park

Bladder Higher ratio D Urine 126/152 and 182/152 Hanke

Hematological malignancies

DLBCL High (D,P), (D,P), D Blood 21, 155, 210 Lawrie

Table 2. MiRNAs detectable in body fluids and their diagnostic and prognostic significance for cancer patients. Legend: The column "Biomarker property" should be read as each letter (or in parenthesis letters) referred to the miRNA

reported in the column "miRNA", according to the sequence order in which these miRNAs are reported. D= Diagnostic biomarker; P= Prognostic biomarker; (D,P)= Diagnostic and Prognostic biomarker. OSCC= Oral Squamous Cell Carcinoma;

HCC= Hepatocellular Carcinoma; DLBCL= Diffuse Large B-Cell Lymphoma.

miRNAs in body fluids as tumor biomarkers in solid tumors Diagnostic biomarkers

The first evidence that circulating miRNAs can be

effectively used to diagnose cancer was provided by

Mitchell et al. in 2008 (Bar et al., 2008). They

found that higher levels of miR-141 in the serum of

25 patients affected by prostate cancer, compared

with 25 healthy control donors identify patients

affected by cancer with a sensitivity of 60%, and a

specificity of 100% (Bar et al., 2008).

Subsequently, Taylor et al. showed that a signature

of 8 circulating miRNAs (enclosed in tumor-

derived exosomes of endocytic origin) can be used

as diagnostic biomarker of ovarian cancer (Chang et

al., 2008). Moreover, in a comparison of 152

patients affected by NSCLC versus 75 healthy

donors, Chen et al., identified higher levels of miR-

25, and miR-223 in the serum of cancer patients

(Aumiller and Forstemann, 2008). Interestingly,

these Authors also demonstrated that circulating

miRNAs resist treatments with HCl, NaOH, and

repeated freeze and thaw cycles, therefore acting as

stable, reliable biomarkers (Aumiller and

Forstemann, 2008). Patients affected by pancreatic

cancer have higher concentrations of circulating

miR-210 (Bar et al., 2008) , -200a, and -200b

(Chemistry, 2010), suggesting that these miRNAs

might be used to successfully screen for pancreatic

cancer. High levels of circulating miR-29a, -92 and

-17-3p have been found in patients affected by

colorectal cancer (Anand et al., 2010). Interestingly,

miR-92 is not elevated in the plasma of patients

with irritable bowel disease, suggesting a role for

this miRNA in the differential diagnosis between

this benign condition and cancer. Moreover, the

increased levels of circulating miR-29a and -92

occur already in presence of pre-cancerous

conditions such as colon adenomas (Anand et al.,

2010), revealing that the de-regulation of these two

miRNAs is an early event in colon carcinogenesis

and their increased plasma concentration might be

helpful for the very early (even pre-cancerous)

phase of colorectal tumorigenesis. In breast cancer,

Asaga et al. showed that serum concentrations of

miR-21 correlates with the presence and extent of

breast cancer (Asaga et al., 2011), whereas

Heneghan et al., showed that circulating miR-195

differentiates breast cancer from other malignancies

and is a potential biomarker for the detection of

non-invasive and early stage disease (Henegan et

al., 2010). Finally, in oral squamous cell carcinoma

(OSCC) high levels of circulating miR-31

differentiate patients from healthy controls and the

concentration of this miRNA decreases after

surgical resection of the tumor (Anand et al., 2010),

suggesting that miR-31 might be helpful also for

the early detection of OSCC recurrence.

In addition to blood and plasma, miRNAs can be

detected also in other body fluids and have

diagnostic biomarker properties. High levels of

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miR-31 (Anand et al., 2010), and lower levels of

miR-200a and -125a (Addo-Quaye et al., 2009)

have been identified in the saliva of OSCC patients.

An increased expression of miR-126, -182, and -

199a has been described in the urine of patients

affected by bladder cancer with respect to healthy

controls (Hanke et al., 2010), whereas the ratio

miR-126/miR-152 and miR-182/miR-152 is higher

in patients affected by bladder cancer versus

carriers of urinary tract infections, with a sensitivity

of 72% and 55%, respectively, and a specificity of

82% (Hanke et al., 2010). Similarly, in the blood of

patients with hepatocellular carcinoma (HCC),

Shigoka et al. found that the ratio of miR-92a/miR-

638 is lower than healthy controls, suggesting a

possible role of this non-coding RNA parameter in

the diagnosis of HCC. Also in malignant pleural

effusions of patients affected by lung cancer and

gastric carcinoma, higher levels of miR-24, -26a,

and -30d compared to controls were reported (Dai

et al., 2010).

Prognostic biomarkers

In addition to their role as diagnostic biomarkers,

miRNA can also act as prognostic and theranostic

in several human solid tumors.

Low levels of circulating let-7a are associated with

node positive breast cancer, compared to negative

node disease (Henegan et al., 2010), whereas higher

levels of miR-21 can be detected in patients with

advanced breast cancer with respect to early stage

disease (Asaga et al., 2011). Similarly, circulating

miR-29a expression differs in early stage versus

advanced colorectal cancer (Anand et al., 2010). In

prostate cancer, higher serum levels of miR-375

and -141 are found in patients with advanced

disease (Brase et al., 2011), whereas higher

circulating miR-21 was found in hormone

refractory prostate cancer, with respect to benign

prostatic hyperplasia, localized prostate cancer and

hormone dependent prostate cancer (Bo et al.,

2011).

miRNAs in body fluids as tumor biomarkers in hematological malignancies Diagnostic biomarkers

Higher levels of circulating miR-21, -155 and -210

have been described in patients affected by diffuse

large B-cell lymphoma (DLBCL), compared to

controls (Lawrie, 2008). Interestingly, the same

group had previously shown that the expression of

miR-155 in primary DLBCLs distinguishes

between the activated B-cell phenotype (ABC)

(higher expression of miR-155), than in the

germinal center B-cell-like phenotype (GCB)

(lower expression of miR-155) (Chen and Meister,

2005; Lawrie, 2007). Since, the 5-year survival

rates of the ABC and the GCB subtypes of DLBCL

are 30% and 59%, respectively (Kovanen et al.,

2003), miR-155 expression in DLBCL has a

prognostic value. A correlation between miR-155

and NFkB expression was found in DLBCL cell

lines and patients (Abu-Elneel et al., 2008). In

addition to miR-155, high levels of miR-21 and

miR-221 are also associated with ABC-DLBCL and

severe prognosis (de Yebenes and Ramiro, 2010). It

would be interesting to investigate whether the

expression of circulating miR-155 correlates with

the expression of this miRNA in primary DLBCL,

since it would indicate that miR-155 is a diagnostic

biomarkers not only to put the diagnosis of

DLBCL, but also of subtype of DLBCL.

Prognostic biomarkers

In DLBCL, increased serum levels of miR-21 are

associated with a longer relapse-free survival

(Lawrie, 2008), indicating that circulating miR-21

harbors prognostic implications in patients affected

by DLBCL.

Overall, miRNAs can be detected in body fluids

and increasing evidence shows that their expression

in these fluids allows the diagnosis of cancer

histotype and, in some cases histologic subtype.

Finally, specific signatures of de-regulated miRNAs

in body fluids harbor prognostic implications.

These discoveries cast a new light on the

translational implications of research in the miRNA

field, by suggesting that these non-coding RNAs

could be detected non-invasively and provide key

diagnostic and prognostic clinical information.

miRNAs in invasion, angiogenesis and metastasis In the last few years several studies have pointed

out a critical role of miRNAs in tumor angiogenesis

and metastasis. By regulating these processes

miRNAs have emerged as crucial players, thus

allowing primary tumor cells to invade adjacent

tissues and reach through the systemic circulation

distant sites in which they can finally proliferate as

secondary tumors.

Depending on their role in the modulation of these

processes, miRNAs can be subdivided into two

groups: the anti-angiogenic and the pro-angiogenic

ones.

Poliseno et al. demonstrated that the miR-221/miR-

222 family has anti-angiogenic properties as it

inhibits the angiogenic activity of stem cell factor

SCF by targeting its receptor c-KIT in endothelial

cells (Poliseno et al., 2006).

Since miR-21 plays a crucial role in cancer

progression Sabatel et al. pondered whether it could

also be involved in angiogenesis (Sabatel et al.,

2011). Their in vitro and in vivo study revealed that

mir-21 is a negative regulator of endothelial cell

migration and tubulogenesis. Angiogenesis

inhibition would occur through the targeting of

RhoB, a small GTPase which is responsible for the

assembly of actin stress fibers (Aspenstrom et al.,

2004). However, it seems that miR-21 has a dual

role in the regulation of angiogenesis. Liu et al. in

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fact found that the overexpression of miR-21 in

prostate cancer cell line increases the expression of

HIF-1a and VEGF through the AKT and ERK

pathway, thus acting as a pro-angiogenetic miRNA

(Ayala de la Pena et al., 2011). Other miRNAs are

known to be positive regulators for angiogenesis.

For example, in vascular endothelial cells miR-

130a downregulates the expression of the

antiangiogenic homeobox genes HOXA5 and GAX

in response to mitogens, proangiogenic and

proinflammatory factors (Aumiller and Forstemann,

2008).

By using in vitro and in vivo studies Fang et al.

found that miR-93 promotes angiogenesis and

tumor growth by suppressing integrin-b8

expression and enhancing endothelial activity (Fang

et al., 2011). Indeed this miRNA induces blood

vessels formation, cell proliferation and migration

by targeting the cell death-inducing antigen

integrin-b8. The authors cannot exclude that miR-

93 may also target other genes involved in

tumorigenesis and angiogenesis.

Also, the miR-17-92 cluster promotes angiogenesis

by inhibiting the expression of antiangiogenic

protein thrompospondin-1 (TSP1) and connective

tissue growth factor (CTGF) (Dews et al., 2006);

miR-378 overexpression in glioblastoma cell line

U87 enhanced angiogenesis and tumor growth

through its targeting of tumor suppressor proteins

SUFU and FUS-1 (Barakat et al., 2007); miR-296 is

highly expressed in primary human brain

microvascular endothelial cells and contributes to

angiogenesis by directly targeting the hepatocyte

growth factor-regulated tyrosine kinase substrate

(HGS) mRNA, leading to decreased levels of HGS

and thereby reducing HGS-mediated degradation of

the growth factor receptors VEGFR2 and PDGFR-b

(Gabriely et al., 2008).

Also in the regulation of the metastatic process

miRNAs can be divided into two categories: pro-

metastatic (such as miR-340, miR-92a, miR-10b,

miR-373/520c) or anti-metastatic (such as miR-101,

miR-34a, miR-126, miR-148a, miR-335) ones.

In breast cancer reduced miR-340 expression is

associate with tumor cell migration, invasion and

poor prognosis (Dong et al., 2011).

Of the six mature miRNAs produced by the miR-

17-92a cluster, miR-92a is involved in the

metastatization process. It has been reported that

miR-92a is highly expressed in tumor tissue from

ESCC (Esophageal Squamous Cell Carcinoma)

patients (Cai et al., 2008). Chen et al. verified

whether there is a correlation between the relative

expression of miR-92a in tumor and normal tissues

and lymph node metastasis in ESCC patients. Not

only they found that miR-92a promotes ESCC cell

migration and invasion through the inhibition (by

direct targeting) of CDH1, which is known to

mediate cell-to-cell adhesion, but also that ESCC

patients with up-regulated miR-92a are prone to

lymph node metastasis and poor prognosis (Bao et

al., 2011).

In 2007, Ma et al. reported that miR-10b is highly

expressed in metastatic breast cancer cells, when

compared with non-metastatic cells. However,

when overexpressed in the latter it promotes robust

invasion and metastasis. Induced by the

transcription factor Twist, miR-10 inhibits the

translation of the messenger RNA encoding

HOXD10 (homeobox D10), thus increasing the

expression of the pro-metastatic gene RHOC and

leading to tumor invasion and metastasis (Derby et

al., 2007).

Through the transduction of a non-metastatic breast

cancer cell line with a miRNA expression library

Huang et al. studied which miRNAs could allow

the cells to migrate. MiR-373 and miR-520c were

found to promote cell invasion and metastasis both

in vitro and in vivo through the inhibition of the

expression of CD44, a protein involved in cell

adhesion (Abdurakhmonov et al., 2008).

As previously reported, miRNAs are known also to

have an anti-metastatic role. One of them is miR-

101, whose expression decreases during prostate

cancer progression, as depicted by Varambally et al.

(Varambally et al., 2008). The authors showed that

during this process there's a negative correlation

between the expression of miR-101 and EZH2, a

mammalian histone methyltransferase

overexpressed in solid tumors (Varambally et al.,

2002) and involved in the epigenetic silencing (Yu

et al., 2007; Cao et al., 2008) of genes responsible

for tumor invasion and metastasis.

By performing experiments based on computational

analysis the authors showed also that miR-101

targets EZH2. Loss of miR-101, paralleled by

increased levels of EZH2 in the tumor, leads to

dysregulation of epigenetic pathways and cancer

progression.

Another miRNA typically downregulated in tumors

(colorectal cancer (Tazawa et al., 2007), pancreatic

cancer (Chang et al., 2007), and neuroblastoma

(Welch et al., 2007)) is miR-34a. Li et al. observed

that in hepatocellular carcinoma miR-34a is also

down-regulated (Li et al., 2009) and its expression

is inversely correlated with that of the receptor for

the hepatocyte growth factor c-MET (Leelawat et

al., 2006), involved in cell invasion and metastasis.

In their study the Authors demonstrated that miR-

34a targets c-MET when ectopically expressed in

Hep-G2 cells and observed reduced cell scattering,

migration and invasion.

Crk (v-crk sarcoma virus CT 10 oncogene

homolog) is a protein that regulates cell motility,

differentiation and adhesion (Kobashigawa et al.,

2007). High expression levels of this protein are

found in several human tumors such as breast,

ovarian, lung, brain, stomach and chondrosarcoma

(Wang et al., 2007) and knock down of Crk

decreases cell migration and invasion (Rodrigues et

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al., 2005; Wang et al., 2007). Crawford et al.

showed that Crk is a functional target of miR-126

in NSCLC tumors and that overexpression of miR-

126 induces a decrease in adhesion, migration and

invasion (Crawford et al., 2008).

Finally, the list of anti-metastatic miRNAs includes

miR-206 and miR-335. In a manuscript published

in 2008 Tavazoie and coworkers took under

consideration a set of miRNAs whose expression

was lost in human breast cancer cells (Tavazoie et

al., 2008). Among these they considered miR-206

and miR-335. By restoring their expression through

retroviral transduction they found that the ability of

these cells to migrate to the lung was lost. MiR-335

exerts its anti-metastatic role by targeting PTPRN2

(receptor-type tyrosine protein phosphatase)

(Varadi et al., 2005), MERTK (the c-Mer tyrosine

kinase) (Graham et al., 1995), SOX4 (SRY-box

containing transcription factor), the progenitor cell

transcription factor (van de Wetering et al., 1993;

Hoser et al., 2007) and TNC (tenascin C) (Ilunga et

al., 2004), which is an extracellular component of

the matrix.

Therapeutic implications of miRNAs in oncology The involvement of miRNAs in different aspects of

human carcinogenesis, such as cell proliferation,

apoptosis, differentiation, angiogenesis, motility

and metastasis, has raised the question whether

reverting these aberrations of the miRNome can be

effectively used for therapeutic purposes.

Preclinical data encourage this hypothesis and

provide the biological rationale for clinical studies

in this direction. Re-expression of miRNAs down-

regulated in cancer (e.g. miR-15a and miR-16 in

BCL2 positive CLL) and/or silencing of miRNAs

up-regulated in the tumor (e.g. miR-155 in lung

cancer) may lead to cancer cell apoptosis and exert

a therapeutic effect. Before this becomes a reality in

patients though, several issues need to be solved.

First, there is a need to know the full spectrum of

targets and effects that a given miRNA has on a

given genome. It has been estimated that a single

miRNA cluster (namely, the miR-15a/16-1 cluster)

is able to affect, directly and indirectly, the

expression of about 14% of the whole human

genome (Calin et al., 2008). Also it is clear that

each miRNA is able to target both OGs and TSGs,

and that the phenotype induced by the external

manipulation of a miRNA is the result of this

combined targeting effect on several genes.

Therefore, one of the goals of the preclinical

research is to fully clarify this aspect before any

clinical application can even be taken into

consideration. Secondly, it needs to be established

how can we reach a tumor-specific delivery of the

miRNAs of interest? This question is more general,

and involves the whole field of gene therapy, being

not limited to the research on miRNAs. The advent

of nanoparticles, able to target tumor-specific

antigens hopefully will address this concern and

allow tumor specificity. Another aspect of

relevance consists in determining how the

modulation of miRNA expression can integrate the

existing anti-cancer therapies (chemo-, radio-,

hormonotherapy)? Interestingly, some studies have

been published showing that miRNAs can restore

sensitivity to current therapeutic options to which

the tumors became resistant, and this encourages a

certain optimist on miRNA-inclusive association

regimens. The other questions on what is the best

formulation of miRNAs to be administered, and

what are the pharmacokinetics and

pharmacodynamics of these ncRNAs in humans

will be answered (as always) by the established

phases of the clinical studies.

Conclusion The involvement of miRNAs in human cancer

development and progression has been proven

without any doubt by several studies. Other aspects

of miRNA research are still under development,

such as their role as molecular biomarkers (the

published studies still suffer in most cases from a

limited number of patients, which questions the

statistical power of certain results), the

identification of the full spectrum of targets of a

given miRNA (in particular, there is a need to

critically interpret the plethora of the identified

targets in light of the specific genome in which the

effect is observed, and in relation to the other

identified and validated targets of that same

miRNA), and their interaction with the existing

treatments (the number of published studies on this

regard is still relatively small to allow any safe

conclusion). Nonetheless, despite there seems to be

still a lot of work ahead, it is promising that in such

a relatively small amont of time, from the discovery

of their involvement in human cancer, till today so

much has been discovered about miRNAs and

cancer. The effort devoted by the scientific

community in this research field is unprecedented,

allowing a certain optimism for the years to come,

in which the introduction of these ncRNAs in the

clinical practice seems about to become a realistic

option.

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Case Report Section Paper co-edited with the European LeukemiaNet




Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda,

Andrea Montella, Maurizio Longinotti

Clinical Genetics, Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B

07100 Sassari, Italy (FC, GF, AM); Azienda Ospedaliero-Universitaria Sassari, Italy (PMC, CF, LP,

AM, ML); Institute of Hematology, University of Sassari, Italy (CF, LP, ML)

Published in Atlas Database: September 2011

Online updated version : http://AtlasGeneticsOncology.org/Reports/der918p10q10CambosuID100057.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI der918p10q10CambosuID100057.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics

Age and sex

66 years old male patient.

Previous history

No preleukemia. No previous malignancy. No

inborn condition of note.

Organomegaly

Hepatomegaly (enlarged liver (+ 20 cm)),

splenomegaly, no enlarged lymph nodes , no central

nervous system involvement.

Blood WBC : 46 X 10

9/l

HB : 8.5 g/dl

Platelets : 239 X 109/l

Blasts : 15%

Bone marrow : 25%

Cyto-Pathology Classification

Cytology: NA

Immunophenotype: NA

Rearranged Ig Tcr: NA

Pathology: NA

Electron microscopy: NA

Diagnosis

Polycythemia vera. Myelofibrosis: hypocellular

bone marrow with marked increase in reticulin

fibres. AML M2.

Survival

Date of diagnosis: 01-1980

Treatment

Bleeding therapy and acethylsalicylic acid. 2005 -

2008: Etanercept (anti-TNF alpha). 2007:

Hydroxyurea. Sept. 2008: Splenectomy. Feb. 2008:

Pomalidomide, suspended after 1 month because of

a severe neutropeny. Feb 2009: Bone Marrow

allograft.

Complete remission : no (March-November 2009:

complete hematological remission; molecular

remission not reached (JAK-2 positivity in June

2009))

Treatment related death : no

Relapse : no

Status: Death. Last follow up: 11-2010 (due to

gastrointestinal hemorrhage).

Survival: nearly 30 years.

Karyotype

Sample: Bone marrow biopsy in Dec. 2008

Culture time: 24 and 48 h.

Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis

Cambosu F, et al.


Banding: Cytogenetic analysis performed in QFQ

banding; band level: 400.

Results

46,XY, +9,der(9;18)(p10;q10) in 25/25 cells

scored.

Probes: whole-chromosome painting probes (wcp) and

centromeric (CEP) probes of chromosomes 9 (9p11-q11 alpha satellite DNA) and 18 (D18Z1) (Abbott

Molecular/Vysis).

Comments Polycythemia Vera (PV) is a clonal

myeloproliferative disorder characterized by

excessive erythrocyte production, which may

evolve into myelofibrosis and acute myeloid

leukemia. Transformation to myelofibrosis occurs

in 15-20% of cases and leukemic transformation in

5-10% of patients. The median survival time is 8-11

years and the median age at diagnosis is over 60

years. Normal karyotype is present at diagnosis in

the majority of patients, while during

transformation several acquired chromosome

anomalies are present as trisomy 9 and gains in 9p.

The activating JAK2 V617F mutation, present in

the majority of patients with PV, seems to have a

primary role in the pathogenesis of

myeloproliferative neoplasms. The JAK2 gene

maps to 9p24, so patients carrying gains of 9p have

an extra copy of the gene, in its normal or mutated

form, leading to a gain of function.

The rearrangement here reported,

der(9;18)(p10;q10), is rarely detected in patients

with PV, myelofibrosis, essential thrombocythemia

and therapy-related AML. Some authors suggest

that the simultaneous presence of both JAK2

V617F mutation and this rearrangement could

define a subgroup of PV patients with the

proliferative phenotype of the disease, at high risk

of transformation into postpolycythemic

myelofibrosis and potentially acute myeloid

leukemia.

We describe a new case of der(9;18)(p10;q10)

detected in a patient with AML evolved from post-

polycythemic myelofibrosis. The patient was

diagnosed with PV in 1980 and died in 2010. He

was in good health for several years after diagnosis

with bleeding treatment and low dose aspirin, then

he showed a progressive worsening of anemia with

liver enlargement and splenomegaly. In February

2008 the diagnosis was of myelofibrosis post PV in

progression. In December 2008, when the leukemic

transformation was evident, the cytogenetic

analysis on bone marrow aspirate found the

unbalanced translocation leading to

der(9;18)(p10;q10), with trisomy of the short arms

of chromosome 9 and monosomy of the short arms

of chromosome 18. FISH experiments with specific

alphoid centromeric probes for chromosome 9 and

18 showed both positive signals on the der(9).

Subsequent molecular analysis detected the

presence of the JAK2 V617F mutation.

The patient here reported had a classical evolution

of the disease, after a very long polycythemic phase

with a noteworthy survival time likely correlated to

the young age of the patient when PV occurred.

Because of the absence of cytogenetic results at

diagnosis and during the polycythemic phase, we

cannot fully evaluate the significance of

der(9;18)(p10;q10) in the natural history of the

Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis

Cambosu F, et al.


disease before its evolution. Future reports could

make clear this not negligible aspect.

References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4

Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23

Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83

Larsen TS, Hasselbalch HC, Pallisgaard N, Kerndrup GB. A der(18)t(9;18)(p13;p11) and a der(9;18)(p10;q10) in polycythemia vera associated with a hyperproliferative phenotype in transformation to postpolycythemic

myelofibrosis. Cancer Genet Cytogenet. 2007 Jan 15;172(2):107-12

Ohyashiki K, Kodama A, Ohyashiki JH. Recurrent der(9;18) in essential thrombocythemia with JAK2 V617F is highly linked to myelofibrosis development. Cancer Genet Cytogenet. 2008 Oct;186(1):6-11

Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL: http://AtlasGeneticsOncology.org/Genes/der0918XuID100044.html .


Cambosu F, Fogu G, Campus PM, Fozza C, Podda L, Montella A, Longinotti M. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):69-71.

Educational Items Section




Weird animal genomes and sex chromosome evolution Jenny Graves

La Trobe University, Melbourne, Australia (JG) (Paper co-edited with the European Cytogeneticists

Association)


Online updated version : http://AtlasGeneticsOncology.org/Educ/SexChromID30061EL.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI SexChromID30061EL.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Embryonic diapause: blastocyst goes into

suspended animation for up to 11 months.

Premature birth of underdeveloped Young: limb,

organ development still going on. Provides

opportunities for observation and manipulation of

development that are impossible in mouse.

Lactation complex: big changes in milk

composition between newborn and 3 months pouch

young. Premmies? Control?

There are 26 species of kangaroo.

We chose the tammar wallaby as our model

kangaroo. Small, easy to handle, most of the classic

work on marsupial physiology is done on this

species.

Weird animal genomes and sex chromosome evolution Graves J


Inter-island crosses like M. musculus x M. spretus

because they are very different.

- Lots of markers: microsatellite (variable numbers

of repeats).

- Have loads of phenotypic differences including in

reproductive characters like diapauses.

Mono and tammar differ by about 10

interchromosomal rearrangements.



Degeneration of the sex-specific element (Y or W)

from an original autosome, with examples of

animal species which exhibit this level of

differentiation.



Nice examples of neofunctionalization (SRY,

RBMY) and subfunctionalization.




Graves J. Weird animal genomes and sex chromosome evolution. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):72-81.



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