p57 kip2 beckwith-wiedemann syndrome
DESCRIPTION
p57 Kip2 Beckwith-Wiedemann Syndrome. Chris Joubert March 31, 2005. Beckwith-Wiedemann Syndrome (BWS). Hans-Rudolf Wiedemann (1964) and J. Bruce Beckwith (1969) Congenital exomphalos, macroglossia, and gigantism In the US: US frequency is estimated at 1 in 15,000 live births. - PowerPoint PPT PresentationTRANSCRIPT
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p57Kip2 Beckwith-Wiedemann Syndrome
Chris JoubertMarch 31, 2005
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Beckwith-Wiedemann Syndrome (BWS)
•Hans-Rudolf Wiedemann (1964) and J. Bruce Beckwith (1969)•Congenital exomphalos, macroglossia, and gigantism •In the US: US frequency is estimated at 1 in 15,000 live births. •Children affected with BWS have a propensity to develop tumors such as Wilms’ tumor, hepatoblastoma, and rhabdomyosarcomas.
http://www.emedicine.com/ped/topic218.htm
Mainprize et al. (2001) J Neuro-Oncol 51:205-218
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Beckwith-Wiedemann Syndrome
•Approximately 80% of BWS patients demonstrate genotypic abnormalities of the distal region of chromosome arm 11p •The BWS region of 11p was the first identified example of imprinting in mammals •Several 11p genes are imprinted, including p57, IGF2, and H19.
http://www.emedicine.com/ped/topic218.htmMainprize et al. (2001) J Neuro-Oncol 51:205-218
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Maternal Paternal
Imprinting
Only one allele is expressed
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p57 - Lessons from Knockout Mice
Mainprize et al. (2001) J Neuro-Oncol 51:205-218
Nakayama et al. (1998) BioEssays 20:1020-1029
P57-/- - Embryonic/neonatal lethality,Multiple developmental defects,altered cellular proliferation
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Mice Knockouts
Similarities to BWS
•Omphalocele
•Enlargement of the adrenal cortex, adrenal cytomegaly, and renal medullary dysplasia
Zhang et al. (1997) Nature 387:151-158
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p57
•Member of family of Cip/Kip inhibitors along with p21Cip1 and p27Kip2
•Inhibit wide range of CDKs and bind to both the cyclin and cyclin-dependant kinase.•Cip/Kip inhibitors are not specific to any particular cyclin/CDK complex.
Mainprize et al. (2001) J Neuro-Oncol 51:205-218
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p57
CDK Inhibitory Domain
Proline Rich Domain
Acidic Domain
QT Domain
•316 Amino-acids•Performs majority of function in nucleus and contains nuclear localizing sequences at C-terminal end.
Mainprize et al. (2001) J Neuro-Oncol 51:205-218
Nakayama et al. (1998) BioEssays 20:1020-1029
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Russo et al. (1996) Nature 382:325
CDK Inhibitory Domain
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Cyclin A
CDK2
Russo et al. (1996) Nature 382:325
•CDK inhibitory domain binds conserved cyclin box of cyclin and binds CDK, occupying its catalytic cleft
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p57Kip2
Cyclin D/ E
CDK 4/2
Courtesy of Dr. Duronio
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Mainprize et al. (2001) J Neuro-Oncol 51:205-218
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p57
How does this relate to cancer?
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p57 and cancer
•P57Kip2 localizes to chromosome 11p15.5, a region containing several imprinted genes.•Paternal allele of p57Kip2 is transcriptionally silent in mice and humans.•800 Kbp centromeric to the gene encoding insulin-like growth factor-2 (IGF-2), which is also imprinted and expressed only by the paternal allele
Mainprize et al. (2001) J Neuro-Oncol
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Mechanisms for downregulation of p57 in BWS
•Maternally inherited mutations• 5-10% - sporadic• 30-50% - familial
•IGF-2 downregulates mRNA expression of p57Kip2
-Increased levels of IGF-2 caused by one of three possible events:
1) Mutation in Igf2R gene – IGF2R decreases levels of IGF-2
2) Loss of imprinting (LOI) of IGF-23) Inherit 2 paternal alleles
Joyce et al. (1997) Hum. Mol. Genet. 6:1543Mainprize et al. (2001) J Neuro-Oncol
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p57Kip2
Cyclin D/ E
CDK 4/2
Courtesy of Dr. Duronio
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Mainprize et al. (2001) J Neuro-Oncol 51:205-218
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•Exomphalos, macroglossia, gigantism•Mouse knockouts•Cip/Kip inhibitor•Cancer
•Complete loss•Chronic low levels
Summary