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Genes & Development Graduate Program

The University of Texas MD Anderson Cancer CenterThe University of Texas Graduate School of Biomedical Sciences at Houston

www.mdanderson.org/departments/genesdev

Genes & Development

A Ph.D. program of

The University of Texas Graduate School of Biomedical Sciences at Houston

in the

Department of Genetics and the Department of Biochemistry & Molecular Biology

at

The University of Texas MD Anderson Cancer Center


Table of Contents

1 Genes & Development Program 6 UT Graduate School of Biomedical Sciences 7 MD Anderson Cancer Center 8 Houston 11 Faculty 11 Swathi Arur, Ph.D.

RAS-ERK signaling; germ cell development; C. elegans genetics

11 Michelle Barton, Ph.D.chromatin; p53; embryonic stem cells; liver regeneration; breast cancer

12 Richard R. Behringer, Ph.D.mammalian developmental genetics; reproductive biology and disease; stem cells, homeostatis, and regeneration; evolution and development

12 Andreas Bergmann, Ph.D.apoptosis; cell survival; tumor suppression

13 Benoit de Crombrugghe, M.D.cell fate determination; cell differentiation; chondrocytes; osteoblasts

13 Sharon Y.R. Dent, Ph.D.epigenetics; mitosis; histone modifying enzymes; stem cells and embryo development

14 Elsa R. Flores, Ph.D.mouse models; tumor suppressor genes; metastasis; stem cells

14 Yasuhide Furuta, Ph.D.ocular development; neural stem cells; brain tumor; mouse molecular genetics

15 Michael Galko, Ph.D.Drosophila genetics; molecular genetics of tissue repair; cell migration; cell signaling and signal transduction; pain sensitization

15 Howard B. Gutstein, M.D.proteomic approaches to addiction and opioid tolerance; interaction of pain and analgesic signal transduction mechanisms; translational pain studies

16 Georg Halder, Ph.D.organ size control; regeneration; tumor suppressor genes; Drosophila genetics; cancer mechanisms

16 Vicki Huff, Ph.D.human genetics; cancer genetics; familial cancer predisposition; kidney development

17 Hamed Jafar-Nejad, M.D.developmental glycobiology; Notch signaling; intracellular trafficking; asymmetric divisions

17 Randy L. Johnson, Ph.D.mouse genetics; Hippo pathway; tumor suppressor genes; mouse models for cancer research

18 Ann M. Killary, Ph.D.tumor suppressor genes; breast and pancreatic cancer; cancer genetics

18 William H. Klein, Ph.D.development mechanisms; transcription factors in development; mouse models for human disease; gene regulatory networks and systems biology

Ribonuclear foci of toxic (CCUG)DM2 RNA expressed from DM2 mutation. (courtesy of Dr. Ralf Krahe’s lab)

A 13.5 day Sox9-EGFP knockin mouse gonad imaged using brightfield (left) and fluorescence (middle) microscopy to build a 3D model (right) of the developing testis. (courtesy of Dr. Richard Behringer’s lab)

Graduate student presenting research at annual G&D retreat poster session.

G&D Directors’ Roundtable where students and directors meet over lunch twice a year to discuss program affairs and suggestions.


19 Ralf Krahe, Ph.D.human and molecular genetics; neurogenetics; cancer genetics; genomics

19 Leslie Krushel, Ph.D.RNA; protein synthesis; Alzheimer’s disease; neuronal development

20 Jian Kuang, Ph.D.cell-cycle control; signal transduction; Alix functions and regulation

20 John E. Ladbury, Ph.D.biophysical analysis; tyrosine kinase signalling; protein complexes; protein-ligand interactions; drug development; structural-thermodynamic correlations

21 Mong-Hong Lee, Ph.D.cell cycle; ubiquitination; 14-3-3 and cancer; gene knock out; p53 signaling

21 Randy Legerski, Ph.D.cellular responses to DNA damage; DNA repair; cell cycle checkpoint signaling

22 Guillermina (Gigi) Lozano, Ph.D.tumor suppressors; mouse models; apoptosis

22 Sadhan Majumder, Ph.D.connection between normal development and disease; adult and embryonic stem cells; brain tumors; mouse models

23 James F. Martin, M.D., Ph.D.tissue regeneration; heart disease; mouse genetics; birth defects

23 Angabin Matin, Ph.D.germ cell tumors; biology of germ cells; genetic dissection of disease susceptibility; mouse models

24 William Mattox, Ph.D.RNA biology; germ cell development; genetic models of disease

24 Gregory S. May, Ph.D.fungal genetics; fungal pathogenesis; signal transduction

25 Pierre D. McCrea, Ph.D.catenin biology; development; intracellular and nuclear signaling

25 Lalitha Nagarajan, Ph.D.human cancer; stem cell; mouse models

26 Jill M. Schumacher, Ph.D.chromosome dynamics; cell cycle; mitotic kinases; Aurora kinases; C. elegans

26 Xiaobing Shi, Ph.D.genomic instability and cancer; epigenetics; protein lysine methylation; stem cells

27 Shinako Takada, Ph.D.transcription regulation; TATA-less promoters; chromatin regulation; PARP-1/DNA-PK/TopoIIβ complex

27 Jessica Tyler, Ph.D.epigenetics; gene expression; DNA repair; aging

28 Bin Wang, Ph.D.DNA damage response; genomic instability and cancer; BRCA1 signaling; ubiquitin signaling

Graduate student preparing a polymerase chain reaction (PCR) to screen for transgenic mice.

Intestinal cells used to study the function of the p53 inhibitor, Mdm2; turquoise staining shows cells expressing the proliferative marker Ki-67. (courtesy of Dr. Gigi Lozano’s lab)

Two FGFR cytoplasmic domain monomers (magenta and green) bound to ATP in the crystallographic unit . (courtesy of Dr. John Ladbury’s lab)

The Genes & Development Program (G&D) at the University of Texas MD Anderson Cancer Center is a Ph.D. program for students seeking advanced training in biomedical research on the fundamental molecular mechanisms that control growth and cell differentiation, and that cause cancer.

The Program offers an exceptionally rich environment for graduate education, with world-renowned faculty and research programs. From cutting-edge research labs with state-of-the-art facilities, to coursework, seminars and program activities, the G&D Program provides an intellectually stimulating atmosphere that fosters faculty-student interactions, the development of independent scientific thought and analysis, and the pursuit of scientific discovery.

Based primarily within the Department of Genetics and the Department of Biochemistry & Molecular Biology at MD Anderson, the G&D Program offers students the unique opportunity to study and conduct research at one of the premier cancer centers in the United States, located within the largest medical center in the world – the Texas Medical Center. The high concentration of scientific research centers and programs within walking distance facilitates many inter-institutional collaborations. It also provides the opportunity for students to attend seminars and meetings with scientists and trainees at nearby institutions.

Faculty and Research

The G&D faculty is made up of a diverse group of faculty leading internationally recognized research programs. Many program faculty have leadership positions in the scientific community, including editorial responsibilities for major scientific journals, memberships on advisory boards and NIH and NSF peer-review panels, and the organization of national and international meetings.

G&D faculty and graduate students conduct research covering a broad spectrum of modern biomedical interests on diverse experimental systems including mice, frogs, worms, fruit flies, sea urchins, bats, yeast and human cells. You will find a description of each professor’s research starting on page 11 and on our program website at www.mdanderson.org/departments/genesdev. The scope of research in our program labs falls into these general areas:

Cancer Biology: The genes and processes that affect cancer development.Genetics: Study of heredity and the basis for variation in organisms.Proteomics & Genomics: System wide changes in proteins and nucleic acids in response to disease and other biological processes. Stem Cells & Developmental Biology: The mechanisms by which cells differentiate and form complex tissues or organ systems.Organ Growth & Cell Signaling: Cellular processes that regulate organ growth and cellular activities.Biomolecular Structure & Function: Analysis of the function of macromolecules through structural determination by crystallography and other methods.Gene Regulation & Epigenetics: The mechanisms by which changes in chromatin structure, transcription, RNA processing and translation determine patterns of gene expression.

Genes & Development Program


Graduate student presenting poster at G&D retreat.

RNA splicing regulates male-specific behavior in fruit flies by affecting the synthesis of proteins secreted from fat cells (red). (courtesy of Dr. William Mattox’s lab)

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Program of Study

The training for the Ph.D. degree includes a broad knowledge of gene regulation, biochemistry, molecular biology and developmental biology. These are acquired through coursework, three 10-week laboratory rotations during the first year, participation in research seminars and journal clubs, and a dissertation research project.

The rotations expose students to a variety of experi-mental approaches and assist them in the selection of their research advisor. Most coursework is completed during the first two years of study. The specific course requirements depend on which of three G&D tracks the student chooses: Cancer Biology, Developmental Biology or Structural Biology. Students advance to Ph.D. candidacy after com-pleting a written and oral candidacy exam during the first

semester of their third year. After advancing to candidacy, students concentrate on completing their dissertation research. Students generally complete the requirements for the Ph.D. in five to six years.

Core program courses:

Experimental Genetics: Covers concepts that are central to contemporary genetics and current approaches used in the analysis of classical eukaryotic genetic systems including humans, mice, flies, nematodes and yeast. Eukaryotic Gene Expression: An advanced molecular genetics course with a primary emphasis on the regulation of gene expression. Topics in Genes & Development: In the fall semester, instruction is on developing scientific writing skills with a focus on writing research proposals and manuscripts for publication. The spring semester is focused on developing oral scientific presentations. Students present seminars on their research and participate in the critique of presentations. Critical Thinking in Science: Develop skills to critically and professionally evaluate the significance, logic and presentation of scientific studies. Topics include experimental design, the logical interpretation of results, scientific fraud, controversial results, dogma, and effective critique.Track-dependent courses:

Cancer Cell Signaling: In-depth study of oncogenes including assays to detect activated oncogenes, role of oncogenes in tumorigenesis, and their relationship to growth regulation and differentiation.Developmental Biology: Provides an understanding of the mechanisms of embryogenesis and cellular differentiation as well as the methods used to investigate them. Structure and Function of Biological Macromolecules: Provides an in-depth examination of the chemistry, structure and function of biological macromolecules with an emphasis on proteins, nucleic acids and their complexes.Additional courses include GSBS requirements, such as biochemistry, biomedical statistics and ethics.



Microscopy core manager and graduate student analyze time-lapse images collected on a spinning disc confocal microscope.

X-gal stained transgenic mouse embryo showing the expression of Lmx1b at E11.5. (courtesy of Dr. Randy Johnson’s lab)

G&D program laboratories in the Mitchell Basic Science Research Building at The University of Texas MD Anderson Cancer Center.

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Program Activities

As part of our commitment to educate and train graduate students for successful biomedical careers, the G&D Program sponsors numerous events and activities. Through these activities, G&D students work together with classmates and faculty to develop their experimental reasoning and communication abilities, further their core scientific knowledge, and establish important scientific contacts for their future. Activities include:

Weekly research seminars and journal clubs where students present their research project or discuss recent advances described in the current literature. Weekly Blaffer Lecture Series with internationally prominent scientists who are invited to speak about their latest research, and meet with G&D students over lunch. Annual Spring Retreat at a Texas seaside or piney woods resort where faculty and students discuss and present their research, and enjoy time together. The retreat is divided into short research talks, an evening student poster session, and free time for informal discussion and fun. The retreat is one of the highlights of the year!G&D Student Dialog Series where students meet informally several times a year with an invited guest from the Houston scientific community to talk about careers, scientific topics, and other points of interest. Directors Roundtable where twice a year students meet with the G&D Directors over lunch to discuss suggestions, concerns, and questions about the Program. Annual faculty/student dinner, ice cream socials and other events that bring program faculty and students together for a mix of scientific and social exchange.

G&D Students

There are approximately 40 students in the G&D Program who publish in top journals such as Nature, Science, Cell, Nature Genetics, Cancer Cell, and Nature Cell Biology. Former students of the Program are now tenure-track professors at major universities in the U.S., including Rice University, The Ohio State University, University of Connecticut, University of Alabama, University of California San Francisco, University of Kansas, University of Massachusetts Medical School, and Yale University. Other graduates have pursued non-academic careers in biotechnology, government service, patent law and technology transfer.

Funding and Awards

All students in the program receive full financial support throughout their training. This support includes tuition and fees, as well as a generous stipend to support living expenses and health insurance. The 2010-2011 stipend level is $26,000. Annual competitive awards are also available for outstanding research projects and posters, and to support student travel to national and international scientific conferences. In addition, the University of Texas Graduate School of Biomedical Sciences (GSBS) offers competitive fellowships throughout the year to eligible students.



Student, postdoc and faculty volleyball game at the G&D retreat at Camp Allen.

G&D professor and student at retreat.

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Research Facilities

The G&D Program, the Department of Genetics and the Department of Biochemistry & Molecular Biology are located in the Mitchell Basic Sciences Research Building at MD Anderson. Completed in 2005, the building also houses GSBS administrative offices and classrooms.

Extensive resources are available to pursue biochemical, molecular, cell and developmental biological experiments. They include state-of-the-art microscopy and digital imaging capabilities, a DNA analysis core facility, a microarray facility, a genome analyzer for epigenetic ChIP-Seq or methylation sequencing studies, a genetically engineered mouse facility, and a 122,000 sq. ft. vivarium. Structural biology resources include major equipment for protein purification and analysis, mass spectrometry, X-ray generator and detectors, and a computational modeling lab.

How to Apply

The Genes & Development Program is part of The University of Texas Graduate School of Biomedical Sciences at Houston (GSBS). All students interested in joining the program must apply and be admitted to GSBS; all GSBS students are eligible to join the G&D Program. Near the end of the first year of study, students who have joined the lab of a G&D faculty member can join the Program with the approval of the G&D Program Director; no additional application is required.

GSBS admissions information and online applications are available on the GSBS website at www.uthouston.edu/gsbs/future-students/admissions/. The priority application deadline for U.S. applicants seeking fall admission is December 15, with a final deadline of February 1. However, December 15 is the recommended deadline, as GSBS will begin reviewing applications and inviting qualified applicants to interview in December. The deadline for international applicants is November 15.

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At left, the cell layers of a mature mouse retina. At right, the retinal ganglion cell gene regulatory network. (courtesy of Dr. William Klein’s lab)


Going down the chromatin assembly energy funnel. (courtesy of Dr. Jessica Tyler’s lab)

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Image of wound site (black dot in middle) in the epidermis of a Drosophila larva bearing fluorescent transgenes that label epidermal cell membranes in green and epidermal cell nuclei in red. (courtesy of Dr. Michael Galko’s lab)


A one-cell C. elegans embryo stained with tubulin and pAurora kinase antibodies. (courtesy of Dr. Jill Schumacher’s lab)

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Graduate School of Biomedical Sciences


The University of Texas Graduate School of Biomedical Sciences (GSBS) offers programs to obtain an M.S., Ph.D. or combined M.D./PhD. Its more than 500 faculty members are drawn from the University of Texas Health Science Center at Houston, The University of Texas MD Anderson Cancer Center, and the Texas A&M University Institute of Biosciences and Technology. This combination of faculty and institutions provides one of the world’s most outstanding environments for graduate training in the biomedical sciences.

GSBS differs from many graduate schools in that students are admitted to the school itself and not to a particular program or department. This provides an extraordinary degree of flexibility to new students who are free to choose among 14 Ph.D. programs, of which Genes & Development is one. Students generally decide on a program at the end of their first year after they have completed three 10-week laboratory tutorials and have selected their thesis advisor.

The GSBS lies in the heart of the Texas Medical Center (TMC), in the new Mitchell Basic Sciences Research Building at MD Anderson, and is within blocks of more than 40 TMC member institutions, including two medical schools, four nursing schools, and 13 renowned hospitals. In this setting, GSBS graduate students and faculty have access to the most sophisticated biomedical research facilities available. The proximity to neighboring institutions, including Baylor College of Medicine, The University of Texas Medical School, and Rice University fosters inter-institutional collaborations, joint research interest group meetings, and easy access to research seminars by local and visiting world-renowned scientists.

Graduate School Admissions

To apply to The University of Texas Graduate School of Biomedical Sciences, please visit their website below for admissions information and the online application. The priority application deadline for U.S. applicants seeking fall admission is December 15, with a final deadline of February 1. However, December 15 is the recommended deadline, as GSBS will begin reviewing applications and inviting qualified applicants to interview in December. The deadline for international applicants is November 15.

For More Information on GSBS and Application Materials:

Dr. Mary Ellen Lane Assistant Dean for Admissions The University of Texas-Graduate School of Biomedical Sciences at Houston P.O. Box 20334 Houston, TX 77225-0334 1-800-UTH-GSBS (or locally at 713-500-9850) Fax: 713-500-9877 [email protected] www.uthouston.edu/gsbs/future-students/admissions/

“GSBS is a great place to experience the excitement of contemporary biomedical research along with the satisfaction of making important contributions.”

Dean George M. Stancel, Ph.D.

Mitchell Basic Sciences Research Building, completed in 2005 and the home of the G&D Program and GSBS.

Chromosomes isolated from a mouse pancreatic tumor hybridized with chromosome specific paint probes.

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The University of Texas MD Anderson Cancer Center offers outstanding opportunities for students beginning their careers in the biomedical sciences. MD Anderson Cancer Center is today recognized internationally as a worldwide leader in cancer research, treatment, prevention and education.

In 2010, U.S. News & World Report again ranked MD Anderson No. 1 in cancer care in its annual “America’s Best Hospitals” survey. This is the fourth consecutive year, and the seventh time in the last nine years, that MD Anderson has ranked No. 1 in this influential annual listing. It is one of the nation’s original three Comprehensive Cancer Centers designated by the National Cancer Act of 1971. These honors stem in part from MD Anderson’s standing as a research facility and its contributions to our basic understanding of cancer and normal development.

Research activities range from inquiry into fundamental aspects of cell growth and differentiation, as exemplified by the Genes & Development Program, to the development of gene therapy strategies for patients. Opportunities exist for students interested in clinically relevant research to couple techniques of modern molecular biology with problems in cancer biology. In many cases, students can take advantage of the unique availability of patient tissues and tumor samples at MD Anderson. State-of-the-art facilities amply serve the needs of many diverse research interests.

Each year, MD Anderson holds an international symposium on recent developments in basic research. Eminent scientists from all over the world participate in this event, and students at the Cancer Center can attend free of charge.

Graduate students at MD Anderson are an essential and highly valued part of the research team. The faculty are committed to supporting students in their education and to assist them in becoming successful and outstanding contributors in the biomedical research community.

For More Information on MD Anderson:

www.mdanderson.org

MD Anderson Cancer Center


Skywalk across Holcombe Boulevard, linking buildings of the MD Anderson Cancer Center.

Graduate student and postdoc preparing a western blot for exposure in order to monitor the expression levels of transcription factors.

Live image of human embroyonic stem cells with green and red fluorescent protein reporters taken with a deconvolution microscope. (courtesy of Dr. Richard Behringer’s lab)

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Houston, Texas

Texas Medical Center, with downtown Houston in the background and Rice University adjacent to the left

Texas wildflowers

Houston skyline

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Houston is the fourth largest city in the U.S., home to a dynamic and ethnically diverse population. Here you will find a wide variety of cultural and recreational opportunities, including world-class symphony, opera, ballet and theater companies, numerous professional sports teams, bustling downtown and midtown districts, oustanding restaurants and an extensive museum district with 18 museums located within a small area near MD Anderson.

Houston’s tropical, southern climate permits outdoor activities year-round, including biking, tennis, softball, soccer, golf, walking and jogging. Galveston Island and beaches on the Gulf of Mexico are less than an hour drive away, and the Texas Hill Country, Austin and San Antonio are just three hours away.

Unlike many other medical centers, the Texas Medical Center is in an excellent location that is safe and convenient. It is adjacent to the Museum District, The Houston Zoo, Rice Village, Rice University, and the Miller Outdoor Theater’s free musical, dance and theatrical performances.

Houston’s diverse economy provides attractive job opportunities for family members. Energy services, IT, space science, biotechnology and healthcare all contribute significantly to the local economy. In addition, the cost of living in Houston remains below that of many other cities, allowing students to find affordable housing within walking, biking, and shuttle bus distance of MD Anderson.

For More Information on Houston:

www.houston.citysearch.com www.houstontx.gov downtownhouston.org

Tranquility Park in downtown Houston, created in honor of the first moon landing during the Apollo 11 mission

Brazos Bend State Park, wildlife haven and birdwatching destination

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Confocal image of a third-instar Drosophila eye imaginal disc. The yellow staining shows the expression pattern of the four jointed gene, which is known to be regulated by the Fat protocadherin. The disc also contains clones of cells that are homozygous mutant for warts, which encodes a Ser/Thr kinase that acts in the Hippo tumor-suppressor pathway. The warts mutant clones, marked by the absence of GFP expression (in blue), induce the expression of four jointed. This result exemplifies the regulation of a common set of target genes by the tumor suppressor Fat and the Hippo pathway. This and additional data suggest that the protocadherin Fat acts as a receptor of the Hippo tumor-suppressor pathway. (courtesy of Dr. Georg Halder’s lab)

Research interests• chromatin• p53• embryonicstemcells• liverregeneration• breastcancer

Research areasGene Regulation & EpigeneticsStem Cells & Developmental BiologyCancer Biology

Contact [email protected]

Michelle Barton, Ph.D.Professor, Department of Biochemistry & Molecular Biology

Research description

Our laboratory is focused on basic mechanisms of regulated and aberrant gene expression during differentiation, tissue regeneration and cancer, especially as dictated by members of the p53- family, their interacting protein partners, and chromatin structure. We are using deep sequencing, proteomic analyses and bioinformatics to determine chromatin interactions, post-translational modifications and protein partners of p53. Our model systems of interest are embryonic stem cells, liver regeneration and breast cancer. A major focus is TRIM24, a previously unknown E3-ubiquitin ligase of p53 that we identified. TRIM24 co-activates estrogen receptor and is a histone reader of a unique signature present at estrogen-regulated genes in breast cancer cells. Additionally, we are currently defining the impact of TRIM24, and other p53 regulatory proteins, on p53-functions in embryonic stem cells, and how p53-mediated regulation is temporally controlled during liver regeneration.

Selected publications

Kurinna S, Stratton SA, Tsai WW, Akdemir KC, Gu W, Singh P, Goode T, Darlington GJ, Barton MC (2010) Direct activation of Foxo3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice. Hepatology, in press.Taube JH, Allton K, Duncan SA, Shen L, Barton MC (2010) Foxa1 functions as a pioneer transcription factor at transposable elements to activate AFP during differentiation of embryonic stem cells. J Biol Chem 285(21): 16135-44. Allton K, Jain A, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC (2009)Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A 106(28): 11612-16.

Swathi Arur, Ph.D.Assistant Professor, Department of Genetics


The RAS oncogene is the single most common cause of cancer. It normally functions to relay extracellular growth signals via a conserved kinase cascade that ends in activation of ERK. Active ERK executes multiple cellular and developmental events by phosphorylating downstream substrates, and it is the deregulated activity of the ERK substrates that are the likely cause of tumorogenesis. Thus, it is imperative to identify these substrates in vivo and understand how they normally function to regulate each ERK-dependent event.

However, since RAS-ERK pathway governs multiple biological processes simultaneously, identification of substrates that govern each cellular event concurrently has been a challenge. Using Caenorabhditis elegans germline development as a model system, we discovered 30 evolutionarily conserved substrates of ERK, each of which functions in its own signaling module to govern at least one of nine ERK dependent events. This forms a well-integrated regulatory network that we call the ‘ERK-substrate network’. Our future research aims to understand the contribution of each substrate in this intricate regulatory network to a specific developmental process and how perturbations to this network can lead to disease. Given the conservation of these substrates, findings from our study have strong implications to human development and oncogenesis.


Arur S, Ohmachi M, Nayak S, Hayes M, Miranda A, Hay A, Golden A, Schedl T (2009) Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development. Proc Natl Acad Sci U S A 106(12): 4776-81.Arur S, Uche UE, Rezaul K, Fong M, Scranton V, Cowan AE, Mohler W, Han DK (2003) Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev Cell 4(4): 587-98.

Research interests• RAS-ERKsignaling• germcelldevelopment• C. elegans genetics

Research areasGenetics Stem Cells & Developmental Biology Organ Growth & Cell Signaling


www.mdanderson.org/departments/genesdev11

Andreas Bergmann, Ph.D.Associate Professor, Department of Biochemistry & Molecular Biology


We are utilizing the highly accessible genetic model system Drosophila melanogaster to gain a comprehensive understanding of the biological principles that underlie the regulation of apoptosis in the context of a multi-cellular organism. Knowledge obtained in these studies may provide new insights into human diseases that are associated with altered rates of apoptosis.

We have developed a novel genetic screening method to identify genes involved in cell death control and execution in Drosophila. However, unexpectedly, we also identified genes involved in growth control and tumor suppression. The role of these interesting genes for normal development and tumorigenesis is currently under intensive study in the lab.

A tutorial in our lab will provide a detailed introduction into modern Drosophila techniques with emphasis on visualizing gene activity and cell death in wild-type and various mutant background, phenotypic analysis, generating transgenic flies and small scale genetic screens. In addition, students will gain experience in basic molecular biology and protein chemistry. The experiments will be aided by state-of-the-art facilities.


Fan Y, Lee TV, Xu D, Chen Z, Lamblin A-F, Steller H, Bergmann A (2010) Dual roles of Drosophila p53 in cell death and cell differentiation. Cell Death & Differentiation 17: 912-21.Herz H-M, Madden LD, Chen Z, Bolduc C, Buff E, Gupta R, Davuluri R, Shilatifard A, Hariharan IK, Bergmann A (2010) The H3K27me3-demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Molecular and Cellular Biology (MCB) 30: 2485-97.Wang Y, Chen Z, Bergmann A (2010) Regulation of EGFR and Notch signaling by distinct isoforms of D-cbl during Drosophila development. Developmental Biology 342: 1-10.

Research interests• apoptosis• cellsurvival• tumorsuppression

Research areasOrgan Growth & Cell SignalingCancer BiologyGene Regulation & Epigenetics


Richard R. Behringer, Ph.D.Professor, Department of Genetics


Our research focuses on the molecular and cellular mechanisms that lead to the formation of the mammalian body plan, the differentiation of tissues and morphogenesis organs during embryogenesis, and the pathology of developmental defects. In addition, we study the genetic mechanisms that result in organ morphology and physiology differences that have evolved between species. We utilize genetic, embryological, and comparative approaches.


Nel-Themaat L, Vadakkan TJ, Wang Y, Dickinson ME, Akiyama H, Behringer RR (2009) Morphometric analysis of testis cord formation in Sox9-EGFP mice. Dev Dyn 238: 1100-10.Cretekos CJ, Wang Y, Green ED, NISC Comparative Sequencing Program, Martin JF, Rasweiler JJ IV, Behringer RR (2008) Regulatory divergence modifies forelimb length in mammals. Genes Dev 22: 141-51. Pask AJ, Behringer RR, Renfree MB (2008) Resurrecting DNA function from the extinct Tasmanian tiger. PLoS One 3: e2240.

Research interests• mammaliandevelop- mental genetics• reproductivebiology and disease• stemcells,homeostasis, and regeneration• evolutionand development

Research areasGeneticsStem Cells & Developmental Biology


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Benoit de Crombrugghe, M.D.Professor, Department of Genetics


My laboratory is interested in the molecular mechanisms that control the fate of several cell types including chondrocytes and osteoblasts, aiming at identifying and studying the function and regulation of transcription factors that control the differentiation pathways for these cell types.

We have shown that the transcription factor SOX9 is a critical factor to control differentiation of multiple cell lineages in vivo, including chondrocytes and intestinal Paneth cells. OSTERIX is another transcription factor that we have identified and shown to be absolutely required for the differentiation of osteoblasts during embryonic development. We have more recently shown that SOX9 is needed for the integrity of articular cartilage and intervertebral discs in adult mice. We have also provided evidence that OSTERIX is required in adult mice to maintain bone homeostasis. Our present effort is focusing on biochemical mechanisms by which SOX9 and OSTERIX control the genetic programs of chondrocyte and osteoblast differentiation and homeostasis.

In other recent projects, we have developed and studied mouse models for human fibrotic diseases by activating the TGFβ pathway, as well as by overexpressing the secreted signaling molecule Connective Tissue Growth Factor, demonstrating possible involvement of these signaling pathways in disorders including systemic sclerosis.


Zhou X, Zhang Z, Feng JQ, et al (2010) Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice. Proc Nat Acad Sci, in press.Coustry F, Oh CD, Hattori T, et al (2010) The dimerization domain of SOX9 is required for transcrip-tion activation of a chondrocyte-specific chromatin DNA template. Nucleic Acids Res 2010 May 19. Zhang C, Cho K, Huang Y, et al (2008) Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix. Proc Natl Acad Sci USA 105(19): 6936-41.

Research interests• cellfatedetermination• celldifferentiation• chondrocytes• osteoblasts

Research areasStem Cells & Developmental BiologyGene Regulation & EpigeneticsOrgan Growth & Cell Signaling



Sharon Y.R. Dent, Ph.D.Professor and Chair, Department of Molecular Carcinogenesis


The chromatin field was galvanized by the identification of histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and other chromatin modifying enzymes. It was further stimulated by the discovery that specialized motifs in nonhistone proteins specifically bind to modified histone isoforms and the realization that particular histone modifications regulate one another to create feedback and feed forward regulatory swithches. However, the functions of many histone modifying enzymes in vivo are still not well defined. Nor is it clear whether post-translational modifications in other proteins are cross-regulated as they are in histones. Research in my lab addresses these important questions using a combination of genetic, molecular, and biochemical approaches. We use both mice and yeast as model systems. Our research is divided into three main projects: 1) Defining the functions of the Gcn5 acetyltransferase during mouse development 2) Defining regulatory cross-talk between methylation, acetylation, and phosphorylation events in histone and non-histone proteins and 3) defining epigenetic changes in embryonic stem (ES) cells, induced pluripotent (iPS) cells and differentiating cells.


Atanassov BS, Evrard YA, Multani AS, Zhang Z, Tora L, Devys D, Chang S, Dent SY. (2009) Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance. Mol Cell 35(3): 352-364.Latham JA, Dent SYR (2007) Cross-regulation of histone modifications. Nat Struct Mol Biol 14(11): 1017-1024.Zhang K, Lin W, Latham JA, Riefler GM, Schumacher JM, Chan C, Tatchell K, Hawke DH, Kobayashi R, Dent SYR (2005) The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 122(5): 723-734.

Research interests• epigenetics• mitosis• histonemodifying enzymes• stemcellsandembryo development

Research areasGene Regulation & EpigeneticsStem Cells & Developmental BiologyCancer Biology


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Yasuhide Furuta, Ph.D.Associate Professor, Department of Biochemistry & Molecular Biology


The research in our laboratory is aimed at understanding the genetic mechanisms underlying organ formation and homeostasis. In particular, we focus on the following two major areas; 1) vertebrate ocular development that ultimately affects visual function, and 2) regulation of neural stem/progenitor cells in the adult brain that have implications to brain tumor stem cells. We approach these problems by studying the signaling pathways initiated by a family of secreted signaling molecules called bone morphogenetic proteins (BMPs). We employ molecular and genetic approaches in the mouse, and are analyzing a series of BMP signaling-defective mutant mice that exhibit symptoms reminiscent of certain disorders in the eye or pre-cancerous pathologies in the brain. It is our hope that elucidating the role of BMP signaling in the visual system and postnatal brain will contribute to our better understanding of the cause of various visual and neurological disorders and brain cancers. The principles learned from these in vivo studies will provide valuable insights into our understanding of genetic mechanisms underlying fundamental processes of tissue aging, regeneration, and tumorigenesis, in which various secreted signaling molecules apparently play important roles.


Satoh S, Tang K, Iida A, et al (2009) The spatial patterning of mouse cone opsin expression is regulated by bone morphogenetic protein signaling through downstream effector COUP-TF nuclear receptors. J Neurosci 29: 1240-41.Plas DT, Dhande OS, Lopez JE, et al (2008) Bone morphogenetic proteins, eye patterning, and retinocollicular map formation in the mouse. J Neurosci 28(8): 7057-67.Murali D, Yoshikawa S, Corrigan R, et al (2005) Distinct developmental programs require different levels of Bmp signaling during mouse retinal development. Development 132: 913-23.


Research interests• oculardevelopment• neuralstemcells• braintumor• mousemolecular genetics

Research areasStem Cells & Developmental BiologyGeneticsOrgan Growth & Cell Signaling


Elsa R. Flores, Ph.D.Associate Professor, Department of Molecular and Cellular Oncology


The interests of my laboratory are to understand the interplay of the p53 family of genes in anti-tumorigenic processes including DNA damage, apoptosis, tumor suppression, and metastasis. The goal is to use this knowledge to design more targeted therapies for cancer patients with mutations in the p53 pathway. Given the structural similarity of p63 and p73 to p53, much excitement resulted over the potential of these genes to be tumor suppressors. Unfortunately, data from human tumors have been difficult to interpret due to the existence of multiple isoforms of p63 and p73 including transactivation competent (TA) isoforms and those lacking the transactivation domain (∆N). To understand the mechanisms of these isoforms of p63 and p73 in anti-tumorigenic pathways, my laboratory has used an in vivo approach by engineering mouse models that are deficient for the TA or ∆N isoforms of p63 and p73. These mouse models are being used to understand the roles of the p63/p73 isoforms in stem cell renewal, aging, tumorigenesis, and metastasis.


Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung M, El-Naggar A, Crieghton CJ, Flores ER (2010) TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature, in press.Su X, Paris M, Gi Y-J, Tsai KY, Cho MS, Lin Y-L, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER (2009) TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell 5(1): 64-75.Lin Y-L, Sengupta S, Gurdziel K, Bell, G, Jacks T, Flores ER (2009) p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genetics 5(10): e1000680.Su X, Cho MS, Gi YJ, Ayanga BA, Sherr CJ, Flores ER (2009) Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf. EMBO J 28(13): 1904-15.

Research interests• mousemodels• tumorsuppressorgenes• metastasis• stemcells

Research areasCancer BiologyStem Cells & Developmental BiologyGene Regulation & Epigenetics


14

Michael Galko, Ph.D.Assistant Professor, Department of Biochemistry & Molecular Biology


Multicellular organisms have evolved a variety of tissue repair responses to cope with tissue damage. Some of these responses (wound closure) are aimed at restoring structure and function to the damaged tissue(s) while others (inflammation and nociceptive sensitization) are aimed at protecting the organism from further infection or injury. My laboratory is interested in identifying the elusive signals that initiate and terminate different aspects of the organismal tissue repair response, as well as the genes that are required to execute each specific response. Ultimately, we wish to understand in molecular detail how the activities of diverse damage-responsive cell types are coordinated in space and time to give a functional tissue repair program. To pursue these interests we have developed a variety of tissue repair/response assays in the highly genetically tractable model organism Drosophila melanogaster, and are focusing our efforts on two critical responses: epidermal wound closure, and nociceptive sensitization (lowering of the threshold for sensing painful stimuli following injury). Given that tissue repair responses are an ancient survival mechanism of multicellular animals, we expect that the functional importance of many of these genes we identify will be conserved between flies and vertebrates.


Wu Y, Brock AR, Wang Y, Fujitani K, Ueda R, Galko MJ (2009) A blood-borne PDGF/VEGF-like ligand initiates epidermal wound closure in Drosophila larvae. Current Biol 19(17): 1473-1477.Babcock DT, Landry C, Galko MJ (2009) Cytokine signaling mediates UV-induced nociceptive sensitization in Drosophila larvae. Current Biol 19(10): 799-806.Galko MJ, Krasnow MA (2004) Cellular and genetic analysis of wound healing in Drosophila. PLoS Biology 2(8): e239.

Howard B. Gutstein, M.D.Professor, Department of Anesthesiology, Department of Biochemistry & Molecular Biology


The primary focus of our research is to understand the molecular mechanisms underlying the development of opioid tolerance and dependence and the interactions of pain and analgesic signaling. The overall goal of these projects is to develop more effective therapies for treating chronic pain without causing the devastating side effects of tolerance, dependence and addiction. We employ a multidisciplinary approach to understand these problems using cutting-edge techniques. After demonstrating clinical and physiological relevance in animal behavioral studies, we dissect underlying mechanisms using proteomics to determine which changes in cellular signaling are responsible. Trainees gain experience with techniques such as in situ hybridization, immunocytochemistry, cell culture and transfection, 2-D gel electrophoresis, mass spectrometry, laser capture microdissection, image analysis and behavioral studies to explore important neurobiological questions from many perspectives. Close relations with clinical colleagues in the pain clinic provide opportunities to translate our basic findings into clinical practice and eventually see the direct application of our efforts.


Gutstein HB, Morris JS, Annangundi SP, Sweedler JV (2008) Microproteomics: The analysis of protein expression in small cell groups. Mass Spectrometry Reviews 27(4): 316.Morris JS, Clark BN, Gutstein HB (2008) A fast, automatic and accurate method for detecting and quantifying protein spots in 2-dimensional gel electrophoresis data. Bioinformatics 24(4): 529.Gutstein HB, Akil H (2006) “Opioid Analgesics” in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, eleventh edition, Brunton L, Ed., McGraw-Hill, pp. 547-90.

Research interests• proteomicapproaches to addiction and opioid tolerance• interactionofpain and analgesic signal transduction mechanisms• translational pain studies

Research areasOrgan Growth & Cell Signaling Proteomics & Genomics


Research interests• Drosophila genetics• moleculargeneticsof tissue repair• cellmigration• cellsignalingand signal transduction• painsensitization

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell Signaling Genetics



Vicki Huff, Ph.D.Professor, Department of Genetics


My research program focuses on identifying and understanding the function of genes whose alteration is critical for the development of Wilms tumor (WT), a childhood kidney cancer. Aberrant kidney development is thought to be a major feature in the etiology of WT. One gene critical for kidney development is WT1, the germline mutation of which results in WT predisposition, genitourinary anomalies, and early onset renal failure. We are investigating WT1’s role in development and cancer by molecular analyses of primary human tumors and the generation and use of Wt1-mutant mouse strains. From this we know that WT1 mutation results in distinctive gene expression and loss of heterozygosity profiles in tumors. Our Wt1+/R394W mice develop early onset renal failure with a pathology identical to that in patients. Using our Wt1 conditional knock-out strain (Wt1CKO), we have determined that Wt1 ablation in the testes results in a dramatic loss of testes architecture and in the developing kidney Wt1 loss results in a complete block in nephrogenesis. Additionally, we have generated the first endogenous mouse model for WT which we are now using to understand early stages of tumorigenesis and to identify cellular signaling pathways that are abrogated in tumors and that may be therapeutic targets. Overall, these studies of humans and mice will further the understanding of the biology and genetics of WT.


Hu Q et al (2010) J Clin Invest, in press.Ruteshouser EC, et al (2008) Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for a third of tumors. Genes Chromosomes Cancer 47: 461-70.Gao F, et al (2006) The Wilms tumor gene, Wt1, is required for Sox9 expression and normal tubular architecture in the developing testis. Proc Natl Acad Sci USA 103: 11987-92.


Research interests• humangenetics• cancergenetics• familialcancer predisposition• kidneydevelopment

Research areasGeneticsCancer BiologyStem Cells & Developmental Biology


Georg Halder, Ph.D.Associate Professor, Department of Biochemistry & Molecular Biology


Growth is fundamental to development, yet remarkably little is known about the mechanisms that control organ size. How do cells know when to stop dividing after an organ has reached its proper size, and how do injured organs regenerate damaged or missing parts? We are using the fruit fly Drosophila as a model system to address these questions and to discover signaling pathways that regulate growth and regeneration. The combination of the powerful genetic tools and the capacity of its developing tissues to regenerate make Drosophila a superb system in which to study growth control and regeneration.

Through genome-wide genetic screens we discovered a novel growth control pathway, the “Hippo pathway”. Animals carrying mutations in hippo develop severely overgrown structures and have tumorous overgrowths. Strikingly, the Hippo pathway is highly conserved in vertebrates where it also regulates growth and is often mutant in cancer. We are currently studying extracellular signals that regulate the Hippo pathway and how Hippo signaling and other pathways are normally involved in growth control and regeneration and how misregulation of the Hippo pathway leads to cancer.


Hamaratoglu F, Gajewski K, Sansores-Garcia L, Morrison C, Halder G (2009) The Hippo tumor suppressor pathway regulates apical domain size in parallel to tissue growth. J Cell Science 122(14): 2351-59. Willecke M, Hamaratoglu F, Sansores-Garcia L, Halder G (2008) Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc Natl Acad Sci USA 105(39): 14897-902.Hamaratoglu F, Kango-Singh M, Nolo R, Hyun E, Tao C, Jafar-Nejad H, Halder G (2006) The tumour suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biology 8: 27-36.

Research interests• organsizecontrol• regeneration• tumorsuppressor genes• Drosophila genetics• cancermechanisms

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell SignalingGenetics


16


Randy L. Johnson, Ph.D.Professor, Department of Biochemistry & Molecular Biology


Research in my laboratory focuses on genetic regulation of growth and pattern formation with an emphasis on limb, liver, and intestinal development, function, and disease. Our primary experimental systems are transgenic mice and manipulation of embryonic (ES) stem cells. At present we are using these systems to address novel pathways involved in mammalian tumor suppression, including the recently described Hippo pathway. Current and future research is directed at the design and analysis of novel mouse models for cancer research and therapy.


Lu L, Li Y, Kim SM Bossuyt W, Liu P, Wang Y, Halder G, Finegold MJ, Lee JS, Johnson RL (2010) Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 107: 1437-42.Li Y, Qiu Q, Watson SS, Schweitzer, Johnson RL (2010) Uncoupling skeletal and connective tissue patterning: conditional deletion of lmx1b in cartilage progenitors reveals autonomous requirements for lmx1b in dorsal-ventral limb patterning. Development 137: 1181-88.Blitz E, Viukov S, Sharir A, Schwartz Y, Galloway JL, Pryce BA, Johnson RL, Tabin C, Schweitzer R, Zelzer, E (2009) Bone ridge patterning during musculoskeletal assembly is mediated through scx regulation of bmp4 at the tendon-skeletal junction. Dev Cell 17: 861-73.Alton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC (2009) Trim24 targets endogenous p53 for degredation. Proc Natl Acad Sci USA 106: 11612-16.

Hamed Jafar-Nejad, M.D.Assistant Professor, The Institute of Molecular MedicineThe University of Texas Health Science Center at Houston


Our group is interested in the role of glycosylation in animal development. Our focus is to understand the role of a recently identified glycosyltransferase called Rumi in the regulation of the Notch signaling pathway. Notch signaling is an evolutionarily conserved pathway that regulates numerous processes during animal development and in adult organisms. Mutations in this pathway cause leukemia, cerebrovascular dementia, developmental disorders including congenital heart disease, and several other human diseases. We use Drosophila and mouse genetics and cell culture experiments to study the mechanisms of Notch pathway regulation by the level and distribution of carbohydrates attached to Notch pathway components. These studies are complemented by state-of-the-art biochemical experiments by our collaborators.


Jafar-Nejad H, Leonardi J, Fernandez-Valdivia, R (2010) Role of Glycans and Glycosyltransferases in the Regulation of Notch Signaling. Glycobiology, in press. (invited review)Simcox AS*, Austin CL, Jacobsen TL, Jafar-Nejad H* (2008) Drosophila embryonic ‘fibroblasts’: Extending mutant analysis in vitro. Fly 2(6): 306-09. (*corresponding author)Acar M*, Jafar-Nejad H*, Takeuchi H*, Rajan A, Ibrani D, Rana D, Pan H, Haltiwanger RS, Bellen HJ (2008) Rumi Is a CAP10 Domain Glycosyltransferase that Modifies Notch and Is Required for Notch Signaling. Cell 132(2): 247-58. (*equal contribution)Jafar-Nejad H, Andrews HK, Acar M, Bayat V, Wirtz-Peitz F, Mehta SQ, Knoblich JA, Bellen HJ (2005) Sec15, a member of the exocyst, promotes Notch signaling during the asymmetric division of Drosophila sensory organ precursors. Developmental Cell 9(3): 351-63.

Research interests• developmental glycobiology • Notchsignaling• intracellulartrafficking• asymmetricdivisions

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell Signaling Genetics

Contact informationhamed.jafar-nejad@ uth.tmc.edu713-500-3483

Research interests• mousegenetics• Hippopathway• tumorsuppressor genes• mousemodelsfor cancer research

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell Signaling Cancer Biology


17

William H. Klein, Ph.D.Professor and Chair, Department of Biochemistry & Molecular Biology


Differentiated cells arise from multipotent progenitor cells. We study how progenitors regulate programs of gene expression in embryos and adults. In one project, we constructed a transcription factor network that regulates the differentiation of ganglion cells in the retina. Ganglion cells transmit electrical impulses to the brain via the optic nerve. Although ganglion cells are essential for vision, how they form and why they die in retinal disease is poorly understood. Several transcription factors are critically positioned within the retinal ganglion cell gene regulatory network with multiple inputs and outputs. We use genetically engineered mice to manipulate the network and achieve a systems- level understanding of how gene programs are regulated. We generated a mouse model for optic nerve degeneration and are applying this model to stem cell replacement therapy to repair damaged optic nerves.

In a second project, we are studying the transcription factor myogenin during adult muscle repair and regeneration. We generated a mouse model in which we removed myogenin from adult muscle. We discovered that myogenin regulates exercise capacity and skeletal muscle metabolism. We are using our mouse model to develop novel strategies for improving muscle performance and preventing muscle wasting in muscular and neuromuscular diseases.


Moresi V, Williams AH, Meadows E, Flynn JM, McAnally J, Shelton JM, Backs J, Klein WH, Richardson JA, Bassel-Duby R, Olson EN (2010) Myogenin and class II HDACs control skeletal muscle atrophy by inducing E3 ubiquitin ligases. Cell, in press. Mu X, Fu X, Beremand PD, Thomas TL, Klein WH (2008) Gene regulation logic in retinal ganglion cell development: Isl1 defines a critical branch distinct from but overlapping with Pou4f2. Proc Natl Acad Sci USA 105: 6942-47.

Research interests• development mechanisms• transcriptionfactors in development• mousemodelsfor human disease• generegulatorynetworks and systems biology

Research areasStem Cells & Developmental BiologyGene Regulation & EpigeneticsGenetics


Ann M. Killary, Ph.D.Professor, Department of Genetics


Little is known about the genetic pathways that discriminate breast cancer in young women from those that occur more commonly in the general population with later age of onset. Our laboratory has identified a novel tumor suppressor gene DEAR1 which we have evidence of its role in the evolution of breast cancer and for its potential as a prognostic marker in early onset breast cancer. Functional characterization studies indicate that DEAR1 regulates polarity and acinar morphogenesis in 3D culture. A major project in the laboratory involves the characterization of DEAR1 function to elucidate its role in development and cancer.

Our laboratory is also a biomarker discovery laboratory funded by the Early Detection Research Network at the National Cancer Institute. Goals in this regard are focused on the use of functional genomic strategies to identify pathways aberrant in pancreatic cancer from which novel biomarkers for the early detection of pancreatic cancer can be identified.


Lott ST, Chen N, Chandler D, Yang Q, Wang L, Rodriguez M, Xie H, Balasenthil S, Buchholz TA, Sahin A, Chaung K, Zhang B, Olufemi S-E, Chen J, Adams H, Band V, El-Naggar A, Frazier ML, Keyomarsi K, Hunt K, Sen S, Haffty B, Hewitt S, Krahe R, Killary AM (2009) DEAR1 is a Dominant Regulator of Acinar Morphogenesis and Independent Predictor of Local Recurrence-Free Survival in Early Onset Breast Cancer. PLoS Med 6(5): e1000068. Wang J, Chen J, Chang P, LeBlanc A, Li D, Abbruzzesse JL, Frazier ML, Killary AM, Sen S (2009) MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res 2(9): 807-13.

Research interests• tumorsuppressorgenes• breastandpancreatic cancer• cancergenetics

Research areaGeneticsCancer Biology


18

Ralf Krahe, Ph.D.Associate Professor, Department of Genetics


My research focuses on the identification and characterization of human genes and their mutations, using classic and molecular genetic approaches.

Myotonic dystrophy is caused by mutant (CTG)n or (CCTG)n expansions that when transcribed cause disease. It is unclear how these mutant (CUG)n/(CCUG)n RNAs mediate their disease-causing effects at the molecular and cellular level. To dissect the pathophysiology, we are using functional genomics approaches and have generated transgenic and knock-in mouse models.

Li-Fraumeni syndrome (LFS) is a genetically heterogeneous, rare inherited cancer syndrome. Most cases are due to mutations in the tumor suppressor p53. We have mapped another LFS locus to 1q23, which we are positionally cloning. In p53 and non-p53 LFS, there is evidence for risk modifiers and factors in addition to the inherited susceptibility. We are using integrated approaches combining genomic and epigenomic profiling to dissect the complex genetic and epigenetic events underlying LFS tumorigenesis. LFS predisposition and/or modifier genes may also be functionally important in other tumor types lacking a clear genetic predisposition. The molecular characterization of sporadic cancers (head and neck, lung and brain) through genomics methodologies to identify genomic, epigenomic and transcriptomic changes underlying tumor initiation, progression and metastasis is another focus.


Richards KL, et al (2009) Genome-wide hypomethylation in head and neck cancer is more pronounced in HPV-negative tumors and is associated with genomic instability. PLoS One 4: e4941.Bachinski LL, et al (2009) Premutation allele pool in myotonic dystrophy type 2. Neurology 72: 490-97.Colella S, et al (2008) Molecular signatures of tumorigenesis and metastasis in head and neck cancer. Head Neck 30: 1273-83.

Research interests• humanandmolecular genetics• neurogenetics• cancergenetics• genomics

Research areasCancer BiologyGeneticsProteomics & Genomics


Leslie Krushel, Ph.D.Associate Professor, Department of Biochemistry & Molecular Biology


Our lab is interested in the mechanisms and regulation of protein synthesis and how these translational mechanisms contribute to cancer and Alzheimer’s disease.

We utilize a variety of approaches including: biochemical analyses to characterize RNA secondary structure and identify novel proteins, cell culture to monitor protein synthesis, microscopy to image protein synthesis dynamically in cell bodies but also in neuronal dendrites and axons, and finally creating transgenic mice to determine the effectiveness of our in vitro results on cancer and Alzheimer’s disease.


Veo BL, Krushel LA (2009) Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis 16(2): 271-75.Beaudoin ME, Poirel VJ, Krushel LA (2008) Regulating amyloid precursor protein synthesis through an internal ribosomal entry site. Nucleic Acids Res 36(21): 6835-47.Dobson T, Kube E, Timmerman S, Krushel LA (2008) Identifying intrinsic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5’ leader. BMC Mol Biol 9: 89.

Research interests• RNA• proteinsynthesis• Alzheimer’sdisease• neuronaldevelopment

Research areaCancer BiologyGene Regulation & Epigenetics



John E. Ladbury, Ph.D.Professor, Department of Biochemistry & Molecular Biology


Specificity in Tyrosine Kinase-Mediated Signal Transduction – A Cellular to Atomic Level Investigation. Eukaryotic cells react to the external environment through interaction with membrane-bound receptors. Distinct types of receptors respond to different stimuli, but all are capable of sensing a binding event outside, and initiating signal transduction inside the cell. Most fundamental cellular processes including the cell cycle, migration, differentiation, survival, proliferation, immune response and metabolism are transduced through receptor tyrosine kinase (RTK)-mediated signal transduction. For transduction without corruption, the protein-protein interactions involved have to produce mutually exclusive responses. Aberrancies in these pathways are responsible for many disease states including cancer, immunodeficiency and diabetes. Many of the signalling pathways emanating from RTKs involve interactions of distinct domains (e.g. SH2, SH3, PTB). Our data suggest that binding of these domains to cognate ligands are not sufficiently specific to ensure mutual exclusivity of signalling. We are thus investigating alternative ways in which the integrity of a signal from a RTK can be maintained. Focusing on early signalling events (within 1 hour of stimulation) we are exploring the structural, biophysical, and cellular outcomes of protein complex formation at the receptor. Perturbation of these complexes by inhibiting assembly or modifying the time course (by making mutations) reveals how the exquisite sensitivity of early signalling complex formation can ensure specificity.


Ahmed Z, George R, Lin C-C, Suen KM, Levitt JA, Suhling K, Ladbury JE (2010) Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function. Cellular Signalling 22: 23-33. Stevens CN, Simeone A-M, John S, Ahmed Z, Lucherini O, Baldari CT, Ladbury JE (2010) T cell receptor early signalling complex activation in response to interferon-a receptor stimulation. Biochemical Journal 428: 429-37.

Research interests• biophysicalanalysis• tyrosinekinase signalling• proteincomplexes• protein-ligand interactions• drugdevelopment• structural-thermodynamic correlations

Research areasBiomolecular Structure & FunctionOrgan Growth & Cell Signaling


Jian Kuang, Ph.D.Associate Professor, Department of Experimental Therapeutics


The central theme of my research is to understand the molecular mechanism that controls cell proliferation and transformation. One of the major components in the program is aimed at identifying crucial missing links in the regulatory system that control the G2/M transition in the eukaryotic cell cycle, including previously unrecognized kinases and phosphatases that regulate Cdc25 activity, enzymes that generate and eliminate the mitosis-specific epitope recognized by the monoclonal antibody MPM-2 and the non-Cdc2 components of maturation promoting factor activity.

The other focus of my research is to understand the functions and regulations of a multifunctional scaffold protein called Alix, which is critically involved in endosomal sorting, retroviral budding, cytokinesis, apoptosis, actin cytoskeleton assembly, cell adhesion and extracellular matrix assembly. Besides, we also study the functions and regulations of Alix-related protein HD-PTP for its malignancy- inhibitory functions.


Pan S, Wang R, Zhou X, Kloc M, Corvera J, Koomen J, Kobayashi R, Sifers R, Gallick GE, Lin SH, Kuang J (2008) Extracellular Alix Regulates Integrin-Mediated Cell Adhesions And Extracellular Matrix Assembly. EMBO J 27(15): 2077-90.Zhou X, Pan S, Sun L, Corvera J, Lin SH, Kuang J (2008) The HIV-1 p6/EIAV p9 docking site in Alix is autoinhibited as revealed by a conformation-sensitive anti-Alix monoclonal antibody. Biochem J 414(2): 215-20.Wang R, He G, Nelman-Gonzalez M, Ashorn CL, Gallick GE, Stukenberg PT, Kirschner MW, Kuang J (2007) Regulation of Cdc25C by ERK-MAP kinases during the G2/M transition. Cell 128: 1119-32.

Research interests• cell-cyclecontrol• signaltransduction• Alixfunctionsand regulation

Research areaOrgan Growth & Cell Signaling


20

Mong-Hong Lee, Ph.D.Professor, Department of Molecular and Cellular Oncology


We are interested to characterize the mechanism of cell cycle regulations involved in cancer. We show that there is an inverse correlation between HER-2/neu oncogene protein and p27 Kip1, a CDK inhibitor, in cancer. To address the molecular mechanism, we found that reduction of p27 is caused by enhanced ubiquitin-mediated degradation. Also, HER-2/neu activity causes mislocation of p27 and JAB1, an exporter of p27 and subunit of COP9 signalosome, into the cytoplasm, thereby facilitating p27 degradation. These results reveal that HER-2/neu signals reduce p27 stability and thus present potential points for therapeutic intervention in HER-2/neu associated cancers. Also, we identified 14-3-3 sigma as a new class of CKI that inhibits Akt activity and blocks Akt-mediated acceleration of p27 turnover. We show that 14-3-3 sigma functions as a positive regulator of p53 by antagonizing the activity of MDM2. These findings define 14-3-3 sigma as a negative regulator of the cell cycle progression. We have identified 14-3-sigma-associated proteins and are using knock-out mouse models to study their roles in cancer.


Gully CP, Zhang F, Chen J, Yeung JA, Velazquez-Torres G, Wang E, Yeung SC, Lee MH (2010) Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer 9: 42. Li DQ, Ohshiro K, Reddy SD, Pakala SB, Lee MH, Zhang Y, Rayala SK, Kumar R (2009) E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proc Natl Acad Sci USA 106: 17493-98. Chen J, Kobayashi M, Darmanin S, Qiao Y, Gully C, Zhao R, Yeung SC, Lee MH (2009) Pim-1 plays a pivotal role in hypoxia-induced chemoresistance. Oncogene 28: 2581-92.

Research interests• cellcycle• ubiquitination• 14-3-3andcancer• geneknockout• p53signaling

Research areasCancer Biology


Randy Legerski, Ph.D.Professor, Department of Genetics


The overall objective of my laboratory is the study of molecular mechanisms of cellular responses to DNA damage in mammalian systems, and their implications for the degenerative processes of carcinogenesis and aging in humans. A current major focus is the mechanisms by which the cell cycle is regulated in response to DNA damage and other forms of cellular stress. In this regard, we are investigating the functions of a small gene family referred to as SNM1. This family includes Artemis, Apollo, and SNM1A all of which we have demonstrated to have roles in cell cycle regulation in response to cellular stress.

A second goal is to define the mechanisms by which DNA interstrand cross-links (ICLs) are repaired in mammalian cells. Repair of ICLs is a significant topic for human health since important chemotherapeutic agents used against cancer induce these lesions. Repair of ICLs is poorly understood in mammalian cells and the elucidation of these pathways can lead to the development of more efficacious drugs, and the identification of targets for chemo-sensitization.


Yan Y, Zhang X, Akhter S, Legerski RJ (2010) The Multifunctional SNM1 Gene Family: Not Just Nucleases. Future Oncology, in press.Lam YC, Akhter S, Gu P, Gu P, Ye J, Poulet A, Giraud-Panis MJ, Bailey SM, Gilson E, Legerski RJ, Chang S (2010) SNMIB/Apollo Protects Leading-Strand Telomeres Against NHEJ-Mediated Repair. EMBO J, in press.Wang H, Zhang X, Geng L, Teng L, Legerski RJ (2009) Artemis Regulates Cell Cycle Recovery from the S Phase Checkpoint by Promoting Degradation of Cyclin E. J Biol Chem 284: 18236-43.

Research interests• cellularresponsesto DNA damage• DNArepair• cellcyclecheckpoint signaling

Research areasCancer BiologyOrgan Growth & Cell Signaling



Sadhan Majumder, Ph.D.Professor, Department of Genetics, Department of Neuro-Oncology


The current research in our laboratory involves deciphering how cellular flexibility regulates both normal development and cancer and how such knowledge can be used in therapeutic interventions. We earlier found that the abnormal expression of the transcriptional repressor REST causes medulloblastoma, one of the most malignant brain tumors in children, by blocking differentiation of neural stem cells. In addition, we found that REST is also a potential therapeutic target in these tumors. We are currently pursuing these studies further to shed light on human brain tumor formation and treatment.

In a second line of work previously we found that forced activation of REST target genes in neural stem cells or even muscle progenitor cells can reprogram them into a physiologically active neuronal phenotype. These studies provided evidence that cells are more flexible than was previously thought: cell fates can be switched by simple manipulation of a few transcription factors. We are currently utilizing this information to understand important regulations in stem cell biology and human health. In a third line of work we previously found that REST maintains self-renewal and pluripotency of embryonic stem cells (ESCs). These studies provided a new mechanistic avenue in our on-going work to study how ESCs and cancer stem-like cells are maintained in self-renewal mode and how environmental factors contribute to these mechanisms.


Singh S, Kagalwala M, Parker-Thornburg J, Adams H, Majumder S (2008) REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453: 223-27.Watanabe Y, Kameoka S, Gopalakrishnan V, Aldape KD, Pan ZZ, Lang FF, Majumder S (2004) Conversion of myoblasts to physiologically active neuronal phenotype. Genes & Dev 18: 889-900.Lawinger P, Venugopal R, Guo ZS, Immaneni A, Sengupta D, Lu W, Rastelli L, Marin Dias Carneiro A, Levin V, Fuller GN, Echelard Y, Majumder S (2000) The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nature Medicine 6: 826-31.

Research interests• connectionbetween normal development and disease• adultandembryonic stem cells• braintumors• mousemodels

Research areasCancer BiologyStem Cells & Developmental BiologyGenetics


Guillermina (Gigi) Lozano, Ph.D.Professor and Chair, Department of Genetics


The tumor suppressor p53 is activated in response to numerous aberrant signals and initiates apoptosis and senescent pathways to prevent abnormal cell proliferation. Inactivation of p53 in tumor development occurs through mutations of p53 itself or expression of high levels of two p53 inhibitors, Mdm2 and Mdm4. The overall goal of my laboratory is to understand the signals that regulate the p53 pathway and the consequences of expressing wild-type or mutant p53 in vivo. Toward this goal, we have generated numerous mouse models. Mice with p53 missense mutations common in human cancers exhibit gain-of-function phenotypes. Mice with mutations that distinguish apoptosis from senescent activities show the importance of both programs as tumor suppressor mechanisms. Reactivation of p53 in spontaneous tumor models causes tumor stasis or regression depending on cell type and context. Other mouse models have probed the importance of Mdm2 and Mdm4 in development and tumorigenesis.


Post SM, Quintas-Cardama A, Pant V, Iwakuma T et al (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell, in press.Terzian T, Suh YA, Iwakuma T, Post SM, et al (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22: 1337-44.Terzian T, Wang Y, Van Pelt CS, Box NF, et al (2007) Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol Cell Biol 27: 5479-85.Lang GA, Iwakuma T, Suh YA, Liu G, et al (2004) Gain-of-function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119: 861-72.

Research interests• tumorsuppressors• mousemodels• apoptosis

Research areasCancer BiologyGene Regulation & Epigenetics


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James F. Martin, M.D., Ph.D.Professor, Department of Molecular and Cellular MedicineInstitute of Biosciences & Technology, Texas A&M Health Science Center


The Martin lab is interested in the genetic pathways that regulate development, diversification, and maintenance of cardiac progenitor/stem cells. During early development, progenitor cells are sequestered away from the forming heart. At later stages, cardiac progenitors invade the heart and contribute to cardiac muscle, endothelial cells that line the heart, and smooth muscle that encases the great vessels. We use mouse genetics and gene targeting in embryonic stem cells to investigate fundamental questions of progenitor/stem cell biology. In addition, we are interested in the role of left right asymmetry in cardiac morphogenesis and adult human disease such as atrial fibrillation.


Wang J, Klysik E, Sood S, Johnson RL, Wehrens XHT, Martin JF (2010) Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci USA 107: 9753-58.Ai D, Fu X, Wang J, Lu MF, Chen L, Baldini A, Klein WH, Martin JF (2007) Canonical Wnt signaling functions in second heart field to promote right ventricular growth. Proc Natl Acad Sci USA 104: 9319-24.Ma L, Lu MF, Schwartz RJ, Martin JF (2005) Bmp2 is essential for atrioventricular cushion formation and myocardial patterning. Development 132: 5601-11.

Research interests• tissueregeneration• heartdisease• mousegenetics• birthdefects

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell Signaling


Angabin Matin, Ph.D.Associate Professor, Department of Genetics


My laboratory studies the genetics and biology of testicular germ cell tumor development. Predisposition to testicular germ cell tumors (commonly known as testicular cancer) is a complex genetic trait. These tumors originate from germ cells during fetal development.

We utilize consomic, congenic and genetically modified mouse strains to unravel the complex genetics of germ cell tumor development. We identified that inactivation of the dead-end (Dnd1) gene is one cause of tumor development. Dnd1 encodes an RNA-binding protein that interacts with the 3’-untranslated region of mRNAs to prevent microRNA mediated translational repression. A major goal in our laboratory is to elucidate how loss of Dnd1 causes germ cell tumors.

In addition, we are evaluating the role of a number of candidate tumor genes. Using techniques in mouse genetics, development and molecular biology, we plan to determine how dysfunction of individual genes and gene interactions cause germ cell tumor development.


Bhattacharya C, et al (2008) Mouse apolipoprotein B editing complex 3 (APOBEC3) is expressed in germ cells and interacts with dead-end (DND1). PLoS ONE 28:3(5): e2315.Youngren K, et al (2005) The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435: 360.

Research interests• germcelltumors• biologyofgermcells• geneticdissectionof disease susceptibility• mousemodels

Research areaCancer BiologyGeneticsStem Cells & Developmental Biology



Gregory S. May, Ph.D.Professor, Department of Laboratory Medicine


My laboratory seeks to understand how the fungal cell wall is made. The cell wall is a logical target for the development of novel antifungal drugs. Unfortunately, little is known about cell wall synthesis. We have undertaken genetic experiments in the model fungus Aspergillus nidulans to begin to address this deficiency. We are isolating two classes of mutants, those resistant to echinocandin drugs and those that are hypersensitive to the drug. Since this drug interferes with the synthesis of a key wall component, we anticipate identifying additional genes that contribute to wall synthesis and assembly. We have determined that resistance is the results from mutations in the gene for the enzyme beta-1,3-d-glucan synthase.

My laboratory also works with the human pathogenic fungus Aspergillus fumigatus. We are interested in the genetic pathways utilized by this fungus during infectious growth. Using whole genome microarray approaches, we have identified specific changes in fungal gene expression in response to host cells and in vitro conditions that simulate host defense mechanisms. We are currently defining the transcriptional signaling responses of the fungus in response to human neutrophils, a major cell type of the innate immune system that is essential in combating fungal pathogenesis.


Chamilos G, Bignell EM, Schrettl M, Lewis RE, Leventakos K, May GS, Haas H, Kontoyiannis DP (2010) Exploring the concordance of Aspergillus fumigatus pathogenicity in mice and Toll-deficient flies. Med Mycol 48: 506-510.Spikes S, Xu R, Nguyen CK, Chamilos G, Kontoyiannis DP, Jacobson RH, Ejzykowicz DE, Filler SG, May GS (2008) Gliotoxin production in Aspergillus fumigatus contributes to host specific differences in virulence. J Infectious Diseases 197: 479-86.

Research interests• fungalgenetics• fungalpathogenesis• signaltransduction

Research areasOrgan Growth & Cell Signaling Proteomics & GenomicsGene Regulation & Epigenetics


William Mattox, Ph.D.Associate Professor, Department of Genetics


Greater than 90% of human genes produce RNA transcripts that are alternatively spliced into multiple distinct mRNAs. This allows individual genes to express different proteins in different tissues. My lab is interested in understanding how splicing is regulated. We are using high throughput sequencing methods and genetic screens to identify both important the protein factors that affect splicing and their target transcripts. Using this approach we are determining the molecular mechanisms through which appropriate splice sites are first identified. These mechanisms have importance not only for regulation of alternative splice junctions but also, more generally, for ensuring that exons are joined in the correct order and with single nucleotide precision. Other studies in our lab focus on the growth and differentiation of germ cells. Using Drosophila as a model system, we have identified splicing factors that control the execution of programmed cell divisions within this tissue. Finally, we are also using Drosophila to develop genetic models to study the molecular mechanisms underlying several muscle diseases.


Su S, O’Day D, Wang S, Mattox W (2010) “Analysis of alternative splicing in Drosophila genetic mosaics” in The Complete Guide to RNA Splicing. Ed(s) Stamm S, Smith C, and Luhrmann R. Wiley-VCH: Weinheim, Germany. Qi J, Su S, Mattox W (2007) The doublesex splicing enhancer components Tra2 and Rbp1 also repress splicing through an intronic silencer. Molecular and Cellular Biology 27: 699-708.Lazareva AA, Roman G, Mattox W, Hardin PE, Dauwalder B (2007) A role for the adult fat body in Drosophila male courtship behavior. PLoS Genetics 3: 115-22.

Research interests• RNAbiology• germcelldevelopment• geneticmodels of disease

Research areasGene Regulation & Epigenetics



Pierre D. McCrea, Ph.D.Professor, Department of Biochemistry & Molecular Biology


Using both mammalian cell-based and vertebrate model systems (Xenopus laevis/ frog embryos), our lab studies the catenin family of proteins. Catenins transduce Wnt and other developmental signals from the cytoplasm into the nucleus. Being multi-functional, catenins also bind the cyto-domains of cadherin cell-cell adhesion proteins that span junctional regions, as well as modulate small-GTPases (eg. RhoA or Rac1) participating in cytoskeletal control.Our overall goals are: 1) Reveal roles of the canonical Wnt pathway (beta-catenin mediated), as well as non-canonical Wnt pathways in animal development; and 2) Examine the developmental functions of lesser understood catenins such as p120-catenin, ARVCF-catenin, delta-catenin and most recently plakophilin-3 (PKP3). This aim occupies most of our current efforts.


Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD (2010) Shared molecular mechanisms regulate multiple catenin proteins. J Cell Sci, in revision.McCrea PD, Gu D (2010) The catenin family at a glance. J Cell Sci 123: 637-42.Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, Sokol SY, McCrea PD (2006) Frodo links Dishevelled to the p120-catenin/ Kaiso pathway: distinct catenin sub-families promote Wnt signals. Developmental Cell 11: 683-95.Park JI, Kim SW, Lyons JP, Ji H, Nguyen T, Cho K, Barton MC, Deroo T, Vleminckx K, Moon RT, McCrea PD (2005) The Kaiso transcriptional repressor and p120-catenin regulate canonical Wnt signaling in vertebrate development. Developmental Cell 8: 843-54.Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM, McCrea PD (2004) Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nature Cell Biology 6: 1212-20.

Research interests• cateninbiology• development• intracellularand nuclear signaling

Research areasStem Cells & Developmental BiologyOrgan Growth & Cell Signaling Gene Regulation & Epigenetics


Lalitha Nagarajan, Ph.D.Associate Professor, Department of Genetics


The research in my laboratory focuses on two major areas: (1) My laboratory cloned a candidate leukemia suppressor gene SSBP2 (sequence specific single

stranded DNA binding protein 2) SSBP2 containing transcriptional complexes regulate differentiation of hematopoietic and several other lineages. Normal differentiation program is compromised in the absence of SSBP2. Mice with targeted disruption of Ssbp2 are predisposed to B cell lymphomas and carcinomas. Current studies focus on understanding on the mechanistic basis of SSBP2 mediated regulation of HSCs and the consequence of loss of SSBP2 expression in human malignancies.

(2) The MIXL gene pathway in hematopoiesis and leukemia: The MIXL gene, a paired type homeobox transcription factor mediates mesoderm induction in amphibians. Very little is known about the function of MIXL in humans. Our preliminary studies shows MIXL expression is restricted to hematopoietic stem cells and some leukemia cells. We are interested in identifying factors that regulate MIXL expression as well as target genes that are regulated by MIXL.


Wang Y, Klumpp S, Amin HM, Liang H, Li J, Estrov Z, Zweidler–McKay P, Brandt SJ, Agulnick A, Nagarajan L (2010) SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability. Oncogene 29: 3044-53.Xu Z, Meng X, Cai Y, Liang H, Nagarajan L, Brandt SJ (2007) Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins. Genes and Development 21: 942-55.Fleisig H, Orazio N, Liang H, Tyler AF, Adams HP, Weitzman MA, Nagarajan L (2007) Adenoviral Oncoprotein E1b55k binds and sequesters leukemia candidate suppressor SSBP2 in aggresomes. Oncogene 26: 4797-805.

Research interests• humancancer• stemcell• mousemodels



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Xiaobing Shi, Ph.D.Assistant Professor, Department of Biochemistry & Molecular Biology


Our laboratory is interested in epigenetic regulation of gene expression during development and in pathogenesis of cancers and other human diseases. Epigenetics is termed as heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. One of the mechanisms is through covalent modifications, including methylation, of histones, the basic proteins wound by DNA to form chromatin in the eukaryotic cells. Histone methylation is dynamically regulated by enzymes that add and remove the methyl marks, which induces interactions with protein “effectors” that dictate the “on” or “off” states of the underlying genes. Mutation or deletion of either the enzymes or the effectors for histone methylation have been involved in multiple human diseases including cancer.

Our long-term goal is to understand the molecular mechanisms of epigenetic regulation during development, and how disruption of the chromatin homeostasis leads to pathological development including cancers. Current projects focus on: (1) Genome-wide identification of protein effectors that recognize distinct histone methylation using peptide microarrays. (2) Identification and characterization of novel histone methyltransferases and novel methylation events on histones and non-histone proteins. (3) Elucidating the role of histone methylation in determining stem cell identity.


Shi X, Kachirskaia I, Yamaguchi H, et al (2007) Modulation of p53 function by SET8-mediated methylation at lysine 382. Molecular Cell 27: 636-46.Shi X, Hong T, Walter KL, et al (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442: 96-99. Comments in: Nature 442: 31-32; Nature Rev 7: 469; Nature Struct & Mol Biol 13: 573-74; Cell 126: 23-24.

Research interests• genomicinstability and cancer• epigenetics• proteinlysine methylation• stemcells




Jill M. Schumacher, Ph.D.Associate Professor, Department of Genetics


Our research is focused on the regulation of chromosome dynamics during the eukaryotic cell cycle. For these studies, we utilize genetic, biochemical, and cell biological methods using the soil nematode C. elegans as a model system. We have concentrated our efforts on the myriad of mitotic functions controlled by the highly conserved Aurora B kinase. Aurora B displays a “chromosomal passenger” mitotic localization pattern. This kinase associates with condensing mitotic chromosomes in prophase, concentrates at the inner centromere by metaphase, and then translocates to central spindle microtubules at anaphase. Aurora B functions include the regulation of chromosome conden- sation, microtubule/kinetochore attachments, and the organization of the central spindle, a structure that is essential for the completion of cytokinesis. We have identified two highly conserved activators of Aurora B, INCENP and the Tousled kinase. Although INCENP clearly has a role in mitotic chromosome segregation, Tousled has been previously implicated in chromatin assembly and transcription. We hypothesize that each activator-Aurora B complex may have a distinct subset of substrates that are involved in specific aspects of chromosome structure and dynamics. We are now undertaking molecular and genetic screens to find such substrates and associated regulatory proteins.


Heallen TR, Adams HP, Furtua T, Verbrugghe KJ, Schumacher JM (2008) An Afg2/Spaf-related Cdc48-like AAA ATPase regulates the stability and activity of the C. elegans Aurora B kinase AIR-2. Dev Cell 15: 603-16. Reifler GM, Dent SR, Schumacher JM (2008) Tousled-Mediated Activation Of Aurora B Kinase Does Not Require Tousled Kinase Activity In Vivo. J Biol Chem 283: 12763-68.

Research interests• chromosome dynamics• cellcycle• mitotickinases• Aurorakinases• C. elegans

Research areasGeneticsOrgan Growth & Cell SignalingStem Cells & Developmental Biology


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Shinako Takada, Ph.D.Assistant Professor, Department of Biochemistry & Molecular Biology


The majority of mammalian promoters lacks the core promoter element TATA box and exhibits multiple dispersed transcriptional start sites. However, how transcriptional initiation from this type of promoters is regulated remains unclear. Our laboratory has been working to determine what set of factors and DNA elements drive transcription from this type of promoters. Our observations are consistent with the ideas that transcriptional start site selection is not random and that transcription from these promoters shows different factor requirements from those for TATA-containing promoters. However, our in vitro studies with dispersed promoters also suggest that there are many other DNA sequences that can function as core promoter elements. We hypothesize that the total transcriptional initiation rate from a dispersed promoter is largely determined by proximal promoter-binding factors through inducing promoter-specific chromatin structures and recruiting transcription machinery, but that core promoter elements may play passive roles. We are currently characterizing a proximal promoter-binding factor NRF-1 and testing whether NRF-1 changes chromatin structures in proximal promoter regions using the PARP-1/DNA-PK/TopoIIβ-containing complex.


Hossain MB, Ji P, Anish R, Jacobson RH, Takada S (2009) Poly (ADP-ribose) Polymerase 1 (PARP-1) Interacts with Nuclear Respiratory Factor 1 (NRF1) and Plays a Role in Transcriptional Regulation by NRF1. J Biol Chem 284: 8621-32.Anish R, Jacobson RH, Takada S (2009) Characterization of Transcription from TATA-less Promoters: Identification of a New Core Promoter Element XCPE2 and Analysis of Factor Requirements. PLoS ONE 4: e5103.Tokusumi Y, Ma Y, Song X, Jacobson RH, Takada S (2007) A new core promoter element XCPE1 (X core promoter element 1) found in TATA-less promoters directs activator-, mediator-, and TBP-dependent but TFIID-independent RNA polymerase II transcription. Mol Cell Biol 27: 1844-58.

Research interests• transcriptional regulation• TATA-lesspromoters• chromatinregulation• PARP-1/DNA-PK/ TopoIIβ complex

Research areaGene Regulation & Epigenetics


Jessica Tyler, Ph.D.Professor, Department of Biochemistry & Molecular Biology


My lab studies the epigenetic regulation of gene expression and genomic integrity. All the activities of the Eukaryotic genome, including DNA repair, gene expression, and DNA replication are tightly regulated by packaging the DNA together with histones into chromatin and by dynamic alterations to this chromatin structure. The goal of our research is to discover novel ways in which the chromatin structure is altered during gene expression and double-strand DNA repair, and to understand how these chromatin dynamics regulate these key nuclear processes. Our studies use a combination of molecular genetic in budding yeast, tissue culture studies, biochemistry, biophysics and structural approaches. The proteins and processes that we study are so highly conserved through eukaryotic evolution, that what we learn in the highly genetically malleable yeast system is directly relevant to the situation in humans. In addition to learning how chromatin regulates fundamental processes in the cell, our studies are helping us to understand how defects in the chromatin structure lead to gene dysfunction and genomic instability, in turn causing human aging and disease states including cancer and leukemia.


Ransom M, Dennehey BK, Tyler JK (2010) Chaperoning histones during DNA replication and repair. Cell 140(2): 183-95.Das C, Lucia MS, Hansen KC, Tyler JK (2009) CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459(7243): 113-17.Chen C-C, Carson J, Feser J, Tamburini B, Zabaronick S, Linger J, Tyler JK (2008) Acetylation of lysine 56 on histone H3 drives chromatin assembly after repair and signals for the completion of double-strand DNA repair. Cell 134: 231-43.

Research interests• epigenetics• geneexpression• DNArepair• aging

Research areasGene Regulation & EpigeneticsBiomolecular Structure & FunctionGenetics



Research interests• DNAdamageresponse• genomicinstability and cancer• BRCA1signaling• ubiquitinsignaling

Research areasCancer BiologyGene Regulation & EpigeneticsProteomics & Genomics



Bin Wang, Ph.D.Assistant Professor, Department of Genetics


Defects in the ability of cells to properly respond to and repair DNA damage result in genomic instability and underlie many forms of cancer. The goal of our research is to understand how cells respond to DNA damage and safeguard the integrity of the genome. The DNA damage response is a complex signaling network that coordinates cell cycle arrest, DNA repair, transcription, apoptosis and other cellular processes in response to genotoxic stress. Mutations that impair the functions of this signaling pathway are often associated with cancer predisposition syndromes (e.g. p53, Brca1, Brca2, Chk2 mutations). We are currently investigating several key players in the DNA damage response pathway. We have identified a novel BRCA1 associated protein complex, the Rap80/Abraxas/BRCA1 complex. In addition we identified an Ubc13/RNF8 E3 ubiquitin ligase that initiates a DNA damage induced ubiquitin signaling that is required for recruiting Rap80/Abraxas/BRCA1 complex to sites of DNA damage and BRCA1’s tumor suppressor function. We are interested in using various biochemical and genetic approaches, such as gene knockouts, mass spectrometry, and genetic screens using siRNA libraries, to identify important players in the DNA damage response and define the roles of these proteins in maintaining genomic stability and tumor suppression.


Wang B, Hurov K, Hofmann K, Elledge S.J. (2009) NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev 23(6): 729-39. Wang B, Elledge SJ (2007) Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/ Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 104(52): 20759-63.Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi S, Elledge SJ (2007) Abraxas and Rap80 form a BRCA1 protein complex required for the DNA damage response. Science 316: 1194-98.

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Newborn mouse skeleton visualized for bone (red) and cartilage (blue).

G&D students Avinash Venkatanarayan, Lindsey Cauthen and Mark Nolte.

Dr. Vicki Huff and G&D student Le Huang.

G&D students Avinash Venkatanarayan, Lindsey Cauthen and Mark Nolte.G&D students Avinash Venkatanarayan, Lindsey Cauthen and Mark Nolte.

G&D Events Genes & DevelopmentFaculty and Student Dinner

All G&D Students, Faculty and First Year GSBS Students are invited* Please RSVP to Elisabeth Lindheim by October [email protected]

Student Research Achievement Awards and Student Service Award will be presented! If you need a ride or have any questions, contact Elisabeth Lindheim (see above) Casual Dress *No Spouses Please

Paulie’s2617 W. Holcombe, near Kirby

Wednesday, October 156:30 pm

Paulie’s2617 W. Holcombe, near Kirby. Free parking in lot shared with Rice Epicurean.

5th Annual G&DIce Cream Social

for faculty and ALL students in G&D labs

Friday August 174:00 pm

14th floor conf. room(S14.8136)

Ice cream bars& sandwiches!

…………Cookie

decoratingcontest!

For more information, contactElisabeth at [email protected]

Support generously provided by Randalls at Westheimer and Shepherd

Support generously provided by Randalls at Westheimer and Shepherd

Dept. of Biochemistry & Molecular Biology | Dept. of Genetics

Genes & DevelopmentSPRING RETREAT

March 25-26, 2010M. D. Anderson Cancer Center

Cancer Prevention Building (CPB), 8th Floor Conference CenterSign up at www.mdanderson.org/departments/genesdev by February 15

“On the Origin of the G&D Species”

Flag Your Hometown on New G&D World Maps!

Enjoy Afternoon Social with Students & Faculty!

Tuesday, June 9, 2009 at 4:00 PM BSRB 14th Floor Conference Room, S14.8136

Starbucks Coffee & Other Refreshments Served!

Hosted by John Latham Sponsored by the G&D Program

* For All Students & Faculty in G&D Labs *

A segment of an NMR spectrum showing chemical shift perturbation on binding of a ligand to an SH2 domain. (courtesy of Dr. John Ladbury’s lab)

If you would like more information about the Genes & Development Program, please contact us directly or visit our website at www.mdanderson.org/departments/genesdev

Genes & Development Graduate ProgramGeorg Halder, Ph.D., Program DirectorPhone: 713-834-6288E-mail: [email protected]

Elisabeth Lindheim, Program ManagerPhone: 713-834-6352E-mail: [email protected]

The Genes & Development Graduate ProgramThe University of Texas M. D. Anderson Cancer Center1515 Holcombe Blvd., Unit 1010Houston, TX 77030www.mdanderson.org/departments/genesdev

Credits Faculty Advisor: Dr. Georg HalderProject Manager: Elisabeth LindheimGraphic Design/Production: Leisa McCordCover Photo: Dr. Stevan MarcusMicroscopic Images: Hank Adams

Genes & Development Graduate Program

Georg Halder, Ph.D., Program DirectorPhone: 713-834-6288E-mail: [email protected]

Elisabeth Lindheim, Program ManagerPhone: 713-834-6352E-mail: [email protected]

The Genes & Development Graduate ProgramThe University of Texas M. D. Anderson Cancer Center1515 Holcombe Blvd., Unit 1010Houston, TX 77030www.mdanderson.org/departments/genesdev

08-2010

he University of TexasTGraduate School of Biomedical Sciences

at Houston

genes & development graduate program · logic and presentation of scientific studies. topics...

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