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Marian L. Waterman
Positions:
Professor, Microbiology & Molecular Genetics
School of Medicine

Vice Chair, Microbiology & Molecular Genetics
School of Medicine

Associate Director, Cancer Research Institute
Research Centers and Institutes

picture of Marian L. Waterman
Degree:
PH.D., University of California, San Diego
Academic
Distinctions
American Cancer Society Postdoctoral Fellowship
Special Fellow, Leukemia Society
   
Research
Interests:
Wnt signaling, cancer, gene expression, development; intestine; stem cells; LEF and TCF transcription factors
Research
Abstract:
OVERVIEW
The goal of research in the Waterman laboratory is to understand how the Wnt signaling pathway regulates target genes through the actions of LEF/TCF transcription factors. Dysfunctional Wnt signals misregulate gene expression and cause cancer and most of our work on LEF/TCFs is within the context of the final step of this dysregulated pathway. LEF/TCF proteins bind to Wnt Response Elements in target genes and recruit ß-catenin for gene activation or repressors for gene silencing. There are two main areas of research: 1) Regulation of LEF/TCF expression, and 2) Structure and activities of LEF/TCFs. Our work in these two areas has led to new insights on LEF/TCF structure, Wnt response element recognition, signals from the tumor microenvironment and chromatin regulators that modify the types and amounts of LEF/TCFs. In almost every aspect LEF/TCF expression and/or function has been distorted in cancer.

REGULATION OF LEF/TCF TRANSCRIPTION AND TRANSLATION
Transcription: The LEF1 locus has two promoters for RNA polymerase II transcription, where each promoter produces a differently acting form of LEF-1. One promoter is activated in Wnt-linked cancers (P1), the other promoter is silenced (P2). We aim to identify the regulatory elements, transcription factors and signaling pathways that create this pattern, as the activated-silenced pattern produces only Wnt-promoting forms of LEF-1. We are also working to define common themes of transcription regulation of all four mammalian LEF/TCFs for a more comprehensive view of expression of this family is modulated during development and disease.
Translation: LEF1 mRNA produced from P1 contains two Internal Ribosome Entry Sites in its long 5’ UTR. We have discovered a cancer-relevant signaling pathway that regulates IRES activity and LEF-1 protein production. Current efforts are focused on a new method to isolate LEF1 mRNA/protein complexes for mass spectrometry analysis and IRES-factor discovery.

STRUCTURE AND ACTIVITIES OF LEF/TCFS
A new DNA binding domain: We have discovered a second DNA binding domain in the C-terminus of TCFs. Previously known as the CRARF region, we refer to it as the “C-clamp” because of four invariant and essential cysteines. The C-clamp is a new type of DNA binding domain and appears to be critical for TCF-mediated growth control. We aim to define the role of this domain in carcinogenesis and obtain structural and gene targeting information to develop ways to interfere with its function.
Nuclear export of TCFs: Another major effort in the laboratory is a focus on subcellular trafficking of LEF/TCFs. Our early research identified nuclear localization activities and receptors that ushered LEF/TCFs into the nucleus. More recently, we have discovered that certain mammalian TCFs engage in nuclear/cytoplasmic shuttling – an activity that is active and distorted in cancer. We have discovered a Wnt-linked kinase cascade that can control this shuttling, linking TCF trafficking to extracellular signals that may be aberrant in the tumor microenvironment. The Wnt-linked signal has elements of “canonical” and “non-canonical” signaling, and we are working to define these novel elements as well as the molecular changes in LEF/TCFs when export is triggered.
Publications:
Tsai, B.P., X. Wang, L. Huang, M.L. Waterman. 2011. Quantitative profiling of in vivo-assembled RNA-protein complexes using a novel integrated proteomic approach. Mol Cell Proteomics, 10(4):M110.007385.
 
Najdi, R., R. Holcombe, and M.L. Waterman. 2011. Wnt signaling and colon carcinogenesis: Beyond APC. J. Carcinogenesis 10:5.
 
Yokoyama, N., K.T. Pate, S. Sprowl, and M.L. Waterman. 2010. A role for YY1 repression of dominant negative LEF-1 expression in colon cancer. Nucleic Acids Res. 38:6375-88
 
Wang, Y., R. Dhopeshwarkar, R. Najdi, M.L. Waterman, C. E. Sims, and N. Allbritton. 2010. Microdevice to capture colon crypts for in vitro studies. Lab on Chip. 10:1596-1603
 
Sikandar, S. S., K.T. Pate, S. Anderson, D. Dizon, R.A. Edwards, M.L. Waterman and S.M Lipkin. 2009. NOTCH signaling is required for colon cancer initiating cell tumor formation, self-renewal and repression of secretory cell lineage differentiation. Cancer Res. 70:1469-78.
 
Najdi, R., A. Syed, L. Arce, H. Theisen, J.T. Ting, F. Atcha, R.A. Edwards, J.L. Marsh*, M.L. Waterman*. 2009. Nuclear exclusion of growth-suppressing TCF-1 via a Wnt-mediated signal in colon cancer. Oncogene. 28:4133-46
 
Arce L., K. T. Pate, M.L. Waterman. 2009. Groucho recognizes a peptide motif in LEF-1 for HDAC-dependent repression in a subset of colon cancers. BMC Cancer, 9:159
 
Hoverter, N.P. and M.L. Waterman. 2008. “A Wnt-fall for gene regulation: repression”. Science Signal. 1:43-46
 
Yang, M., M.L. Waterman, and R.K. Brachmann. 2008. hADA2 and hADA3 are essential for acetylation, transcriptional activity and proliferative effects of beta-catenin. Cancer Biol. Ther.7: 120-128
 
Semler, B. L., and M. L. Waterman. 2008. IRES-mediated pathways to polysomes: nuclear versus cytoplasmic routes. Trends Microbiol.,16:1-5.
 
Atcha, F.A., A. Syed, J.E. Munguia, J-H. T. Ting, J.L. Marsh*, and M.L. Waterman*. 2007. Inclusion of a second DNA binding domain by alternative splicing converts TCF-1 and TCF-4 into stronger Wnt effectors. Mol. Cell. Biol. 27:8352-8363
 
Li, B., C. Rheaume, A. Teng, V. Bilanchone, J.E. Munguia, M. Hu, S. Jessen, S. Piccolo, M.L. Waterman, and X. Dai. 2007. Characterization of developmental phenotypes of mice deficient for pygopus 2. Genesis, 45:318-32
 
Theisen, H., A. Syed, B.T. Nguyen, T. Lukacsovich, J. Purcell, G. P. Srivastava, D. Iron, K. Gaudenz, Q. Nie, R.Y.M. Wan, M.L. Waterman, and J.L. Marsh. 2007. Wingless directly represses DPP morphogen expression via an armadillo/TCF/Brinker complex. PLoS ONE 2:e142
 
Arce, L., N.N. Yokoyama and M.L. Waterman. 2006. Diversity of LEF/TCF action in development and disease. Oncogene 25:7492-7502
 
Li, T. W.-H., J.-H. T. Ting, N. Yokoyama, A. Bernstein, M. van de Wetering, and M.L. Waterman. 2006. WNT activation and alternative promoter repression of LEF1 in colon cancer. Mol. Cell. Biol. 26: 5284-5299
 
Jimenez, J.J., G.M. Jang, B.L. Semler and M.L. Waterman. 2005. An internal ribosome entry site mediates translation of Lymphoid enhancer factor-1. RNA 11:1385-1399
 
Atcha, F.A., J.E. Munguia., W.-H. Li, K. Hovanes, M.L. Waterman. 2003. A new b-catenin dependent activation domain in T Cell Factor. J Biol Chem 278:16169-16175
 
Ishitani, T., S. Kishida, J. Hyodo, N. Oeno, J. Yasuda, M. L. Waterman, H. Shibuya, R.T. Moon, J. Ninomiya-Tsuji, and K. Matsumoto. 2003. The TAK1-NLK MAPK cascade functions in the Wnt-5a/Ca+2 pathway to antagonize Wnt/ß-catenin signaling. Mol. Cell Biol. 23:131-139
 
Hovanes, K.H., J.E. Munguia, T. Truong, T. Milovanovic, T.W.H. Li, J. L. Marsh, R.F. Holcombe and M.L. Waterman. 2001. Selective expression of b-catenin-sensitive forms of Lymphoid Enhancer Factor-1 in Colon Cancer. Nature Genetics 28:53-57.
 
Hovanes, K.H., T.W.H. Li, and M.L. Waterman. 2000. The human LEF-1 gene contains a promoter preferentially active in lymphocytes and encodes multiple isoforms derived from alternative splicing. Nucleic Acids Res. 28(9):1994-2003.
 
Ishitani, T., J. Ninomiya-Tsuji, S.I. Nagai, M. Nishita, M. Meneghini, N. Barker, M. Waterman, B. Bowerman, H. Clevers, H. Shibuya, and K. Matsumoto. 1999. The TAK1-NLK MAP kinase-related pathway antagonizes b-catenin-TCF signalling. Nature. 399:798-802.
 
Prieve, M.P. and M.L. Waterman. 1999. Nuclear Localization and formation of b-catenin-Lymphoid Enhancer Factor-1 complexes is not sufficient for activation of gene expression. Mol. Cell. Biol. 19:4503-4515.
Professional
Society
AAAS
 
Address
University of California
Rm B251 Medical Sciences I
School of Medicine
Mail Code: 4025
Irvine, CA 92697
Phone:
(949) 824-2885, 3096
Fax:
(949) 824-8598
Email:
mlwaterm@uci.edu
URLs
Department of Microbiology and Molecular Genetics
UCI Chao Family Comprehensive Cancer Center
Cellular and Molecular Biosciences Graduate Program
Center for Complex Biosystems
Sue and Bill Gross Stem Cell Center
Updated 08/31/2011

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