Molecular genetic analysis of colon cancers has established that Wnt signaling pathway is involved in early tumor development. The transcription factors that commute Wnt signals into changes in target gene expression are members of the Lymphoid Enhancer Facto/T Cell Factor (LEF/TCF) family. There are full-length activating, and truncated dominant negative forms of LEF/TCFs as well as alternatively spliced isoforms. Based on previous work and results from other laboratories the following hypotheses are proposed. First, the hypothesis that full-length, activating isoforms of TCFs predominate in colon cancer as compared to normal tissue will be tested by defining the expression patterns of TCFs in normal, adenoma and adenocarcinomas (Specific Aim 1). Second, experiments are proposed to test two different hypotheses for the mechanism underlying previously reported unique activities of TCF isoforms (Specific Aim 2). Wild type and mutant TCF proteins will be studied in DNA binding assays. Third, the hypothesis that TCF family members and isoforms carry unique target gene specificities to impart distinct effects in cancer will be tested by two different strategies that disrupt TCF function in colon cancer cells. Effects will be assessed by global expression profiles and cell growth and viability assays (Specific Aim 3). Collectively, the work proposed will address important unknowns about the role that TCF proteins play in directing Wnt signals toward cell transformation and cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108697-03
Application #
7216223
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Thurin, Magdalena
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$248,417
Indirect Cost
Name
University of California Irvine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Pate, Kira T; Stringari, Chiara; Sprowl-Tanio, Stephanie et al. (2014) Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J 33:1454-73
Hoverter, Nate P; Zeller, Michael D; McQuade, Miriam M et al. (2014) The TCF C-clamp DNA binding domain expands the Wnt transcriptome via alternative target recognition. Nucleic Acids Res 42:13615-32
Chodaparambil, Jayanth V; Pate, Kira T; Hepler, Margretta R D et al. (2014) Molecular functions of the TLE tetramerization domain in Wnt target gene repression. EMBO J 33:719-31
Wu, Beibei; Piloto, Sarah; Zeng, Weihua et al. (2013) Ring Finger Protein 14 is a new regulator of TCF/ýý-catenin-mediated transcription and colon cancer cell survival. EMBO Rep 14:347-55
Konstorum, Anna; Sprowl, Stephanie A; Waterman, Marian L et al. (2013) Predicting mechanism of biphasic growth factor action on tumor growth using a multi-species model with feedback control. J Coupled Syst Multiscale Dyn 1:459-467
Hoverter, Nate P; Ting, Ju-Hui; Sundaresh, Suman et al. (2012) A WNT/p21 circuit directed by the C-clamp, a sequence-specific DNA binding domain in TCFs. Mol Cell Biol 32:3648-62

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