Inappropriate activation of the Wnt-signaling protein, ?-catenin causes cancer in a wide range of organs, including ~90% of colorectal cancers. ? -catenin has also been shown to promote self-renewal of adult stem cells and embryonic stem cells. Several studies suggest that effects of ? -catenin on stem cells are directly linked to its ability to cause cancer;however the downstream mechanisms connecting Tcf- ? -catenin effects on stem cells and tumor formation remain a significant question in the field. In order for ? -catenin to stimulate tumor formation and stem cell self-renewal, it binds to members of the Tcf family of proteins, which function as the DNA-binding effectors of Wnt- ? -catenin signaling. One Tcf protein, Tcf3, is expressed in several different types of stem cells (hematopoietic, neural, embryonic, hair follicle) that are sensitive to ?-catenin levels. Our preliminary studies demonstrate that Tcf3 functions as an inhibitor of ? -catenin in stem cells, suggesting the possibility that Tcf3 has tumor suppressor-like functions. This proposal focuses on the effects of Tcf3 in mice specifically as they relate to stem cell self renewal and tumor formation. We propose two specific aims: (1) to determine the function of Tcf3 in preventing cancer in organs where it is highly expressed (prostate, colon) and in an organ (uterus) that we found to develop tumors in TCF3+/- mice, and (2) to elucidate the downstream molecular mechanisms used by Tcf3 that regulate stem cell self renewal. Examination of the downstream mechanisms (Aim 2) in TCF3 conditional knockout mice (Aim 1) will be used to determine the underlying cause of defects in mice. The proposed experiments will generate important new understanding into the underlying molecular controls of stem cell self renewal and tumor formation. Should they demonstrate that loss of Tcf3 leads to tumor formation, they will identify a potentially novel tumor suppressor gene. Should they reveal that loss of Tcf3 does not confer a susceptibility to cancer, they will identify new avenues for safe cell-based therapeutics to promote stem cell self renewal.

Public Health Relevance

The proposed research will elucidate fundamental mechanisms by which genes in stem cells determine whether stem cells will make more stem cells, make different cell types, or stop dividing. In addition, powerful genetic experiments using mice will determine how defects affecting the molecular control of these fundamental mechanisms in adult stem cells could lead to malignancies in organs such as the uterus, colon and prostate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128571-05
Application #
8281356
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2008-08-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$309,082
Indirect Cost
$107,807
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ho, Ritchie; Papp, Bernadett; Hoffman, Jackson A et al. (2013) Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Rep 3:2113-26
Shy, Brian R; Wu, Chun-I; Khramtsova, Galina F et al. (2013) Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/*-catenin signaling. Cell Rep 4:1-9
Hoffman, Jackson A; Wu, Chun-I; Merrill, Bradley J (2013) Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification. Development 140:1665-75
Atlasi, Yaser; Noori, Rubina; Gaspar, Claudia et al. (2013) Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation. PLoS Genet 9:e1003424
Yi, Fei; Pereira, Laura; Hoffman, Jackson A et al. (2011) Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol 13:762-70
Salomonis, Nathan; Schlieve, Christopher R; Pereira, Laura et al. (2010) Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation. Proc Natl Acad Sci U S A 107:10514-9
Yi, Fei; Merrill, Bradley J (2010) Non-cell-autonomous stimulation of stem cell proliferation following ablation of Tcf3. Exp Cell Res 316:1050-60
Yi, Fei; Pereira, Laura; Merrill, Bradley James (2008) Tcf3 functions as a steady-state limiter of transcriptional programs of mouse embryonic stem cell self-renewal. Stem Cells 26:1951-60