Mutation of the APC tumor suppressor gene is believed to be a rate-limiting and necessary event in the development of most colorectal tumors, both inherited and sporadic. The APC gene product is a component of the Wnt signaling pathway;its ability to interact with and down-regulate beta-catenin is controlled by GSK3IB phosphorylation and affects the expression of genes regulated by transcription factors of the TCF/LEF family (Clevers and van de Wetering, 1997). Therefore, mutation of APC indirectly alters the transcription profile of cells through changes in the expression of genes such as c-myc and cyclin D1 that promote cell growth (He et al., 1998;Tetsu and McCormack, 1999), survivin that inhibits apoptosis (Zhang et al., 2001), and matrilysin that mediates differentiation (Crawford et al., 1999). The role of APC in non-transcriptional mechanisms of growth control and differentiation is less emphasized, but includes effects on cell adhesion, microtubules and chromosome dynamics (Nathke et al., 1996;Kaplan et al., 2001;Mogensen era/., 2002;Bienz and Hamada, 2004). Further functional characterization of APC and its gene product in normal and malignant cells is important for a complete understanding of how its disruption is associated with tumor formation. We have shown that introduction of the APC gene into colon carcinoma cells induces apoptosis and prevents entry into S-phase of the cell cycle through beta-catenin-dependent and -independent mechanisms (Heinen et al., 2002;Carson et al., 2004;Qian et al, 2005). Transcriptionally silent in vitro systems show that full-length APC and defined protein segments accelerate apoptosis and inhibit DNA replication (Steigerwald et al., 2005;Qian et al., 2005;Sarnaik et al., 2005). In addition, we have shown that APC phosphorylation by the cyclin-dependent kinase p34 at M-phase of the cell cycle mediates protein interactions that in turn affect a mitotic checkpoint (Trzepacz et al., 1997;Carson et al., 2005). We will now test the hypothesis that APC contributes to cell cycle control and cell death independently of beta-catenin-induced transcription by determining the post-translational modifications of APC and its dynamic protein-protein interactions. Our immediate goal is to determine the mechanisms by which APC regulates the cell cycle and apoptosis. Our long-term goals are to elucidate the mechanisms and pathways through which APC functions and, by doing so, to contribute to the design of better therapeutic strategies in oncology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063507-14
Application #
7674600
Study Section
Special Emphasis Panel (ZRG1-ONC-J (03))
Program Officer
Yassin, Rihab R,
Project Start
1994-12-13
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
14
Fiscal Year
2009
Total Cost
$256,926
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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