GENES FROM THE FAP LOCUS

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DESCRIPTION: (adapted from the investigator's abstract) The majority of colorectal cancers are associated with somatic mutations of the APC tumor suppressor gene. Similarly, familial adenomatous polyposis (FAP) patients, who inherit germline APC mutations, develop hundreds of colorectal tumors. While it is thus clear that APC mutations play a critical role in the development of colorectal neoplasia, how APC normally functions to suppress tumorigenesis remains obscure. The studies proposed in this project are focused on three major areas and are designed to elucidate the mechanisms underlying APC function in normal and diseased states. 1) APC-Induced Apoptosis. Previous studies have shown that expression of APC in colorectal cancer cells can result in apoptosis. The role of APC-induced apoptosis will be further tested by determining the generality of this observation, by defining the regions of APC critical to this function and by identifying changes in gene expression associated with APC induced apoptosis. 2) APC and beta-Catenin. The discovery that beta-catenin binds to APC jjhas provided an important clue to APC's function. This interaction will be further explored by mapping the regions required for beta-catenin transformation, determining the effects of APC on beta-catenin mediated transformation and identifying catenin-like proteins that are present in normal colonic mucosa and bind to APC. 3) APC and the Wg/WNT Signaling Pathway. Two proteins that bind APC (beta-catenin and GSK3) function in the Wg/WNT signal transduction pathway and signaling in this pathway ultimately results in induction of transcription by beta-catenin/TCF complexes. They will evaluate the relationship between APC and this pathway by identifying the TCF family members that are expressed in colonic epithelial cells, determining the effects of APC on beta-catenin/TCF induced transcription, and elucidating the spectrum of genes induced by beta-catenin/TCF activated transcription. The combination of the above studies should provide important insights into APC's function.