Colorectal tumors provide a unique opportunity to study the molecular events responsible for initiation and progression of a common human tumor type. Previous studies have shown that colorectal tumorigenesis is driven by sequential mutations of oncogenes and tumor suppressor genes. Though mutations in these genes have been well documented, knowledge about the effect of such mutations on the biology and physiology of colorectal tumor cells is rudimentary. We plan to exploit technologies recently developed in our laboratory, as well as classic genetic and biochemical methods, to further investigate three pathways thought to be important in colorectal neoplasia: l. p53 - The p53 gene is inactivated in most colorectal tumors, as well as in many other human tumor types. The p53 gene product is thought to function, in part, by activating the expression of genes controlled by specific p53-binding DNA sequences. A novel method for analyzing gene expression patterns (SAGE) will be used to identify genes that are activated in colorectal tumor cells undergoing growth arrest or apoptosis in response to p53 expression. To test the importance of gene products identified in this way, the relevant genes will be disrupted by homologous recombination and the engineered cells assessed with respect to their response to p53 and other growth-regulating agents. 2. TGF-beta - Most colorectal tumors are insensitive to this negative growth regulator, and mutations in genes participating in this pathway have been identified in a subset of colorectal tumors. other human genes that may participate in the pathway will be identified by homologous cloning methods. Such genes will then be evaluated to determine whether they are mutated in colorectal tumors. Those found to be altered will be disrupted by homologous recombination in appropriate colorectal tumor cell lines and assessed for their impact on TGF-beta signaling. 3. Mismatch repair - Four genes participating in mismatch repair (MMR) have been shown to lead to genetic instability in colorectal tumors when inherited in mutant form. A subset of these mutations are associated with unusual phenotypes or are undetectable by standard assays. We plan to develop genetic systems to evaluate the function of such MMR gene variants. Some of these systems will involve targeted disruption of the genes in suitable recipient cell types. The information derived from this study should illuminate certain basic aspects of MMR as well as provide new diagnostic opportunities.
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