This proposal deals with the roles of CtBP and its mechanism of action in cancer. CtBP is a crucial co-repressor involved in embryonic development, cell differentiation and tumorigenesis. However, little is known about its mechanism of action. I have succeeded in the purification of the CtBP complex. In this application, I propose to 1) Study functional roles of different components of CtBP complex in the CtBP mediated repression using the DNA vector-based RNAi technology which was developed recently by my co-workers and myself. I will use the E-cadherin gene as a model to analyze the contributions of these components to the inactivation of E-cadherin gene and the effects on tumorigenesis. 2) Identify local chromatin changes at the E-cadherin promoter that are associated with CtBP using chromatin immunoprecipitation (CHIP) assays to provide molecular evidence linking chromatin remodeling to CtBP-mediated repression. 3) Characterize a new zinc finger protein ZNF217 in the CtBP complex to reveal the molecular basis for its implied role in breast cancers.
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