REGULATION OF CDK4 BY TGF-BETA

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Deregulation of cell proliferation, often at G1 phase, is a common feature of many human cancers. G1 progression is regulated by cyclins and their cyclin dependent kinases (cdks) partner (cdk2, cdk4 and cdk6). Several lines of evidence suggested that transforming growth factor-beta (TGF- beta) induces G1 arrest by down regulation of cdk4 expression at translation level. Mutant p53 confers resistance to the cytokine. Wide type 53 also represses cdk4 translation with 5' untranslated region (UTR) of CDK4 mRNA dependent manner. I would like to study the role of p53 in the regulation of cdk4 by TGF-beta and the importance of 5'UTR in this process. Specifically, first I will determine whether 5'UTR of CDK4 mRNA plays any role in TGF-beta-induced translational down regulation of cdk4. The effect of TGF-beta on cell transfected with full length or 5'UTR truncate will be determined. The regions of 5'UTR (secondary structure or specific sequence) necessary for translational regulation by p53 will be determined. Various deletion of the 5'end will be used to study the effect of p53 in translational down regulation. The role of p53 in down regulation of cdk4 will also be explored. I will determine whether p53 binds 5'UTR CDK4 mRNA by RNA gel shift assay and which domain of p53 binds the mRNA. Further question will then be whether this domain is sufficient for translational regulation ability. If others also important, then their functions in relation to translational regulation ability of p53 will be explored.