Transforming growth factor beta (TGF-b), a paracrine polypeptide, plays a critical role in regulating cell growth, but its precise mechanism of action is not completely understood. Cyclin dependent kinase 4 (cdk4) is thought to play an important role in the progression through the GI phase of the cell cycle. Downregulation of cdk4 synthesis plays a significant role in the TGF-b-G1 growth arrest mechanism. Resistance to TGF-b is a neoplastic phenotype. The proposed work is aimed at obtaining a better mechanistic understanding of how TGF-b causes a GI cell cycle arrest and whether the principles involved apply to other settings of cell cycle regulation. The work will attempt to determine the how TGF-b prevents the synthesis of cdk4 protein. It will ask if there are proteins induced by TGF-b which specifically bind to the 5 prime untranslated region of CDK4 mRNA and prevent its translation. The tumor suppressor, p53, appears to be involved in the TGF-b pathway. Mutant p53 confers resistance to TGF-b by preventing the downregulation of cdk4 in response to the cytokine. Wild type but not mutant p53 can inhibit the translation of the CDK4 message. The work will attempt to elucidate how p53 affects the translation of CDK4. Deregulated cdk4 synthesis significantly reduces the wild type levels of pS3 protein in lung epithelial cells. The proposed work is aimed at determining how this occurs. The mechanism of radiation induced cell cycle arrest is unclear. However, it is known that p53 plays a significant role in this process. The work will attempt to ask whether some of the circuits operating in the TGF-b pathway also operate in the growth arrest mechanism caused by irradiation. Resistance to TGF-b is seen in many human cancers. Furthermore, this phenotype can be selected for in vitro. Using the mechanistic information gained in studying the TGF-b pathway an effort will be made to determine how resistance to TGF-b occurs when it is selected for. The ultimate goal of this work is aimed at obtaining an understanding of the role G1 cyclin dependent kinases and their regulatory partners (cyclins) play in promoting G1 progression and exit and how tumor suppressors, such as p53, regulate the progression through G1.
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