The transcriptional coactivators p300/CBP have acetyltransferase (AT) activity. Their important functions contribute to cell proliferation and differentiation through the following mechanisms: (1) acetylation of histones, p53 and other transcription factors; and , (2) chromatin modification during transcription. In fact, mutations within the AT domain of p300/CBP genes have been linked to colorectal and gastric and carcinomas, suggesting that aberrant regulation of the AT domain activity may play important roles in cancer. We have demonstrated recently that the adenoviral oncoprotein E1A and INHAT, a novel human cellular complex which contains that Set oncoprotein, regulate p300- mediated histone acetylation, nuclear hormone receptor mediated hormone signaling, and gene transcription (Cell 96, 393, 1999 and Cell 104, 119, 2001). P53 is a common target in most human cancers. Mutations in amino acids that prevent the ability of p53 to bind specific DNA sequences and to activate p53-regulated genes have been implicated in the development of colon, pancreas, stomach, and esophageal cancers. Since p300 acetylation of p53 plays an important role in the ability to bind DNA, we hypothesize that the INHAT complex regulates the biological functions of p53. The following interrelated Specific Aims are proposed: (1) To determine whether the INHAT complex and the oncoprotein Set regulate p53 acetylation and influence its biological function; and (2) To determine the regulation of INHAT subunit expression in digestive tract cancers. Successful completion of the proposed studies will provide insights into novel mechanisms of p53 regulation and may provide therapeutic targets for p53 linked digestive tract cancers.
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