P53 ACETYLATION AND DEACETYLATION IN TUMORIGENESIS

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION: (Adapted from the investigator's abstract) Recently, they have demonstrated, for the first time, that the p53 tumor suppressor can be acetylated both in vitro and in vivo. The studies proposed in this application will test the hypotheses that acetylation/deacetylation of p53 is one of key events for p53 activation in response to DNA damage. It is well established that p53 exerts anti-proliferative effects, including growth arrest and apoptosis, in response to various types of stress such as DNA damage. They have previously found that CBP/p300, acting as a coactivator for p53, can dramatically stimulate p53-mediated transcriptional activity. They have further demonstrated that p53 is a bona fide substrate for p300 acetyltransferase function, and that the acetylation of p53 can strongly enhance its sequence-specific DNA binding activity. Recently, they have identified a functional deacetylase complex for p53 and the p53 target protein in this deacetylase complex (PID) has further been purified and cloned. Since acetylation of p53 can been enhanced in response to DNA damage, a novel pathway for p53 activation involving protein acetylation/deacetylation is proposed. The first specific aim is to demonstrate p53 acetylation in vivo and its functional consequence. Several acetylated p53 specific antibodies will be developed to monitor the regulation of p53 acetylation in vivo. The functional effects on in vivo sequence-specific DNA binding and transcriptional activation of p53 by acetylation in vivo. The functional effects on in vivo sequence-specific DNA binding and transcriptional activation of p53 by acetylation will also be addressed. They will investigate the regulation of p53 deacetylation and its functional consequence by PID. The third aim is to define the physiological function of PID in tumorigenesis. They will use both genetics and molecular biology approaches to test the role of PID in the regulation of p53-dependent cell growth inhibition and apoptosis.