Abstract
p53 was the first non-histone protein shown to be regulated functionally by acetylation and deacetylation and subsequent work has established that acetylation plays a major role in controlling promoter-specific activation of p53 targets during stress responses. The major acetylation sites of human p53 include two lysine residues (K120 and K164) within the DNA-binding domain and a cluster of six lysine residues with the C-terminal domain. The speaker and his research group and others recently showed that p53 is acetylated at K120 by Tip60/MOF, while K164 is acetylated by CBP and p300, but not Tip60/MOF. Both sites are mutated in human tumors and well conserved in all species known to encode p53. To investigate whether p53 acetylation is important for tumor suppression, the speaker and his group generated p53-mutant mice (p53K117R/K117R) in which K117 (K120 in human) is replaced by arginine. In these animals, p53-mediated apoptosis is completely abrogated but p53-dependent cell cycle arrest and senescence remain intact. The group also established mice (p533KR/3KR) in which the three acetylation sites of the DNA-binding domain (K117, K161, K162) were simultaneously replaced by arginine. Significantly, loss of acetylation at these three sites completely abolished the ability of p53 to mediate cell cycle arrest, apoptosis, and senescence in vivo. To evaluate whether these p53-dependent processes are required for tumor suppression, the group monitored tumor formation in cohorts of p53 acetylation-deficient mice. Although p53-null mice rapidly develop spontaneous thymic lymphomas, neither p53K117R/K117R nor p533KR/3KR mice are prone to early-onset tumorigenesis. Since tumor suppression can be mediated by a p53 polypeptide (e.g., p533KR) that lacks the ability to induce p53-dependent cell cycle arrest, apoptosis, and senescence, these results indicate that other aspects of p53 function are sufficient to suppress tumor formation. The speaker will update the phenotypes of these acetylation defective mutant cells and mice. The speaker’s talk will address two major issues: (1) What is the purpose of cell cycle arrest, apoptosis and senescence of p53 in vivo if they are not for tumor suppression? (2) What is the key activity of p53 in the absence of cell cycle arrest, apoptosis and senescence?
About the speaker
Prof Wei Gu received his PhD in Molecular Pathobiology from Columbia University in 1995. He then started his postdoctoral research at the Rockefeller University. In 1999, he returned to Columbia University as Assistant Professor and is currently the Abraham and Mildred Goldstein Endowed Chair Professor and Vice-Chairman for Cancer Research at the Department of Pathology and Cell Biology and Institute for Cancer Genetics in Columbia University.
Prof Gu’s research focus is to understand molecular mechanisms underlying p53 stabilization and activation in tumor suppression. He is recognized internationally for the pioneering contributions to the regulation of p53-mediated tumor suppressor function. He has received many honors including the Ellison Medical Foundation Senior Scholar Award, the Stohlman Scholar Award, the Leukemia and Lymphoma Society Scholar Award, the Stewart Trust Award, the Irma T. Hirshl Trust Scholar Award, the Life Science Research Foundation Postdoctoral Fellowship and the Dean's Award for Outstanding Research Achievement from Columbia University.
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