Mechanisms of targeting oncoprotein SET in tumor suppression

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Project Summary The oncoprotein Mdm2 acts as a key factor in suppressing p53 tumor suppressor in human cancer cells and inhibition of Mdm2 function is a validated approach to restore p53 function for cancer therapy. Nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. The proposed studies aim to dissect the mechanisms of one newly-identified oncoprotein SET in controlling p53-mediated tumor suppression and provide the unequivocal evidence as “proof of concept” for targeting SET in cancer therapy. Inactivation of the p53 tumor suppression pathway is a pivotal event in the formation of most human cancers. To further elucidate the precise mechanisms of p53 regulation in human cancers, we have identified SET as a novel p53-binding protein whose interactions with p53 are totally dependent on its C-terminus. The oncoprotein SET was initially identified from an oncogenic fusion-protein SET- CAN resulted from chromosome translocation in several types of leukemia. Interestingly, the SET-p53 interaction is specifically regulated by the status of the C-terminal acetylation. In our preliminary studies, we found that SET acts as a transcriptional corepressor and inhibits p53-mediated transcriptional activation. SET strongly interacts with unacetylated p53 through its C-terminus; however, upon acetylation at those C-terminal lysine residues, the p53-SET interaction is completely abrogated, which leads to activation of p53 functions. The central hypothesis to be tested here is whether the activities of p53 are tightly controlled by SET in human cancer cells and whether inactivation of SET leads to p53 activation and tumor regression in vivo. The proposed studies include the following two specific aims. In Aim 1, we will perform Mechanistic studies of the SET-p53 interplays in suppressing p53 function and the roles of SET in p53-mediated cell growth repression of human cancer cells. In Aim 2, we will test whether p53 is regulated by SET in vivo and evaluate the physiological significance of the SET-p53 interaction in mouse tumor models.