Mechanisms of targeting oncoprotein SET in tumor suppression

项目摘要 癌蛋白Mdm 2在抑制人癌细胞中的p53肿瘤抑制因子中起关键作用 并且抑制Mdm 2功能是恢复p53功能用于癌症治疗的经验证的方法。然而，尽管如此， Mdm 2的抑制剂如Nutlin-3具有一定的局限性，表明该途径中的其它靶点 需要进一步阐明。这项研究旨在剖析一种新发现的 癌蛋白SET在控制p53介导的肿瘤抑制中的作用，并提供明确的证据作为“证据 在癌症治疗中靶向SET的概念。p53肿瘤抑制通路的失活是一个关键的 在大多数人类癌症的形成过程中。为了进一步阐明p53调控的确切机制， 在人类癌症中，我们已经鉴定SET是一种新的p53结合蛋白，其与p53的相互作用完全 依赖于它的C末端。癌蛋白SET最初是从致癌融合蛋白SET中鉴定出来的- 几种类型白血病的CAN均由染色体易位引起。有趣的是，SET-p53相互作用 由C-末端乙酰化的状态特异性调节。在我们的初步研究中，我们发现SET 作为转录辅阻遏物并抑制p53介导的转录激活。SET强交互 与未乙酰化的p53通过其C-末端;然而，在那些C-末端赖氨酸残基处乙酰化后， p53-SET相互作用被完全消除，这导致p53功能的激活。核心假设是 这里要测试的是，在人类癌细胞中，p53的活性是否受到SET的严格控制， SET的失活导致体内p53活化和肿瘤消退。建议的研究包括 有两个具体目标。在目标1中，我们将进行SET-p53相互作用的机制研究， 抑制p53功能和SET在p53介导的人癌细胞生长抑制中的作用。在 目的2：研究SET对p53蛋白表达的调节作用，探讨SET对p53蛋白表达的调节作用及其生理意义。 小鼠肿瘤模型中的SET-p53相互作用。

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.