Mechanisms of targeting oncoprotein SET in tumor suppression

项目摘要 癌蛋白MDM2是抑制人癌细胞中P53抑癌基因的关键因子 抑制MDM2功能是恢复肿瘤治疗中P53功能的有效途径。不过， MDM2的抑制剂如Nutlin-3有一定的局限性，这表明该途径中的其他靶点 需要进一步澄清。拟议的研究旨在剖析一种新发现的 癌蛋白在控制P53介导的肿瘤抑制中的作用并提供明确的证据作为证据 对于癌症治疗中的靶向设定的概念。P53肿瘤抑制通路的失活是一个关键 大多数人类癌症形成过程中的事件。为了进一步阐明P53基因调控的确切机制。 SET是一种新的P53结合蛋白，其与P53的相互作用 取决于它的C-末端。癌蛋白组最初是从致癌融合蛋白组中鉴定出来的。 在几种类型的白血病中，可以由染色体易位引起。有趣的是，SET与P53的相互作用 受C-末端乙酰化状态的影响。在我们的初步研究中，我们发现 作为转录辅阻遏子，抑制P53介导的转录激活。SET强交互作用 通过其C-末端与未乙酰化的P53结合；然而，当这些C-末端的赖氨酸残基发生乙酰化时， P53-SET的相互作用被完全取消，从而导致P53功能的激活。核心假设是 这里要检验的是，在人类癌细胞中，P53的活性是否受到SET的严格控制，以及 在体内，SET的失活导致P53的激活和肿瘤的消退。建议的研究包括 遵循两个具体目标。在目标1中，我们将对SET-P53相互作用的机制进行研究 抑制P53功能及SET在P53介导的细胞生长抑制中的作用。在……里面 目的2检测体内是否存在SET对P53的调控，评价SET对P53的生理意义。 SET-P53在小鼠肿瘤模型中的相互作用。

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.