Proteolytic Control of Oncoprotein Function

MYC是一种癌蛋白转录因子，在多种人类癌症中发挥重要作用。事实上，它 据估计，美国大约三分之一的癌症死亡与不适当的Myc有关 表情或活动。细胞已经进化出许多机制来限制正常人Myc的表达 细胞，其中之一是泛素(Ub)介导的蛋白分解。销毁Myc的重要性从以下几个方面得到证明 事实上，Myc内的癌症相关突变阻止了它的破坏，并有效地增强了它 致癌活性。这项建议的目标是了解 Ub-蛋白酶体系统对Myc的破坏提出了四个具体目标。AIM 1将调查 调节Myc稳定性的机制。这种分析的大部分将集中在身份识别上 以及与Myc内的一个中心元件相互作用的蛋白质的鉴定，该元件对Myc的后 泛素化破坏。目标2专注于了解腺病毒癌蛋白E1a是如何稳定的 MYC，以及这一活动对E1A致癌能力的贡献。在目标3中，重点将转移到 分析Myc中一个高度保守但研究很少的元件，它对Myc的周转和 通过抑制Myc诱导细胞凋亡的能力而促进致癌转化。最后，在AIM中 4、对一些肿瘤衍生的、稳定的、Myc突变体的活性进行详细研究，了解 Myc功能在癌症中受到干扰的机制。这些研究广泛使用了细胞 基于分析、RNAi、微阵列实验、蛋白质组分析以及尖端的小鼠模型 淋巴增生症、肝细胞癌和乳腺癌。因为Ub-蛋白酶体系统 成为抗肿瘤治疗的有吸引力的靶点，了解Myc是如何以及为什么被摧毁的 为揭示治疗人类癌症的新策略提供了潜力。

Myc is an oncoprotein transcription factor that features prominently in a variety of human cancers. Indeed, it is estimated that approximately one-third of all cancer deaths in the United States involve inappropriate Myc expression or activity. Cells have evolved a number of mechanisms to restrict Myc expression in normal cells, one of which is ubiquitin (Ub)-mediated proteolysis. The importance of Myc destruction is evidenced by the fact that cancer-associated mutations within Myc block its destruction and potently enhance its oncogenic activity. The goal of this proposal is to understand the mechanisms and consequences of the destruction of Myc by the Ub-proteasome system. Four Specific Aims are proposed. Aim 1 will investigate the mechanisms through which Myc stability is regulated. Much of this analysis will focus on the identification and characterization of proteins that interact with a central element within Myc that is important for its post- ubiquitylation destruction. Aim 2 is focused on understanding how the adenoviral oncoprotein E1A stabilizes Myc, and the contribution of this activity to E1A's oncogenic capabilities. In Aim 3, the emphasis will shift to analysis of a highly-conserved, but little-studied, element in Myc that is important for Myc turnover and contributes to oncogenic transformation by dampening the ability of Myc to induce apoptosis. Finally, in Aim 4, the activity of a number of tumor-derived, stable, Myc mutants will be studied in detail to learn the mechanisms though which Myc function is perturbed in cancer. These studies make extensive use of cell based assays, RNAi, microarray experiments, proteomic analyses, as well as cutting-edge mouse models of lymphomagenesis, hepatocellular carcinoma, and breast cancer. Because the Ub-proteasome system is emerging as an attractive target for anti-tumor therapies, understanding how and why Myc is destroyed offers the potential to reveal new strategies for treating human cancer.