HPV E6 protein regulation of the hTERT promoter

描述（由申请人提供）：在世界范围内，宫颈癌是女性癌症的第二大原因，“高危”人乳头瘤病毒在这种恶性肿瘤的发生中起着关键作用。乳头瘤病毒编码两种癌蛋白，E6和E7，这是恶性状态的起始和维持以及细胞永生化诱导所必需的。这些生物活性中的几种似乎分别与E6和E7降解细胞p53和Rb肿瘤抑制蛋白的能力有关。然而，独立于其降解p53的能力，E6可以诱导细胞端粒酶活性，并推测，从而维持染色体端粒长度和持续的细胞增殖。细胞端粒酶活性的限速事件是hTERT蛋白的水平，hTERT蛋白是酶复合物的催化亚基。我们和其他人已经表明，E6蛋白反式激活hTERT启动子，导致hTERT蛋白和细胞端粒酶活性的增加。我们最近的研究表明，E6蛋白与Myc蛋白相关联，它们都结合并协同激活hTERT启动子。有趣的是，只有“高风险”的E6蛋白结合hTERT启动子，进一步支持诱导端粒酶和细胞永生化之间的相关性。目前的建议调查E6与Myc，结合hTERT启动子，并促进基因转录的机制。此外，我们将研究E6是否增强其他Myc调控的基因，以及Myc是否可以模拟E6特异性细胞表型的子集。该基金的总体目标是了解E6在调节基因转录，细胞生长和细胞分化中的作用。

DESCRIPTION (provided by applicant): Worldwide, cervical cancer is the second leading cause of cancer in women and the "high risk" human papillomaviruses play a critical role in the genesis of this malignancy. The papillomaviruses encode two oncoproteins, E6 and E7, that are required for the initiation and maintenance of the malignant state as well as the induction of cell immortalization. Several of these biological activities appear related to the ability of E6 and E7 to degrade the cellular p53 and Rb tumor suppressor proteins, respectively. However, independent of its ability to degrade p53, E6 can induce cellular telomerase activity and, presumably, thereby maintain chromosome telomere length and continued cell proliferation. The rate-limiting event in cellular telomerase activity is the level of hTERT protein, the catalytic subunit of the enzyme complex. We and others have shown that the E6 protein transactivates the hTERT promoter, leading to an increase in hTERT protein and cellular telomerase activity. Our most recent studies indicate that the E6 protein associates with Myc protein and that they both bind and cooperatively activate the hTERT promoter. Interestingly, only the "high risk" E6 proteins bind the hTERT promoter, further supporting the correlation between induction of telomerase and cell immortalization. The current proposal investigates the mechanism by which E6 associates with Myc, binds the hTERT promoter, and facilitates gene transcription. In addition, we will examine whether E6 augments other Myc-regulated genes and whether Myc can mimic a subset of E6-specific cellular phenotypes. The overall goal of the grant is to gain an understanding of the role of E6 in regulating gene transcription, cell growth and cell differentiation.