HPV E6 protein regulation of the hTERT promoter

描述(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，而人乳头瘤病毒在这种恶性肿瘤的发生中起着关键的作用。乳头瘤病毒编码两种癌蛋白E6和E7，它们是启动和维持恶性状态以及诱导细胞永生化所必需的。其中一些生物活性似乎与E6和E7分别降解细胞P53和Rb抑癌蛋白的能力有关。然而，与其降解P53的能力无关，E6可以诱导细胞端粒酶活性，从而可能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是酶复合体的催化亚单位。我们和其他人已经证明，E6蛋白反式激活hTERT启动子，导致hTERT蛋白和细胞端粒酶活性增加。我们最新的研究表明，E6蛋白与Myc蛋白结合，两者结合并协同激活hTERT启动子。有趣的是，只有高危的E6蛋白与hTERT启动子结合，进一步支持了端粒酶的诱导和细胞永生化之间的相关性。目前的方案研究了E6与Myc结合、结合hTERT启动子和促进基因转录的机制。此外，我们将研究E6是否增加了Myc调节的其他基因，以及Myc是否可以模拟E6特有的细胞表型的子集。拨款的总体目标是了解E6在调节基因转录、细胞生长和细胞分化方面的作用。

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.