HPV E6 protein regulation of the hTERT promoter

HPV E6 蛋白对 hTERT 启动子的调节

• 批准号: 7114631
• 负责人: Richard Schlegel
• 金额: $ 2.5万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-16 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114631
• 关键词: HPV; E6; protein; regulation; hTERT

EXCEED THE SPACE PROVIDED. Woddwide, 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。在全世界范围内，宫颈癌是女性癌症的第二大原因，而“高风险”人乳头瘤病毒在这种恶性肿瘤的发生中发挥着关键作用。乳头瘤病毒编码两种癌蛋白E6和E7，它们是恶性状态的启动和维持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 肿瘤抑制蛋白的能力有关。然而，无论其降解 p53 的能力如何，E6 都可以诱导细胞端粒酶活性，并且可能由此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（酶复合物的催化亚基）的水平。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。我们最近的研究表明，E6 蛋白与 Myc 蛋白结合，并且它们都结合并协同激活 hTERT 启动子。有趣的是，只有“高风险”E6 蛋白才能结合 hTERT 启动子，进一步支持端粒酶诱导与细胞永生化之间的相关性。目前的提案研究了 E6 与 Myc 结合、结合 hTERT 启动子并促进基因转录的机制。此外，我们将检查 E6 是否增强其他 Myc 调节的基因以及 Myc 是否可以模仿 E6 特异性细胞表型的子集。该资助的总体目标是了解 E6 在调节基因转录、细胞生长和细胞分化中的作用。表演网站==========================================部分结束====== =======================================