Modulation of a novel cell cycle checkpoint by the HPV oncogene E6

HPV 癌基因 E6 对新型细胞周期检查点的调节

• 批准号: 7388406
• 负责人: JASON J CHEN
• 金额: $ 24.38万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388406
• 关键词: Aneuploidy; Cell Cycle; Cell Cycle Checkpoint; Cell Nucleus; Cells; Cervical; Chromosomes; Cyclins; DNA Damage; DNA biosynthesis; Development; Disease; Disruption; Drug Delivery Systems; Epithelial Cells; Event; Genome; Genomic Instability; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; In Vitro; Infection; Lesion; Light; Localized; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mammalian Cell; Microtubules; Mitosis; Modification; Molecular; Molecular Abnormality; Oncogenes; Oncogenic; Papillomavirus; Pathway interactions; Peptide Initiation Factors; Play; Polyploidy; Process; Protein p53; Replication Initiation; Role; TP53 gene; Testing; Tetrasomy; Thinking; base; c-myc Genes; carcinogenesis; human papilloma virus oncogene; immunosuppressed; keratinocyte; mutant; novel; prophylactic; response

DESCRIPTION (provided by applicant): Infection with human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. Genomic instability caused by HPV may enable cells to accumulate additional genetic abnormalities necessary for carcinogenesis. Genomic instability in the form of polyploidy has been implicated in a causal role in carcinogenesis. Expression of the HPV E6 and E7 oncogenes alone in human keratinocytes also leads to polyploidy, which is enhanced by spindle disruption and DNA damage. Previously, it was thought but not directly shown that E6 and E7 induce polyploidy by abrogating the spindle checkpoint and that degradation of the tumor suppressor p53 by E6 is important for its ability to induce polyploidy. However, our recent studies demonstrate that E6 and E7 do not have a significant effect on the spindle checkpoint in primary human keratinocytes (PHKs). Instead, our results suggest that E6 and E7 abrogate the postmitotic checkpoint to induce polyploidy after microtubule disruption. In addition, E7, and to a lesser extent E6, induce polyploidy in response to DNA damage through re-replication, a process of successive rounds of DNA replication without an intervening mitosis. Interestingly, E6 mutants defective in p53 degradation also induced polyploidy. To further explore the mechanisms by which E6 and E7 induce polyploidy, we propose the following specific aims: 1). To explore the p53-independent functions of E6 in abrogating the postmitotic checkpoint. 2). To elucidate the molecular basis underlying E7-induced re-replication. This application investigates under-studied cell cycle processes and challenges existing dogmas. These studies will shed light on mechanisms by which HPV induces genomic instability and hold promise for the development of drugs that target this process in pre- cancer lesions. Infection with human papillomaviruses (HPV) induces warts and is strongly associated with the development of cervical cancer. Modulation of cell cycle checkpoints by the HPV oncogenes E6 and E7 contributes to HPV- induced genomic instability. These studies will shed light on mechanisms by which HPV induces cancer and hold promise for the development of drugs that target this process.

描述（由申请人提供）：人乳头瘤病毒（HPV）的感染是必要的，但不足以发展为宫颈癌。由HPV引起的基因组不稳定可能使细胞能够积累癌变所需的其他遗传异常。多倍体形式的基因组不稳定性与因果发生在癌发生中的作用有关。 HPV E6和E7癌基在人角质形成细胞中的表达也会导致多倍体，这通过纺锤体破坏和DNA损伤增强。以前，人们认为E6和E7通过废除纺锤体检查点诱导多倍体诱导多倍体，而E6降解了肿瘤抑制p53对于诱导多倍体的能力很重要。但是，我们最近的研究表明，E6和E7对原代人角质形成细胞（PHK）中的主轴检查点没有显着影响。取而代之的是，我们的结果表明E6和E7废除了有丝分裂后检查点以诱导微管破坏后诱导多倍体。此外，E7和较小程度的E6在响应DNA损伤的情况下通过重新复制而诱导多倍体，这是连续的DNA复制过程，而无需干预有丝裂。有趣的是，p53降解中有缺陷的E6突变体也诱导多倍体。为了进一步探索E6和E7诱导多倍体的机制，我们提出了以下特定目的：1）。探索E6在废除有丝分裂后检查点的p53独立函数。 2）。阐明了分子基础E7诱导的重复复制。该应用程序调查了研究不足的细胞周期过程，并挑战了现有的教条。这些研究将阐明HPV诱导基因组不稳定性的机制，并有望开发针对癌症病变中这一过程的药物。人类乳头瘤病毒（HPV）感染可诱导疣，并且与宫颈癌的发展密切相关。 HPV Oncogenes E6和E7对细胞周期检查点的调节有助于HPV诱导的基因组不稳定性。这些研究将阐明HPV诱导癌症的机制，并有望开发针对该过程的药物。