Induction of genomic instability by HPV E6 and E7

HPV E6 和 E7 诱导基因组不稳定

• 批准号: 7467125
• 负责人: JASON J CHEN
• 金额: $ 30.55万
• 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: 2008-09-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467125
• 关键词: Affect; Aneuploidy; Cell Cycle; Cell Cycle Checkpoint; Cell division; Cells; Cervical; Cyclins; Cytokinesis; DNA Damage; DNA biosynthesis; Development; Disruption; Event; Genome; Genomic Instability; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Individual; Infection; Light; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Microtubules; Mitosis; Mitotic/Spindle Checkpoint; Modeling; Modification; Molecular; Molecular Abnormality; Nature; Oncogenes; Papillomavirus; Pathway interactions; Peptide Initiation Factors; Phosphotransferases; Play; Polyploidy; Post-Translational Protein Processing; Process; Protein p53; Proteins; Public Health; RNA Interference; Replication Initiation; Role; TP53 gene; Testing; Viral Proteins; Work; base; c-myc Genes; cancer cell; carcinogenesis; clinically relevant; design; drug development; human papilloma virus oncogene; immunosuppressed; keratinocyte; mutant; prophylactic; response; small hairpin RNA; transition protein 1; tumorigenesis

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infection 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 and has been implicated in a causal role in carcinogenesis. Expression of the HPV E6 and E7 oncogenes in primary human keratinocytes (PHKs) leads to polyploidy, which is enhanced by spindle disruption and DNA damage. Previously, it was hypothesized that E6 and E7 induce polyploidy by abrogating the mitotic spindle checkpoint and that E6 degrades the tumor suppressor p53 to induce polyploidy. Our recent studies demonstrate that E6 and E7 do not have a significant effect on the spindle checkpoint. Instead, they abrogate the postmitotic checkpoint to induce polyploidy after microtubule disruption. Interestingly, E6 mutants defective in p53 degradation also induce polyploidy. Moreover, our studies suggest an important role for Cdk4 and Cdk1 in E6-induced polyploidy. In addition, E7 induces polyploidy in response to DNA damage through re-replication, a process of successive rounds of DNA replication without an intervening mitosis. Furthermore, we find that the DNA replication initiation factor Cdt1, whose uncontrolled expression induces re-replication in human cancer cells, is post-translationally modified during E7-induced re-replication. We hypothesize that activation of cdk4 and cdk1 plays an important role in p53-independent induction of polyploidy by E6, modification of Cdt1 is required for E7 to induce re-replication, and E6/E7-induced polyploidy will enhance the progression into aneuploidy and cancer. The specific aims of the proposal are designed to test these possibilities. These studies will shed light on mechanisms by which HPV induces genomic instability and hold promise for the identification of targets for drug development. PUBLIC HEALTH RELEVANCE: 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 identification of targets for drug development.

描述（由申请人提供）：人乳头瘤病毒（HPV）感染是必要的，但对于宫颈癌的发展不足。由HPV引起的基因组不稳定性可能使细胞能够积累癌变所需的其他遗传异常，并与因果发生在癌变中的作用有关。原代人角质形成细胞（PHK）中HPV E6和E7癌基因的表达导致多倍体，这通过纺锤体破坏和DNA损伤增强。以前，假设E6和E7通过废除有丝分裂主轴检查点诱导多倍体，并且E6降解肿瘤抑制p53诱导多倍体。我们最近的研究表明，E6和E7对主轴检查点没有显着影响。取而代之的是，它们废除了有丝分裂后检查点以诱导微管破坏后诱导多倍体。有趣的是，p53降解中有缺陷的E6突变体也诱导多倍体。此外，我们的研究表明，CDK4和CDK1在E6诱导的多倍体中的重要作用。此外，E7通过重新复制诱导多倍体对DNA损伤的响应，这是连续的DNA复制过程，而无需中间有丝分裂。此外，我们发现在E7诱导的重新复制期间，其未控制的表达诱导了人类癌细胞中的DNA复制起始因子CDT1在人类癌细胞中诱导重新复制。我们假设CDK4和CDK1的激活在p53非依赖性诱导多倍体的诱导中起重要作用，E7需要修改Cdt1才能诱导重复复制，并且E6/E7诱导的多倍体将增强转化为苯酚和癌症。该提案的具体目的旨在测试这些可能性。这些研究将阐明HPV诱导基因组不稳定性的机制，并有望确定药物开发靶标。 公共卫生相关性：与人乳头瘤病毒（HPV）的感染可引起疣，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诱导癌症并有望鉴定药物开发靶标的机制。