Induction of genomic instability by HPV E6 and E7

HPV E6 和 E7 诱导基因组不稳定

• 批准号: 7900009
• 负责人: JASON J CHEN
• 金额: $ 30.72万
• 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/7900009
• 关键词: Affect; Aneuploidy; Cell Cycle; Cell Cycle Checkpoint; Cell division; Cells; Cervical; Cyclins; Cytokinesis; DNA Damage; DNA biosynthesis; Development; 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; Pathway interactions; Peptide Initiation Factors; Phosphotransferases; Play; Polyploidy; Post-Translational Protein Processing; Process; Protein p53; Proteins; 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; public health relevance; 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）感染对于宫颈癌的发展是必要的，但还不够充分。 HPV 引起的基因组不稳定性可能使细胞积累致癌所需的额外遗传异常，并且与致癌作用有关。 HPV E6 和 E7 癌基因在原代人角质形成细胞 (PHK) 中的表达会导致多倍体，纺锤体破坏和 DNA 损伤会增强这种多倍体。此前，假设E6和E7通过消除有丝分裂纺锤体检查点来诱导多倍体，并且E6降解肿瘤抑制因子p53以诱导多倍体。我们最近的研究表明E6和E7对纺锤体检查点没有显着影响。相反，他们废除有丝分裂后检查点，以在微管破坏后诱导多倍体。有趣的是，p53 降解缺陷的 E6 突变体也会诱导多倍体。此外，我们的研究表明 Cdk4 和 Cdk1 在 E6 诱导的多倍体中发挥重要作用。此外，E7 通过再复制诱导多倍体以响应 DNA 损伤，再复制是连续几轮 DNA 复制的过程，没有中间的有丝分裂。此外，我们发现DNA复制起始因子Cdt1在E7诱导的再复制过程中被翻译后修饰，其不受控制的表达会诱导人类癌细胞的再复制。我们假设cdk4和cdk1的激活在E6不依赖于p53的多倍体诱导中发挥重要作用，E7诱导再复制需要Cdt1的修饰，并且E6/E7诱导的多倍体将促进非整倍体和癌症的进展。该提案的具体目标旨在测试这些可能性。这些研究将揭示 HPV 引起基因组不稳定的机制，并为药物开发靶点的鉴定带来希望。 公共卫生相关性：人乳头瘤病毒 (HPV) 感染会诱发疣，并与宫颈癌的发生密切相关。 HPV 癌基因 E6 和 E7 对细胞周期检查点的调节导致 HPV 诱导的基因组不稳定。这些研究将揭示 HPV 诱发癌症的机制，并有望确定药物开发的靶点。