Induction of genomic instability by HPV E6 and E7

HPV E6 和 E7 诱导基因组不稳定

基本信息

批准号：
8305656
负责人：
JASON J CHEN
金额：
$ 29.8万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305656
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 response small hairpin RNA transition protein 1 tumorigenesis

项目摘要

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. 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.

人乳头瘤病毒（HPV）感染是必要的，但不足以发展宫颈癌。由HPV引起的基因组不稳定性可能使细胞能够积累其他遗传异常对于致癌作用，并且与因果发生在癌变中的作用有关。 HPV E6和原代人角质形成细胞（PHK）中的E7癌基因导致多倍体，并通过主轴增强破坏和DNA损伤。以前，假设E6和E7通过废除诱导多倍体有丝分裂主轴检查点和E6降解肿瘤抑制p53以诱导多倍体。我们最近研究表明，E6和E7对主轴检查点没有显着影响。相反，他们废除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，E6突变体 p53降解中有缺陷也诱导多倍体。此外，我们的研究表明CDK4的重要作用 E6诱导的多倍体中的CDK1。另外，E7通过重新诱导DNA损伤诱导多倍体复制，连续的DNA复制过程，而无需干预有丝分裂。此外，我们发现DNA复制引发因子CDT1，其不受控制的表达诱导重新复制人类癌细胞在E7诱导的重复复制期间经过翻译后修饰。我们假设这一点 CDK4和CDK1的激活在p53非依赖于E6的多倍体诱导中起重要作用 E7需要修改CDT1才能诱导重新复制，而E6/E7诱导的多倍体将增强发展为非整倍性和癌症。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并保持的机制有望确定药物开发目标。人类乳头瘤病毒（HPV）感染可诱导疣，并且与发育密切相关宫颈癌。 HPV Oncogenes E6和E7对细胞周期检查点的调节有助于HPV- 诱导基因组不稳定性。这些研究将阐明HPV诱导癌症和对识别药物开发靶标的承诺。