Role of HPV16 E7/SRC-1 interaction in viral oncogenesis

HPV16 E7/SRC-1 相互作用在病毒肿瘤发生中的作用

• 批准号: 6998072
• 负责人: AMY BALDWIN
• 金额: $ 4.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998072
• 关键词: carcinogenesis; cervix neoplasms; clinical research; gene expression; human papillomavirus; immunoprecipitation; neoplastic transformation; oncoproteins; postdoctoral investigator; protein localization; protein protein interaction; steroid hormone receptor; tissue /cell culture; transcription factor; virus protein; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): High-risk human papillomaviruses (HPVs), including HPV16, are present in nearly all cervical carcinomas. However, not all women with high-risk HPVs develop cervical cancer. Although there is evidence for synergism between steroid hormones and HPV in the induction and progression of cervical neoplasia, the molecular mechanism is unknown. Preliminary evidence shows that the HPV16 E7 oncoprotein can interact with a component of steroid hormone signaling, steroid receptor coactivator-1 (SRC-1). This proposal aims to characterize this interaction by mutant mapping, coimmunoprecipitation and reporter assays. Changes in the components and activity of the SRC-1 complex by expression of E7 will be determined using an SRC-1 interaction array and histone modification assays. Lastly, initial studies suggest that E7 re-localizes SRC-1 to the cytoplasm, the mechanism for which will be determined. We propose that HPV16 E7 dysregulates hormone-dependent gene expression through its interaction with SRC-1, and is subsequently the molecular mechanism by which steroid hormones act as a cofactor in the induction of cervical neoplasia. These studies will further the understanding of how viral proteins interact with cellular factors to induce cancer.

描述（由申请人提供）：高危人乳头瘤病毒（hpv），包括HPV16，存在于几乎所有的宫颈癌中。然而，并非所有患有高危hpv的女性都会患上宫颈癌。虽然有证据表明类固醇激素和HPV在宫颈肿瘤的诱导和发展中有协同作用，但其分子机制尚不清楚。初步证据表明，hpv16e7癌蛋白可以与类固醇激素信号的一个组成部分类固醇受体共激活因子-1 （SRC-1）相互作用。本提案旨在通过突变作图、共免疫沉淀和报告者测定来表征这种相互作用。通过SRC-1相互作用阵列和组蛋白修饰实验，可以确定E7表达对SRC-1复合物成分和活性的影响。最后，初步研究表明，E7将SRC-1重新定位到细胞质中，其机制有待确定。我们认为hpv16e7通过与SRC-1的相互作用失调激素依赖基因的表达，随后是类固醇激素作为辅助因子诱导宫颈瘤变的分子机制。这些研究将进一步了解病毒蛋白如何与细胞因子相互作用以诱导癌症。