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

描述(申请人提供)：包括HPV16在内的高危人乳头瘤病毒(HPV)存在于几乎所有宫颈癌中。然而，并不是所有感染高危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在宫颈肿瘤的发生和发展中具有协同作用，但其分子机制尚不清楚。初步证据表明，HPV16E7癌蛋白可与类固醇激素信号转导成分--类固醇受体辅活化子-1(SRC-1)相互作用。这项建议旨在通过突变定位、免疫共沉淀和报告分析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分析，将确定E7表达对SRC-1复合体组成和活性的影响。最后，初步研究表明，E7将SRC-1重新定位到细胞质，其机制将被确定。我们认为，HPV16E7通过与SRC-1的相互作用来失调激素依赖性基因的表达，从而成为类固醇激素在宫颈肿瘤诱导中起辅助作用的分子机制。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而诱发癌症。

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.