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

描述（由申请人提供）：高危人乳头瘤病毒（HPV），包括HPV 16，几乎存在于所有宫颈癌中。 然而，并不是所有高危HPV感染的女性都会患宫颈癌。虽然有证据表明类固醇激素和HPV在宫颈肿瘤的诱导和进展中具有协同作用，但其分子机制尚不清楚。初步证据显示，HPV 16 E7癌蛋白可以与类固醇激素信号传导的组分类固醇受体共激活因子-1（SRC-1）相互作用。该建议旨在通过突变体定位、免疫共沉淀和报告基因测定来表征这种相互作用。将使用SRC-1相互作用阵列和组蛋白修饰测定来确定E7表达引起的SRC-1复合物的组分和活性的变化。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。我们提出HPV 16 E7通过与SRC-1的相互作用而使宫颈癌依赖性基因表达失调，并且是随后类固醇激素作为辅助因子诱导宫颈肿瘤形成的分子机制。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。

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.