高危型人乳头瘤病毒（HPV）感染是诱发宫颈癌的主要病因。HPV使细胞越过G1检验点从而诱导基因组不稳定性是恶性转化的重要机制。我们前期研究发现高危型HPV癌基因E6可通过非p53依赖方式促进细胞越过G1检验点从而诱导基因组不稳定性，免疫印迹及激酶活性分析提示细胞周期蛋白依赖性激酶Cdk1可能是其中的关键因子。本项目将利用RNA干扰、过表达、突变分析等方法明确Cdk1在E6通过非p53依赖途径促进细胞越过G1检验点中的关键作用，并深入研究E6激活Cdk1的分子机制：阐明E6如何通过Akt影响Cdk抑制因子p21的核浆定位并使其失活；研究转录因子E2F1、B-Myb在上调Cdk1表达，RCC1在激活Cdk1活性中的关键作用。本项目将为揭示E6非p53依赖功能、HPV致瘤机制及发现药物治疗靶位提供新的思路，具有重要的理论意义和潜在的应用价值。

The high-risk human papillomavirus (HPV) infections play a causal role in the development of cervical cancer. Genomic instability as a result of G1 checkpoint abrogation by HPV enables cells to accumulate additional genomic aberrations necessary for malignant conversion. Our preliminary studies show that oncogene E6 of the high-risk HPV type 16 abrogates G1 checkpoint upon DNA damage to induce genomic instability by a p53-independent manner and our results from Western blottings and kinase assays indicate that cyclin-dependent kinase 1 (Cdk1) is the key factor. This proposal is designed to further establish the role of Cdk1 in p53-independent abrogation of the G1 checkpoint by HPV E6 through a series of approaches including RNA inteference、overexpression and mutational analysis; explore the mechanism by which E6 activates Cdk1: elucidate the role of Akt in E6-mediated cellular localization of Cdk inhibitor p21; investigate the role of transcription factors E2F1、B-Myb in up-regulating Cdk1 and the role of RCC1 in activating Cdk1. This proposal investigates p53-degradation independent fuction of E6 and a novel mechanism of cervical carcinogenesis and holds promise for the identification of targets for drug development.