HPVE6 ONCOPROTEIN AND ITS ASSOCIATED PROTEIN, E6AP

人乳头瘤病毒（HPV）与特定的人类 癌的 目前已鉴定出65种以上的HPV， 这些与生殖道病变有关。 HPV病毒 与生殖道病变相关的疾病可以根据 他们的临床联系分为两个不同的组。 一组， 包括HPV-6和HPV-11，通常与良性 肛门生殖器疣很少进展为癌症，被认为是 “低风险。“高危”人群，包括HPV-16和HPV-18， 与上皮内肿瘤性病变相关， 恶性进展的风险相对较高。 重要的 确定HPV在良性HPV进展中的作用， 与癌症相关的病变。 在HPV阳性癌症中，病毒基因组 通常整合到宿主基因组中。 整合是以一种 保持了病毒转录调控的完整性， 区域以及病毒E6和E7基因，其总是 在癌症中表达。 高危病毒的E6和E7基因 编码癌蛋白，这些癌蛋白可以共同合作， 永生化原代人类鳞状上皮细胞，正常宿主细胞 对于HPV。 使原代角质形成细胞永生化的能力不是 与低风险HPV的E6和E7基因共有的特征， 这一特性似乎可能与致癌性有关， 高风险HPV。 深入了解这些HPV 可能导致致癌进展的原因来自于 认识到这些病毒编码的癌蛋白和表达的 在癌症的靶向和功能上至关重要的细胞调节中， 蛋白质，包括视网膜母细胞瘤和P53肿瘤抑制基因 产品. E6癌蛋白与p53复合， 刺激其泛素化和蛋白水解。 E6与 p53由称为E6-AP的额外细胞因子介导， E6相关蛋白 本申请中提出的研究是 旨在进一步表征区分E6 高风险和低风险HPV的蛋白质，并扩展研究 E6-AP的结构和功能结构域，因为它们与E6 结合、p53结合和泛素化。

The human papillomaviruses (HPVs) are associated with specific human cancers. Over 65 different HPVs have now been identified and over 20 of these are associated with genital tract lesions. The HPVs that are associated with genital tract lesions can be separated on the basis of their clinical associations into two distinct groups. One group, including HPV-6 and HPV-11, is generally associated with benign anogenital warts that infrequently progress to cancer and is considered "low risk." The "high risk" group, including HPV-16 and HPV-18, is associated with intraepithelial neoplastic lesions that are a comparatively high risk for malignant progression. It will be important to determine the role the HPVs play in the progression of a benign HPV associated lesion to a cancer. In HPV positive cancers, the viral genome is often integrated into the host genome. Integration occurs in a manner that preserves the integrity of the viral transcriptional regulatory region as well as the viral E6 and E7 genes which are invariably expressed in the cancers. The E6 and E7 genes of the high risk viruses encode oncoproteins which together can cooperate to efficiently immortalize primary human squamous epithelial cells, the normal host cell for the HPVs. The ability to immortalize primary keratinocytes is not a characteristic shared with the E6 and E7 genes of the low risk HPVs and it seems likely that this property may be linked to the oncogenic nature of the high risk HPVs. Insight into the mechanism by which these HPVs may be contributing to carcinogenic progression has come from the recognition that the oncoproteins encoded by these viruses and expressed in the cancers target and functionally inactivate key cell regulatory proteins, including the retinoblastoma and P53 tumor suppressor gene products. The E6 oncoprotein complexes with p53 and in doing so, stimulates its ubiquitination and proteolysis. The binding of E6 with p53 is mediated by an additional cell factor called E6-AP standing for E6-Associated Protein. The studies proposed in this application are designed to further characterize those features that distinguish the E6 proteins of the high risk and low risk HPVs, and to extend the studies on the structural and functional domains of E6-AP as they relate to E6 binding, p53 binding, and ubiquitination.