HPVE6 ONCOPROTEIN AND ITS ASSOCIATED PROTEIN, E6AP

人乳头瘤病毒(HPV)与特定的人类 癌症。目前已发现65种不同的HPV，其中20多种 这些都与生殖道损伤有关。人类乳头状瘤病毒 与生殖道损害相关的可以根据 他们的临床联系分为两个截然不同的组。一组， 包括HPV-6和HPV-11，通常与良性 肛门生殖器疣，不常进展为癌症，被认为 “低风险。”高危人群，包括HPV-16和HPV-18，是 与上皮内肿瘤性病变相关，这些病变是 恶性进展的风险相对较高。这将是很重要的 以确定HPV在良性HPV进展中所起的作用 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。整合是以一种方式进行的 这保持了病毒转录调控的完整性 区域以及病毒E6和E7基因，它们总是 在癌症中表达。高危病毒的E6和E7基因 编码癌蛋白，这些蛋白可以共同高效地合作 使原代人类鳞状上皮细胞永生化，这是正常的宿主细胞 对于人类乳头瘤病毒。原代角质形成细胞永生化的能力不是 低危型HPV的E6和E7基因的共同特征 这一特性似乎可能与致癌性质有关。 高危HPV。洞察这些HPV感染的机制 可能导致致癌进展的原因是 认识到由这些病毒编码并表达的癌蛋白 在癌症靶点和功能失活的关键细胞调节 蛋白质，包括视网膜母细胞瘤和p53抑癌基因 产品。E6癌蛋白与p53的复合体，在这样做的过程中， 刺激其泛素化和蛋白质分解。E6与E6的结合 P53由一种称为E6-AP的额外细胞因子介导，E6-AP代表 E6相关蛋白。本申请中建议的研究包括 旨在进一步表征那些区别于E6的功能 高危和低危HPV的蛋白，并扩大研究范围 E6-AP的结构和功能域与E6的关系 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.