Transformation of Epithelial Cell by E6 Oncogene

E6癌基因对上皮细胞的转化

• 批准号: 6752507
• 负责人: Lizi Wu
• 金额: $ 28.26万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752507
• 关键词: binding proteins; binding sites; biological signal transduction; cell differentiation; cell growth regulation; cell surface receptors; cervix; clinical research; epithelium; human papillomavirus; keratinocyte; laboratory mouse; neoplastic transformation; oncogenes; oncoproteins; protein protein interaction; virus protein

DESCRIPTION (provided by applicant): Cervical carcinomas are associated with a few specific subtypes of the human papillomavirus (HPV). However, the molecular mechanisms of cellular transformation by these "high-risk" HPV are not fully understood. Two transforming oncoproteins of HPV, E6 and E7, are required for both initiation and maintenance of cellular transformation. The transforming function of E6 is mediated partially by its ability to induce ubiquitination and degradation of the p53 tumor suppressor protein. However, E6 also has poorly understood transformation activities that are p53-independent. These additional E6 activities have critical roles in the pathogenesis of cancers caused by HPV. Recently, we cloned and characterized a novel human E6-binding protein, MAML1 (mastermind-like-I) that selectively interacts with E6 from high-risk HPV type 16. MAML1 is related to the Drosophila melanogaster mastermind gene, a component of the Notch signaling pathway involved in cell fate determination. We found that MAML1, a nuclear protein, functions as a transcriptional co-activator for mammalian Notch receptors. These studies have now led to our cloning and characterization of two additional members of this novel mammalian mastermind family, MAML2 and MAML3. Like MAML1, both MAML2 and MAML3 preferentially bind to E6 from high-risk HPV16. Furthermore, high-risk HPV16 E6 proteins block Notch signaling. Therefore, the MAML family provides the first direct link between papillomavirus oncoproteins and the Notch pathway. The, goal of this proposal is to determine the mechanisms and significance of the HPV E6 interactions with the three mammalian mastermind family members in E6-mediated cellular transformation. The hypothesis to be tested is that HPV E6 interactions with the Notch pathway, via the MAML family, have a critical role in cellular transformation. Specifically, we hypothesize that E6-MAML interactions result in altered Notch signaling and lead to deregulated growth and differentiation in cervical epithelial cells. Alternatively or in combination, E6-MAML interactions may be required for E6 transformation activities involving cell proliferation, cell cycle regulation and senescence. To test these hypotheses, we will 1) determine whether the interactions of high-risk E6 proteins with MAML proteins are critical for E6 mediated cellular transformation, 2) determine whether and how the interactions of E6 and MAML proteins contribute to cellular transformation via Notch signaling. The proposed research will advance our understanding of the molecular mechanisms of transformation of cervical cancers, as well as provide insight into the novel MAML family and the Notch signaling pathway.

描述（由申请人提供）：宫颈癌与人乳头瘤病毒（HPV）的一些特定亚型有关。 但是，这些“高风险” HPV的细胞转化的分子机制尚未完全了解。 HPV，E6和E7的两个转化癌蛋白是细胞转化的启动和维持所必需的。 E6的转化功能部分是由于其诱导p53肿瘤抑制蛋白的泛素化和降解的能力而部分介导的。但是，E6也对独立于p53的转型活动也很少理解。这些额外的E6活性在由HPV引起的癌症的发病机理中具有关键作用。最近，我们克隆并表征了一种新型的人类E6结合蛋白MAML1（Mastermind-like-I），该蛋白与高风险HPV类型16型与E6有选择地相互作用。MAML1与果蝇Melanogaster Mastermind Gene有关，这是细胞效果确定的Notch信号途径的成分。我们发现MAML1是一种核蛋白，是哺乳动物缺口受体的转录共激活剂。这些研究现在导致了我们对这个新型哺乳动物策划家族MAML2和MAML3的另外两个成员的克隆和表征。像MAML1一样，MAML2和MAML3都优先结合了高风险HPV16的E6。此外，高风险的HPV16 E6蛋白会阻止Notch信号传导。因此，MAML家族提供了乳头瘤病毒癌蛋白和Notch途径之间的第一个直接联系。该提案的目标是确定HPV E6相互作用与E6介导的细胞转化中三个哺乳动物策划者家族成员的机制和意义。要检验的假设是，通过MAML家族，HPV E6与​​Notch途径的相互作用在细胞转化中具有关键作用。具体而言，我们假设E6-MAML相互作用会导致Notch信号变化，并导致颈椎上皮细胞的生长和分化。替代地或组合，涉及细胞增殖，细胞周期调节和衰老的E6转化活动可能需要E6-MAML相互作用。为了检验这些假设，我们将1）确定高危E6蛋白与MAML蛋白的相互作用对于E6介导的细胞转化至关重要，2）确定E6和MAML蛋白的相互作用是否以及如何通过Notch信号导致细胞转化。拟议的研究将提高我们对宫颈癌转化的分子机制的理解，并提供对新型MAML家族和Notch信号通路的见解。