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）的几种特定亚型相关。 然而，这些“高危”HPV的细胞转化的分子机制尚未完全了解。HPV的两种转化癌蛋白E6和E7是启动和维持细胞转化所必需的。E6的转化功能部分由其诱导p53肿瘤抑制蛋白的泛素化和降解的能力介导。然而，E6也有知之甚少的转化活动，是p53-独立的。这些额外的E6活性在HPV引起的癌症的发病机制中具有关键作用。最近，我们克隆并鉴定了一种新的人E6结合蛋白MAML 1（masterd-like-I），它选择性地与高危HPV 16型的E6相互作用。MAML 1与果蝇mastermind基因相关，该基因是参与细胞命运决定的Notch信号通路的一个组成部分。我们发现MAML 1是一种核蛋白，作为哺乳动物Notch受体的转录共激活因子发挥作用。这些研究现在已经导致我们克隆和表征这个新的哺乳动物主谋家族的另外两个成员，MAML 2和MAML 3。与MAML 1一样，MAML 2和MAML 3都优先与高危HPV 16的E6结合。此外，高危HPV 16 E6蛋白阻断Notch信号传导。因此，MAML家族提供了乳头瘤病毒癌蛋白和Notch通路之间的第一个直接联系。本研究的目的是探讨E6介导的细胞转化中HPV E6与三种哺乳动物mastermd家族成员相互作用的机制和意义。待检验的假设是HPV E6通过MAML家族与Notch途径相互作用，在细胞转化中具有关键作用。具体而言，我们假设E6-MAML相互作用导致Notch信号改变，并导致宫颈上皮细胞生长和分化失调。可替代地或组合地，E6-MAML相互作用可能是涉及细胞增殖、细胞周期调节和衰老的E6转化活性所必需的。为了验证这些假设，我们将1）确定高风险E6蛋白与MAML蛋白的相互作用是否对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信号传导促进细胞转化。这项研究将促进我们对宫颈癌转化的分子机制的理解，并为新的MAML家族和Notch信号通路提供见解。