ROLE OF MDM2, P300, P19ARF IN P53 UBIQUITINATION

描述（申请人描述）： 史蒂夫·格罗斯曼（Steve Grossman） 目标是成为一名独立的癌症研究人员，专注于 p53周围的肿瘤发生及其MDM 2的生化调节， p300/CBP和p19 ARF。 从长远来看，从基础研究中产生的想法， 肿瘤机制将特别应用于GI恶性肿瘤领域， 他已经是一名执业临床医生了。 从短期来看，霍华德 特明奖将帮助他过渡到完全独立的癌症 丹娜-法伯癌症研究所的研究科学家，他最近在那里 晋升为助理教授（发展）。 未来一年到两年， 在博士的指导下提高他的研究技能至关重要。 大卫利文斯顿，并建立了在p53生物学领域的存在， 从而能够顺利过渡到独立。 工作环境： 丹娜-法伯癌症研究所和附近的哈佛医学院 学校，提供了一个良好的协作环境，完成 本提案中概述的研究目标-在指导期间和 补助金的无指导阶段。 利文斯顿博士通常被认为是 优秀的科学导师，有一个支持和激励 知识和科学环境保持在他的实验室。 调研： 具体的研究目的是：1. 为了将其纯化至均匀， 泛素连接酶复合物负责p53泛素化，并确定是否 MDM 2和p300/CBP在该复合物中起作用。2. 识别MDM 2后， 翻译修饰，并确定其对MDM 2表达能力的影响。 泛素化并指导p53的降解。 3. 分析 p19 ARF可以调节MDM 2驱动的泛素化的机制， p53降解，并确定p300/CBP在p19 ARF中的任何可能作用 行动上 4. 为了鉴定MDM 2和pl 9ARF两者的新靶标， 泛素化和/或降解，以及MDM 2/p19 ARF的生理作用 这些目标的规范。

DESCRIPTION (Applicant's Description): Candidate: Steve Grossman's career goal is to become an independent cancer researcher focused on the mechanisms of tumorigenesis surrounding p53 and its biochemical regulation by MDM2, p300/CBP and pl9ARF. In the long term, ideas generated from basic research in tumor mechanisms would be applied specifically to the field of GI malignancy, where he is already a practicing clinician. For the short term, the Howard Temin Award will assist his transition to full independence as a cancer research scientist at Dana-Farber Cancer Institute, where he was most recently promoted to Assistant Professor (Developing). The next year to two years will be critical for polishing his research skills under the mentorship of Dr. David Livingston, and establishing a presence in the field of p53 biology, thus allowing for a smooth transition to independence. Environment: The Dana-Farber Cancer Institute and nearby Harvard Medical School, provides an excellent collaborative environment for the completion of the research goals outlined in this proposal-- both during the mentored and unmentored phases of the grant. Dr Livingston is generally regarded as an excellent scientific mentor, and there is a supportive and stimulating intellectual and scientific environment maintained in his laboratory. Research: The specific research aims are: 1. to purify to homogeneity the ubiquitin ligase complex responsible for p53 ubiquitination, and determine if MDM2 and p300/CBP function within this complex. 2. to identify MDM2 post- translational modifications and determine their effect on the ability of MDM2 to ubiquitinate and direct the degradation of p53. 3. to analyze the mechanism by which pl9ARF can regulate the MDM2-driven ubiquitination and degradation of p53, and identify any possible role for p300/CBP in pl9ARF action. 4. to identify novel targets of both MDM2 and pl9ARF for ubiquitination and/or degradation, and the physiologic role for MDM2/pl9ARF regulation of these targets.