ROLE OF MDM2, P300, P19ARF IN P53 UBIQUITINATION

描述(申请人描述)：候选人：史蒂夫·格罗斯曼的职业生涯 目标是成为专注于机制的独立癌症研究人员 围绕P53的肿瘤发生及MDM2对其生化调控的研究 P300/CBP和pl9ARF。从长远来看，从基础研究中产生的想法 肿瘤机制将专门应用于胃肠道恶性肿瘤领域， 在那里他已经是一名执业的临床医生。短期内，霍华德 特明奖将帮助他过渡到完全独立的癌症 达纳-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(发展中)。未来一到两年将 在博士的指导下，对磨练他的研究技能至关重要 David Livingston，并在p53生物学领域建立了自己的存在， 从而实现向独立的平稳过渡。 环境：达纳-法伯癌症研究所和附近的哈佛医学院 学校，为完成以下任务提供了良好的协作环境 本提案中概述的研究目标--在指导期间和 无人指导的拨款阶段。利文斯顿博士通常被认为是 优秀的科学导师，并有一位支持和激励 在他的实验室里维持着智力和科学环境。 研究：具体研究目标是：1.对同质性进行净化 泛素连接酶复合体，负责p53泛素化，并确定是否 MDM2和p300/CBP在这个复合体中发挥作用。2.确定MDM2后- 翻译修饰及其对MDM2能力的影响 泛素化并引导P53的降解。3.分析 PL9ARF调控MDM2诱导的泛素化及其机制 P53的降解，并确定p300/CBP在pl9ARF中的任何可能作用 行动。4.确定mdm2和pl9arf的新目标 泛素化和/或降解以及MDM2/pl9ARF的生理作用 对这些目标的监管。

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.