Post-transcriptional regulation of PML function

PML 功能的转录后调控

• 批准号: 7107156
• 负责人: PIER Paolo SCAGLIONI
• 金额: $ 2.79万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-08 至 2006-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107156
• 关键词: carcinogenesis; cellular pathology; fibroblasts; green fluorescent proteins; immunoprecipitation; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; mitogen activated protein kinase; myelogenous leukemia; nonsmall cell lung cancer; phosphorylation; posttranslational modifications; protein degradation; protein structure function; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): This proposal details a 5-year training program for the development of an academic career in cancer biology. The PI will be mentored by Dr. Pier Paolo Pandolfi, a leading cancer biologist who has trained numerous independent investigators. The program will be enhanced by the collaboration of Dr. C. Cordon-Cardo, Dr. W. Pao, Dr. P. Tempst and by the guidance of an Advisory Committee composed of prominent scientists. Memorial Sloan-Kettering Cancer Center will provide the environmental resources to promote the success of this career development award. Research will focus on the study of the post-transcriptional mechanisms controlling the tumor suppressive function of the promyelocytic leukemia gene (PML). Pandolfi's laboratory has demonstrated that PML function is inhibited by PML-RARa, the product of the t(15;17) of acute promyelocytic leukemia, and that PML plays a critical role in multiple tumor suppressive functions including induction of replicative senescence, a powerful response to cell stress. The laboratory has also shown that PML protein is lost in a large portion of human tumors. PML loss correlated with tumor stage and grade in prostate, breast and central nervous systems tumors. The PI has demonstrated that: 1. PML protein loss is caused by aberrant protein degradation mediated by the ubiquitin/ proteasome system, and 2. PML is a direct substrate of ERK1/2 and p38 MAPK, two mitogen-activated protein kinases (MAPK) that transduce mitogenic and stress signals respectively. ERK1/2 induces PML degradation while p38 MAPK induces PML stabilization and increased activity. These findings indicate that PML is a direct target of the MAPK pathway. The PI hypothesizes that the pathways leading to PML ubiquitinylation and phosphorylation are key regulators of its tumor suppressor activity. The PI will address these hypotheses with the following specific aims: 1. characterization of the mechanisms underlying aberrant PML protein degradation in oncogenesis; 2. characterization of the function of p38 MAPK mediated PML phosphorylation as it pertains to regulation of PML protein stability and activity; 3. study the tumor suppressive function of PML in mouse tumor models where oncogenic K-Ras is conditionally expressed in the lung and in mouse embryonic fibroblasts. The training program outlined in this proposal will launch the PI's independent research career.

描述(由申请者提供)：这份建议书详细说明了一项为期5年的癌症生物学学术生涯发展培训计划。PI将由Pier Paolo Pandolfi博士指导，Pier Paolo Pandolfi博士是一位领先的癌症生物学家，曾培训过许多独立调查人员。该计划将通过C.Cordon-Cardo博士、W.Pao博士和P.Tempst博士的合作以及由著名科学家组成的咨询委员会的指导而得到加强。纪念斯隆-凯特琳癌症中心将提供环境资源，以促进这一职业发展奖的成功。 研究将集中在控制早幼粒细胞白血病基因(PML)的肿瘤抑制功能的转录后机制。Pandolfi的实验室已经证明，PML功能被急性早幼粒细胞白血病t(15；17)的产物PML-RARA抑制，并且PML在多种肿瘤抑制功能中发挥关键作用，包括诱导复制衰老，对细胞应激的强大反应。该实验室还表明，PML蛋白在很大一部分人类肿瘤中丢失。前列腺癌、乳腺肿瘤和中枢神经系统肿瘤的PML丢失与肿瘤分期和分级有关。等电点表明：1.PML蛋白丢失是由泛素/蛋白酶体系统介导的蛋白异常降解引起的；2.PML是ERK1/2和p38MAPK的直接底物，这两个MAPK分别传递有丝分裂和应激信号。ERK1/2诱导PML降解，而p38MAPK诱导PML稳定和活性增加。这些发现表明，PML是MAPK通路的直接靶点。PI假设导致PML泛素化和磷酸化的途径是其肿瘤抑制活性的关键调节因子。PI将以以下特定目标解决这些假说：1.肿瘤发生中PML蛋白异常降解的机制的表征；2.p38MAPK介导的PML磷酸化与调节PML蛋白稳定性和活性相关的功能的表征；3.在致癌K-RAS在肺和小鼠胚胎成纤维细胞中有条件地表达的小鼠肿瘤模型中，研究PML的肿瘤抑制功能。 该提案中概述的培训计划将启动PI的独立研究生涯。