Post-transcriptional regulation of PML function

PML 功能的转录后调控

• 批准号: 7339972
• 负责人: PIER Paolo SCAGLIONI
• 金额: $ 10.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339972
• 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（由申请人提供）：此提案详细说明了癌症生物学学术生涯发展的5年培训计划。PI将由Pier Paolo Pandolfi博士指导，他是一位领先的癌症生物学家，曾培训过许多独立调查员。在C. Cordon-Cardo博士、W. Pao博士和P. Tempst博士的合作下，以及由著名科学家组成的咨询委员会的指导下，该计划将得到加强。纪念斯隆-凯特琳癌症中心将提供环境资源，以促进这个职业发展奖项的成功。