Post-transcriptional regulation of PML function

PML 功能的转录后调控

基本信息

批准号：
7269404
负责人：
PIER Paolo SCAGLIONI
金额：
$ 13.39万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7269404
关键词：
Acute Acute Promyelocytic Leukemia Address Advisory Committees Affect Breast Cancer Biology Cell Aging Cell Differentiation process Cells Central Nervous System Neoplasms Collaborations Data Development Diagnostic Neoplasm Staging Disease regression Embryo Event Fibroblasts Gene Proteins Genes Growth Human Induction of Apoptosis K-Series Research Career Programs Laboratories Localized Lung Maintenance Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Mentors Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Modeling Mus Myeloid Cells Neoplasms Non-Small-Cell Lung Carcinoma Nuclear Nuclear Structure Oncogene Proteins Oncogenic Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Play Post-Transcriptional Regulation Program Development Prostate Regulation Research Research Personnel Resources Role Scientist Signal Transduction Stress System Testing Training Training Programs Tumor Suppressor Genes Tumor Suppressor Proteins Tumor stage Ubiquitin career gene function human MAPK14 protein in vivo leukemogenesis mitogen-activated protein kinase p38 mouse model multicatalytic endopeptidase complex mutant programs protein degradation receptor response success tumor tumorigenesis

项目摘要

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）：该提案详细介绍了一个为期 5 年的癌症生物学学术职业发展培训计划。 PI 将接受 Pier Paolo Pandolfi 博士的指导，Pier Paolo Pandolfi 博士是一位领先的癌症生物学家，曾培训过众多独立研究人员。该计划将在 C. Cordon-Cardo 博士、W. Pao 博士、P. Tempst 博士的合作以及由杰出科学家组成的咨询委员会的指导下得到加强。纪念斯隆-凯特琳癌症中心将提供环境资源来促进这一职业发展奖的成功。研究重点是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的研究。 Pandolfi实验室证明PML功能被PML-RARa（急性早幼粒细胞白血病t(15;17)的产物）抑制，并且PML在多种肿瘤抑制功能中发挥着关键作用，包括诱导复制衰老，这是一种强大的反应对细胞应激。该实验室还表明，PML 蛋白在大部分人类肿瘤中丢失。 PML 损失与前列腺、乳腺和中枢神经系统肿瘤的肿瘤分期和分级相关。 PI 已证明： 1. PML 蛋白丢失是由泛素/蛋白酶体系统介导的异常蛋白降解引起的，并且 2. PML 是 ERK1/2 和 p38 MAPK（两种丝裂原激活蛋白激酶 (MAPK)）的直接底物分别转导有丝分裂和应激信号。 ERK1/2 诱导 PML 降解，而 p38 MAPK 诱导 PML 稳定并增加活性。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 将通过以下具体目标来解决这些假设： 1. 表征肿瘤发生过程中异常 PML 蛋白降解的机制； 2. p38 MAPK 介导的 PML 磷酸化功能的表征，因为它涉及 PML 蛋白稳定性和活性的调节； 3.研究PML在小鼠肿瘤模型中的肿瘤抑制功能，其中致癌K-Ras在肺和小鼠胚胎成纤维细胞中条件性表达。本提案中概述的培训计划将启动 PI 的独立研究生涯。