Regulation of p53 in reespnse to genotoxic stress

p53在基因毒性应激反应中的调控

• 批准号: 7100964
• 负责人: ZHI-XIONG Jim XIAO
• 金额: $ 29.18万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100964
• 关键词: DNA damage; antineoplastic antibiotics; breast neoplasms; chemical stability; disease /disorder model; doxorubicin; enzyme activity; enzyme mechanism; gene expression; laboratory mouse; molecular biology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; p53 gene /protein; peptidylprolyl isomerase; pharmacokinetics; phosphorylation; posttranslational modifications; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): The broad objective of this proposal is to elucidate the molecular mechanism(s) of genotoxic-induced p53 activation, p53 is activated in response to various cellular stresses, including DNA damage and other stresses such as metabolic change, hypoxia, hyperoxia, heat shock, or oncogene expression. DNA damage leads to phosphorylation and rapid accumulation of p53. However, how DNA damage-mediated phosphorylation induces p53 activation is not entirely clear. We and others have demonstrated that Pinl, a member of peptidyl-prolyl cis/trans isomerases (PPIases), binds p53 in DNA-damage induced phosphorylationdependent manner. Our data indicate that p53 is induced for phosphorylation at the Ser/Thr-Pro motifs that facilitates p53-Pinl interaction and that Pinl is required for timely activation of p53 in DNA damage response. Cells lacking Pinl are impaired in p53-mediated cell cycle checkpoint control and apoptosis in response to DNA damage. Base on these observations, we hypothesize that Pinl-mediated modulation of p53 is a novel regulatory mechanism for p53 regulation in response to DNA damage and that Pinl modulation of p53 is important for chemotherapy of human cancer. This proposal will use an integrated molecular approach to investigate the mechanism(s) by which Pinl modulates p53 and the p53 family member, p63. In addition, we will examine the role of Pinl-mediated modulation of p53 in chemotherapy of breast cancer using an animal model. This study may provide insight into a novel mechanism of activating p53 in response to genotoxic stress, the mechanism of human tumorigenesis, and potentially an approach of identifying a new class of cancer therapeutic targets.

描述（由申请人提供）：该提案的广泛目的是阐明遗传毒性诱导的p53激活的分子机制，p53是针对各种细胞应激的响应，包括DNA损伤和其他应激，包括代谢变化，低氧，高氧，热休克，热休克，癌基因表达。 DNA损伤导致p53的磷酸化和快速积累。但是，DNA损伤介导的磷酸化如何诱导p53激活并不完全清楚。我们和其他人已经证明，PINL是肽基 - 丙酰基/反式异构酶（PPIASES）的成员，在DNA损伤诱导的磷酸化依赖性依赖性方式中结合了p53。我们的数据表明，p53是在促进p53-Pinl相互作用的Ser/Thr-Pro基序上诱导的p53，并且在DNA损伤响应中及时激活p53所必需的PINL。缺乏PINL的细胞在p53介导的细胞周期检查点控制和凋亡中受到损害，以应对DNA损伤。基于这些观察结果，我们假设PINL介导的p53调节是响应DNA损伤的新型调节机制，并且PINL的调节p53对人类癌症的化学疗法很重要。该提案将使用一种集成的分子方法来研究PINL调节p53和p53家族成员P63的机制。此外，我们将使用动物模型来研究PINL介导的p53调节p53在乳腺癌化学疗法中的作用。这项研究可能会洞悉响应遗传毒性应激，人类肿瘤发生机制的新型机制，并有可能鉴定出新的癌症治疗靶标的方法。