Regulation of p53 in response to genotoxic stress

p53 响应基因毒性应激的调节

• 批准号: 6680615
• 负责人: ZHI-XIONG Jim XIAO
• 金额: $ 29.88万
• 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/6680615
• 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）：本提案的主要目标是阐明基因毒性诱导的 p53 激活的分子机制，p53 是响应各种细胞应激而激活的，包括 DNA 损伤和其他应激，例如代谢变化、缺氧、高氧、热休克或癌基因表达。 DNA 损伤导致 p53 磷酸化和快速积累。然而，DNA 损伤介导的磷酸化如何诱导 p53 激活尚不完全清楚。我们和其他人已经证明，Pinl 是肽基脯氨酰顺/反异构酶 (PPIases) 的成员，以 DNA 损伤诱导的磷酸化依赖性方式结合 p53。我们的数据表明，p53 在 Ser/Thr-Pro 基序上被诱导磷酸化，从而促进 p53-Pinl 相互作用，并且 Pinl 是 DNA 损伤反应中及时激活 p53 所必需的。缺乏 Pinl 的细胞在 p53 介导的细胞周期检查点控制和响应 DNA 损伤的细胞凋亡中受到损害。基于这些观察，我们假设 Pinl 介导的 p53 调节是一种新的 p53 响应 DNA 损伤调节的调节机制，并且 Pinl 调节 p53 对于人类癌症的化疗很重要。该提案将使用综合分子方法来研究 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研究 Pinl 介导的 p53 调节在乳腺癌化疗中的作用。这项研究可能会深入了解激活 p53 响应基因毒性应激的新机制、人类肿瘤发生的机制，以及识别新型癌症治疗靶点的潜在方法。