Function of a novel, sirtuin-regulated acetylation site on p53.

p53 上一个新的、sirtuin 调节的乙酰化位点的功能。

• 批准号: 7978929
• 负责人: STEVEN B. MCMAHON
• 金额: $ 16.82万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7978929
• 关键词: Acetylation; Age; Apoptosis; Apoptotic; B-Cell Lymphomas; BAX gene; BCL2 gene; Binding; Biochemical; Biological; Biological Assay; Biological Process; Cell Aging; Cell Cycle Arrest; Cell physiology; Cells; Cellular Stress; Clinic; Cytochromes; DNA Binding; DNA Binding Domain; DNA Damage; Data; Deacetylation; Enzymatic Biochemistry; Enzymes; Event; Family; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Half-Life; Human; In Vitro; Individual; Induction of Apoptosis; Knowledge; Lead; Lesion; Longitudinal Studies; Lysine; Malignant Neoplasms; Mediating; Methylation; Minor; Mitochondria; Modeling; Modification; Molecular Profiling; Mutate; Mutation; Normal Cell; Ontology; Outer Mitochondrial Membrane; Pathway interactions; Patients; Phosphorylation; Play; Post-Translational Modification Site; Post-Translational Protein Processing; Protein Family; Protein p53; Proteins; Regulation; Resveratrol; Role; Site; Stem cells; TP53 gene; Testing; Tumor Suppression; Tumor Suppressor Proteins; anti aging; anticancer research; base; cancer cell; carcinogenesis; cofactor; defined contribution; in vivo; insight; knowledge base; metaplastic cell transformation; multicatalytic endopeptidase complex; mutant; novel; novel diagnostics; novel therapeutics; public health relevance; research study; response; senescence; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Activation of the tumor suppressor p53 is critical for avoiding carcinogenesis. This activation is based partly on an increase in the cellular levels of p53 protein. Also critical for activating p53 function in response to genotoxic insults is the addition of specific post- translational modifications on p53. Over the past 15 years, a great deal of effort has been devoted to deciphering how individual modifications control p53 activity. We have recently identified a previously unknown modification, the acetylation of lysine residue 357. This residue lies adjacent to an essential structural domain of p53, the oligomerization domain. However, it remains unknown whether K357 acetylation plays a role in this or some other aspect of p53 function. Furthermore, we know little of the enzymes responsible for adding and removing K357 acetylation. While our data clearly demonstrate that K357 acetylation occurs rapidly after DNA damage, we have been unable to implicate K357 acetylation in the classical cell cycle arrest or apoptosis activities of p53. Instead, our preliminary studies suggest a role for K357 acetylation in a less well-understood aspect of p53 function, the induction of cellular senescence. Furthermore, it appears that K357 acetylation may be reversed by the resveratrol-activated sirtuin family of enzymes. These enzymes have been implicated in aging, presenting the attractive model that their control of K357 acetylation levels may contribute to their ability to regulate cellular senescence and aging. Here we outline an experimental plan that will provide an important knowledge base about the enzymology of K357 acetylation and about its functional consequences. These exploratory studies span in vitro biochemical analysis and in vivo tumor suppression assays. Cumulatively, the successful completion of these Aims should provide us with critical knowledge about the novel p53 acetylation event we have defined. This knowledge base will allow for more long-term studies that might ultimately exploit this pathway in the clinic. PUBLIC HEALTH RELEVANCE: The tumor suppressor p53 is the most commonly mutated gene in human cancer and understanding how it helps protect cells from malignant transformation is a central goal of cancer research. We have identified a new regulatory event, the acetylation of a critical domain of p53, that likely participates in controlling its function. Understanding the role of this acetylation event may lead to new diagnostics in cancer and potentially novel therapeutic strategies in the overwhelming percentage of patients whose tumors harbor lesions in the p53 pathway.

描述（由申请人提供）：肿瘤抑制因子p53的激活对于避免致癌作用至关重要。这种激活部分基于p53蛋白的细胞水平的增加。对于响应于遗传毒性损伤而激活p53功能也至关重要的是在p53上添加特异性翻译后修饰。在过去的15年里，人们付出了大量的努力来破译个体修饰如何控制p53活性。我们最近发现了一个以前未知的修饰，赖氨酸残基357的乙酰化。该残基位于p53的基本结构域（寡聚化结构域）附近。然而，K357乙酰化是否在p53功能的这个或其他方面起作用仍然是未知的。此外，我们对负责添加和去除K357乙酰化的酶知之甚少。虽然我们的数据清楚地表明，K357乙酰化DNA损伤后迅速发生，我们一直无法牵连K357乙酰化在经典的细胞周期停滞或凋亡活动的p53。相反，我们的初步研究表明K357乙酰化在p53功能的一个不太清楚的方面，即诱导细胞衰老中的作用。此外，似乎K357乙酰化可以被白藜芦醇激活的沉默调节蛋白家族的酶逆转。这些酶与衰老有关，提出了一个有吸引力的模型，即它们对K357乙酰化水平的控制可能有助于它们调节细胞衰老和老化的能力。在这里，我们概述了一个实验计划，将提供一个重要的知识基础，酶学K357乙酰化及其功能的后果。这些探索性研究涵盖体外生化分析和体内肿瘤抑制试验。累积起来，这些目标的成功完成应该为我们提供关于我们已经定义的新的p53乙酰化事件的关键知识。这一知识基础将允许更多的长期研究，最终可能在临床上利用这一途径。 公共卫生相关性：肿瘤抑制基因p53是人类癌症中最常见的突变基因，了解它如何帮助保护细胞免受恶性转化是癌症研究的中心目标。我们已经确定了一个新的调节事件，乙酰化的一个关键结构域的p53，可能参与控制其功能。了解这种乙酰化事件的作用可能会导致癌症的新诊断和潜在的新的治疗策略，在绝大多数患者的肿瘤窝藏病变的p53通路。