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

描述（由申请人提供）：肿瘤抑制因子p53的激活对于避免癌变至关重要。这种激活部分是基于细胞中p53蛋白水平的增加。同样关键的是激活p53的功能，以响应基因毒性损伤是在p53上添加特定的翻译后修饰。在过去的15年里，大量的努力已经投入到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。这个残基靠近p53的一个基本结构域，即寡聚化域。然而，目前尚不清楚K357乙酰化是否在p53功能的这方面或其他方面发挥作用。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乙酰化在DNA损伤后迅速发生，但我们无法将K357乙酰化与p53的经典细胞周期阻滞或凋亡活性联系起来。相反，我们的初步研究表明，K357乙酰化在p53功能的一个不太为人所知的方面，即诱导细胞衰老。此外，K357乙酰化可能被白藜芦醇激活的sirtuin家族酶逆转。这些酶与衰老有关，提出了一个有吸引力的模型，即它们控制K357乙酰化水平可能有助于它们调节细胞衰老和衰老的能力。在这里，我们概述了一个实验计划，将为K357乙酰化的酶学及其功能后果提供重要的知识基础。这些探索性研究包括体外生化分析和体内肿瘤抑制分析。累积起来，这些目标的成功完成将为我们提供关于我们所定义的新的p53乙酰化事件的关键知识。这个知识库将允许更多的长期研究，最终可能在临床中利用这一途径。

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.