Role of Tip60 in Oncogene-Induced Senescence and Tumor Suppression

Tip60 在癌基因诱导的衰老和肿瘤抑制中的作用

基本信息

批准号：
9104106
负责人：
PEIQING SUN
金额：
$ 34.88万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104106
关键词：
ATM activation Acetylation Acetyltransferase Apoptosis Binding Biochemical C-terminal Cancer Model Catalytic Domain Cells DNA Damage Data Development Docking Funding Genome Stability Health Human Hydrophobicity In Vitro Investigation Knock-in Mouse Lead MAP Kinase Gene MAPK14 gene Maintenance Malignant Neoplasms Mediating Modeling Molecular Molecular Conformation Molecular Genetics Mus Mutant Strains Mice Mutation Oncogenes Oncogenic Pathway interactions Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Protein Kinase Regulation Roentgen Rays Role Signal Pathway Site Skin Carcinogenesis Structure TP53 gene Testing Time Tumor Suppression Tumor Suppressor Proteins X-Ray Crystallography ataxia telangiectasia mutated protein design dimethylbenzanthracene exhaustion genetic approach in vitro activity in vivo insight knock-down novel response senescence structural biology targeted cancer therapy tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Senescence is a form of stable proliferative arrest historically associated with the exhaustion of replicative potential of cells. Activated oncogenes, such as ras, can induce senescence prematurely in young cells. Recent studies demonstrate that like apoptosis, oncogene-induced senescence is a bona fide tumor suppressing mechanism in vivo, which needs to be compromised during cancer development. However, the signaling pathways responsible for this important anti-tumorigenic response are poorly understood. Studies from our lab indicate that the p38 MAPK and its downstream substrate kinase PRAK play a key role in oncogenic ras-induced senescence and tumor suppression both in vitro and in vivo, and that PRAK is likely to be a tumor suppressor protein. Studies from the last funding period demonstrated that a multifunctional acetyltransferase Tip60 is also essential for oncogenic ras-induced senescence. Further analyses revealed a novel posttranslational modification cascade involving p38, Tip60 and PRAK, which plays an essential role in oncogenic ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158; activated Tip60, which directly interacts with PRAK, in turn induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the pro-senescent function of Tip60 and PRAK, respectively. In the current renewal application, we propose to investigate the mechanism by which Tip60-mediated acetylation induces the activity and function of PRAK (Aim 1), the regulation of a novel Tip60 substrate by the p38-Tip60 pathway (Aim 2), and a possible tumor-suppressing role of this novel posttranslational modification cascade in vivo (Aim 3). In Aim 1, we will test a hypothesis that Tip60-mediated acetylation induces PRAK activity and function by enhancing p38 docking and/or by relieving intramolecular autoinhibition, 2 mechanisms that may not be mutually exclusive. In Aim 2, we will analyze the regulation of a novel Tip60 substrate ATM, a key regulator of ras-induced DNA damage responses, by the p38-Tip60 circuit during ras-induced senescence. Finally in Aim 3, we will investigate the role of the p38-mediated Tip60-Thr158 phosphorylation in tumor suppression in vivo using Tip60-T158A mutant mice in the DMBA-induced mouse skin carcinogenesis model. These studies will likely reveal novel molecular mechanisms that regulate the activity and function of PRAK, and provide new insights into signaling pathways mediating senescence and tumor suppression. Investigation of the p38-Tip60-PRAK cascade in vivo may lead to the development of novel cancer therapies targeting components of the senescence pathway.

描述（由申请人提供）：衰老是一种稳定的增殖停滞形式，历史上与细胞复制潜力的耗尽有关。激活的癌基因，例如ras，可以诱导年轻细胞过早衰老。最近的研究表明，与细胞凋亡一样，癌基因诱导的衰老是体内真正的肿瘤抑制机制，但在癌症发展过程中需要对其进行损害。然而，人们对负责这种重要抗肿瘤反应的信号通路知之甚少。我们实验室的研究表明，p38 MAPK 及其下游底物激酶 PRAK 在体外和体内致癌 ras 诱导的衰老和肿瘤抑制中发挥着关键作用，并且 PRAK 很可能是一种抑癌蛋白。上一个资助期的研究表明，多功能乙酰转移酶 Tip60 对于致癌 ras 诱导的衰老也至关重要。进一步的分析揭示了一种涉及 p38、Tip60 和 PRAK 的新型翻译后修饰级联，它在致癌 ras 诱导的衰老中发挥着重要作用。被 ras 激活后，p38 通过 Thr158 磷酸化诱导 Tip60 的乙酰转移酶活性；激活Tip60，它直接与 PRAK 反过来通过 K364 的乙酰化诱导 PRAK 的蛋白激酶活性，其方式取决于 p38 对 Tip60 和 PRAK 的磷酸化。这些翻译后修饰分别对于 Tip60 和 PRAK 的促衰老功能至关重要。在当前的更新申请中，我们建议研究 Tip60 介导的乙酰化诱导 PRAK 活性和功能的机制（目标 1）、p38-Tip60 途径对新型 Tip60 底物的调节（目标 2）以及这种新型翻译后修饰级联在体内可能具有抑制肿瘤的作用（目标 3）。在目标 1 中，我们将测试一个假设，即 Tip60 介导的乙酰化通过增强 p38 对接和/或缓解分子内自抑制（这两种机制可能并不相互排斥）来诱导 PRAK 活性和功能。在目标 2 中，我们将分析 ras 诱导衰老过程中 p38-Tip60 电路对新型 Tip60 底物 ATM（ras 诱导 DNA 损伤反应的关键调节因子）的调节。最后，在目标 3 中，我们将在 DMBA 诱导的小鼠皮肤癌模型中使用 Tip60-T158A 突变小鼠研究 p38 介导的 Tip60-Thr158 磷酸化在体内肿瘤抑制中的作用。这些研究可能会揭示调节 PRAK 活性和功能的新分子机制，并为介导衰老和肿瘤抑制的信号通路提供新的见解。对体内 p38-Tip60-PRAK 级联的研究可能会导致针对衰老途径成分的新型癌症疗法的开发。