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）：衰老是一种与细胞复制潜力耗尽有关的稳定增殖停滞的一种形式。激活的致癌基因，例如RAS，可以在幼小细胞中诱导衰老过早。最近的研究表明，像凋亡，癌基因诱导的衰老一样，是一种真正的肿瘤抑制体内机制，在癌症发展过程中需要妥协。但是，对这一重要的抗肿瘤反应负责的信号传导途径知之甚少。我们实验室的研究表明，p38 MAPK及其下游底物激酶PRAK在体外和体内都在致癌性RAS诱导的衰老和肿瘤抑制中起关键作用，而PRAK可能是肿瘤抑制蛋白。最后一项资金期的研究表明，多功能乙酰转移酶TIP60对于致癌性RAS诱导的衰老也是必不可少的。进一步的分析显示，涉及p38，tip60和prak的新型翻译后修饰级联反应在致癌性RAS引起的衰老中起着至关重要的作用。 RAS激活后，p38通过THR158的磷酸化诱导TIP60的乙酰转移酶活性。激活的TIP60，直接与 PRAK又通过p38依赖于TIP60和PRAK磷酸化的方式通过K364的乙酰化诱导PRAK的蛋白激酶活性。这些翻译后的修饰对于TIP60和PRAK的亲质功能至关重要。在当前的续约应用中，我们建议研究TIP60介导的乙酰化诱导PRAK的活性和功能的机制（AIM 1），通过p38-TIP60途径对新型TIP60底物进行调节（AIM 2），以及这种新型肿瘤后培养后的肿瘤蛋白抑制作用的作用。在AIM 1中，我们将检验一个假设，即TIP60介导的乙酰化通过增强p38对接和/或通过缓解分子内自抑制，从而诱导PRAK活性和功能，这是2种可能不相互排斥的机制。在AIM 2中，我们将通过在RAS诱导的衰老期间的P38-TIP60电路分析新型TIP60底物ATM的调节，这是RAS诱导的DNA损伤响应的关键调节器。最后，在AIM 3中，我们将使用TIP60-T158A突变小鼠在DMBA诱导的小鼠皮肤致癌模型中使用TIP60-T158A突变小鼠在体内抑制p38介导的TIP60-THR158磷酸化的作用。这些研究可能会揭示调节PRAK活性和功能的新型分子机制，并为介导衰老和抑制肿瘤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靶向衰老途径成分的新型癌症疗法的发展。