Tip60 in p38 and PRAK Mediated Oncogene-Induced Senescence and Tumor Suppression

p38 和 PRAK 介导的癌基因诱导的衰老和肿瘤抑制中的 Tip60

• 批准号: 7844918
• 负责人: PEIQING SUN
• 金额: $ 39.4万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844918
• 关键词: Acetylation; Acetyltransferase; Apoptosis; Binding; Biological; Cancer Model; Cells; Data; Defect; Development; Frequencies; Human; In Vitro; Investigation; Lead; MAP Kinase Gene; MAPK14 gene; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Oncogenes; Oncogenic; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Primary Neoplasm; Protein Kinase; Proteins; Regulation; Role; Sampling; Signal Pathway; Signal Transduction Pathway; Site; Skin Carcinogenesis; Structure; TP53 gene; Testing; Tumor Cell Line; Tumor Suppression; Tumor Suppressor Proteins; Work; cancer cell; cancer therapy; design; exhaustion; gene interaction; histone acetyltransferase; in vivo; insight; malignant breast neoplasm; novel; protein expression; public health relevance; ras Proteins; response; senescence; tumor; tumorigenesis; tumorigenic

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. Our preliminary data reveal that PRAK directly interacts with a multifunctional histone acetyltransferase Tip60. Further investigation indicates that Tip60 is essential for oncogenic ras- induced senescence, and that Tip60 expression and phosphorylation are both induced during senescence induction. Moreover, p38 directly phosphorylates Tip60 on S155 and T158 in cells and in vitro. In addition, increased expression of Tip60 enhances the kinase activity of PRAK, and suppression of Tip60 reduces ras- induced phosphorylation of PRAK at the activation site, suggesting that Tip60-PRAK interaction is important for the activation of PRAK in senescent cells. Together, these findings demonstrate that Tip60 plays a central role in oncogene-induced senescence. We hypothesize that oncogenic Ras activates Tip60 through p38-mediated phosphorylation and protein stabilization, and that activated Tip60 in turn stimulates the kinase activity of PRAK, leading to induction of the tumor-suppressing senescence response. This application is designed to investigate the mechanisms underlying the role of Tip60 in senescence induction and tumor suppression in vitro and in vivo. First, regulation of the phosphorylation, expression and acetyltransferase activity of Tip60 by the Ras-p38 pathway in senescent cells will be examined. Second, the impact of Tip60-PRAK interaction on the expression and activity of each binding partner and p53 during ras-induced senescence will be analyzed. Finally, the contribution of PRAK and Tip60 and their interaction to senescence induction and tumor suppression will be examined in vivo, using mouse cancer models in which tumor development is driven by oncogenic ras, and in human cancers with high frequency of activating mutations in senescence-inducing oncogenes. Results from these studies will delineate the signal transduction pathway mediating the tumor suppressive senescence response, and establish the mechanism underlying the role of Tip60 in oncogene- induced senescence and tumor suppression. The proposed work may lead to the development of new cancer therapies targeting the senescence pathway. PUBLIC HEALTH RELEVANCE: Studies proposed in this application are designed to investigate the mechanism of oncogene-induced senescence, an important tumor suppressive cellular response that is disrupted during human cancer development. These studies focus on a protein kinase PRAK and an acetyltransferase Tip60, both of which are likely to be tumor suppressor proteins. Results from these studies will define the signal transduction pathway mediating the senescence response and tumor suppression, and may lead to the development of novel cancer therapies targeting 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。活化的癌基因（例如RAS）可以过早地诱导幼体细胞衰老。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。我们的初步数据表明，PRAK直接与多功能组蛋白乙酰转移酶TIP60相互作用。进一步的研究表明，TIP60对于致癌性RAS诱导的衰老至关重要，并且TIP60表达和磷酸化均在衰老诱导过程中诱导。此外，p38在细胞和体外直接磷酸化S155和T158上的TIP60。此外，TIP60的表达增加增强了PRAK的激酶活性，而TIP60的抑制降低了激活位点PRAK的RAS诱导的磷酸化，这表明TIP60-PRAK相互作用对于衰老细胞中PRAK的激活很重要。总之，这些发现表明TIP60在致癌基因引起的衰老中起着核心作用。我们假设致癌性RAS通过p38介导的磷酸化和蛋白质稳定激活TIP60，并且激活的TIP60又刺激了PRAK的激酶活性，从而导致诱导肿瘤抑制衰老反应。该应用旨在研究TIP60在体外和体内衰老诱导和肿瘤抑制作用的基础机制。首先，将检查对衰老细胞中RAS-P38途径对TIP60的磷酸化，表达和乙酰基转移酶活性的调节。其次，将分析TIP60-PRAK相互作用对RAS引起的衰老过程中每个结合伴侣和p53的表达和活性的影响。最后，PRAK和TIP60及其相互作用对衰老诱导和抑制肿瘤的相互作用将在体内检查，其中使用小鼠癌模型，其中肿瘤发育是由致癌性Ras驱动的，并且在人类癌症中具有高频率激活衰老突变的人 - 诱导癌基因。这些研究的结果将描述介导肿瘤抑制衰老反应的信号转导途径，并确定TIP60在癌基因诱导的衰老和抑制肿瘤中的作用的机制。拟议的工作可能导致针对衰老途径的新癌症疗法的发展。公共卫生相关性：本应用中提出的研究旨在研究癌基因引起的衰老的机制，这是一种重要的肿瘤抑制性细胞反应，在人类癌症发育过程中受到破坏。这些研究集中于蛋白激酶PRAK和乙酰转移酶TIP60，这两者都可能是肿瘤抑制蛋白。这些研究的结果将定义介导衰老反应和抑制肿瘤的信号转导途径，并可能导致针对衰老途径的新型癌症疗法的发展。