p38 MAPK in Ras-induced Senescence and Transformation

p38 MAPK 在 Ras 诱导的衰老和转化中的作用

• 批准号: 7596890
• 负责人: PEIQING SUN
• 金额: $ 31.94万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596890
• 关键词: 3' Untranslated Regions; Bypass; CDKN2A gene; Cells; EP300 gene; Genes; Genetic Screening; Goals; Human; Knowledge; Lead; Light; MAP Kinase Gene; MAPK14 gene; MEKs; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Mutation; Normal Cell; Oncogene Proteins; Oncogenic; Pathway interactions; Phosphotransferases; Play; Prevention therapy; Proteins; Regulation; Research Personnel; Retinoblastoma Protein; Role; Signal Pathway; Signal Transduction; Stress; TP53 gene; Testing; The Sun; Therapeutic; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; biological adaptation to stress; cancer prevention; defense response; design; genetic regulatory protein; insight; mRNA Stability; novel; premature; response; senescence; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): In primary, normal cells, oncogenic ras activates the Raf-MEK-ERK MARK pathway, which in turn triggers a tumor-suppression defense response known as premature senescence. As a result, additional genetic alterations are required to bypass the senescence response in order for ras to induce transformation. While the downstream effectors mediating the oncogenic activity of ras have been extensively investigated, relatively little is known about the cellular pathway that is essential for ras to induce senescence and the mechanisms by which ras-induced senescence is bypassed in human tumors. Our preliminary studies indicate that the p38 MARK pathway acts downstream of MEK to mediate ras-induced senescence. Thus, the p38 pathway may provide a tumor-suppressing function that limits the oncogenic potential of ras. In addition, p16INK4a a key mediator of senescence, is induced by activated p38 partly through mRNA stabilization. This has revealed a novel mode of p16 regulation in senescence. Moreover, analysis of the adenoviral oncoprotein E1A revealed that E1 A-mediated senescence bypass relied on its ability to inactivate p300/CBP and Rb proteins, and might involve inhibition of p38. The goal of this application is to delineate the signaling pathway that confers senescence and the tumor-suppressing function of p38, and to investigate the potential mechanisms by which ras-induced senescence is bypassed during transformation. First, the potential involvement of p38 downstream kinases PRAK and MK2, p90RSK and p53 will be examined, in order to determine the signaling components that initiate or mediate the tumor suppression function of p38. Second, the impact of p300/CBP inactivation on senescence bypass and ras-induced activation of the p38 pathway will be investigated. These studies will shed lights on the genetic alterations required to overcome ras-induced senescence in human tumors. Finally, the mechanism of p16INK4a mRNA stabilization during senescence will be investigated. Since p16 plays a central role in ras-induced senescence, these studies will identify important proteins that act downstream of the p38 signaling pathway to mediate premature senescence. Overall, since increasing amounts of evidence have suggested a tumor-suppressing function of the p38 pathway, studies proposed here may lead to the discovery of novel tumor suppressor genes and new targets for cancer prevention and therapy.

描述（由申请人提供）：在原发性细胞中，致癌性RA激活RAF-Mek-ERK Mark途径，进而触发肿瘤支持防御反应，称为过早衰老。结果，为了使RAS诱导转化，需要进行其他遗传改变以绕过衰老反应。尽管已经对介导RA的致癌活性的下游效应子进行了广泛的研究，但对于RAS诱导衰老至关重要的细胞途径却相对较少，并且在人类肿瘤中绕过Ras诱导的衰老的机制。我们的初步研究表明，p38 mark途径在MEK的下游作用于介导RAS引起的衰老。因此，p38途径可以提供肿瘤抑制功能，从而限制RAS的致癌潜力。此外，p16ink4a是衰老的关键介体，由激活的p38部分通过mRNA稳定诱导。这揭示了衰老中p16调节的一种新型模式。此外，对腺病毒癌蛋白E1A的分析表明，E1 A介导的衰老搭桥依赖于其失活的P300/CBP和RB蛋白的能力，并且可能涉及抑制p38。该应用的目的是描绘p38的衰老和肿瘤抑制功能的信号传导途径，并研究在转化过程中绕过RAS诱导的衰老的潜在机制。首先，将检查p38下游激酶PRAK和MK2，p90rsk和p53的潜在参与，以确定启动或介导p38肿瘤抑制功能的信号传导成分。其次，将研究p300/cbp失活对衰老旁路的影响和RAS诱导的p38途径激活。这些研究将阐明克服RAS诱导的人类肿瘤所需的遗传改变。最后，将研究衰老过程中p16ink4a mRNA稳定的机理。由于p16在RAS诱导的衰老中起着核心作用，因此这些研究将确定重要的蛋白质，这些蛋白质在p38信号传导途径下游作用以介导早期衰老。总体而言，由于越来越多的证据表明p38途径具有肿瘤抑制功能，因此这里提出的研究可能导致发现新型肿瘤抑制基因和用于预防癌症和治疗的新靶标。