p38 MAPK in Ras-induced Senescence and Transformation

描述(申请人提供)：在原代正常细胞中，致癌ras激活Raf-MEK-ERK Mark通路，进而触发称为早衰的肿瘤抑制防御反应。因此，为了使ras诱导转化，需要额外的基因改变来绕过衰老反应。虽然介导ras致癌活性的下游效应已经得到了广泛的研究，但对于ras诱导衰老所必需的细胞途径以及在人类肿瘤中绕过ras诱导衰老的机制知之甚少。我们的初步研究表明，p38Mark途径作用于MEK下游，介导ras诱导的衰老。因此，p38通路可能提供了一种肿瘤抑制功能，从而限制了ras的致癌潜力。此外，p16INK4a是衰老的关键调节因子，p38的激活部分是通过mRNA稳定来诱导的。这揭示了p16在衰老过程中的一种新的调控模式。此外，对腺病毒癌蛋白E1a的分析表明，EAA介导的衰老旁路依赖于其灭活p300/CBP和Rb蛋白的能力，并可能涉及对p38的抑制。本研究的目的是阐明p38的衰老信号通路和肿瘤抑制功能，并研究ras诱导的衰老在转化过程中被绕过的可能机制。首先，我们将研究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抑瘤功能的信号成分。其次，我们将研究p300/CBP失活对衰老旁路和ras诱导的p38通路激活的影响。这些研究将阐明克服ras诱导的人类肿瘤衰老所需的基因改变。最后，对p16INK4a基因在衰老过程中的稳定机制进行了探讨。由于p16在ras诱导的衰老中起核心作用，这些研究将确定在p38信号通路下游调节早衰的重要蛋白质。总体而言，由于越来越多的证据表明p38通路具有肿瘤抑制功能，这里提出的研究可能会导致发现新的肿瘤抑制基因和癌症预防和治疗的新靶点。

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.