Inhibition of Ras mitogenic signaling by the 38 pathway

描述：(改编自调查人员的摘要)RAS已知活跃 三种丝裂原活化蛋白激酶(MAPK)途径，包括细胞外 信号调节蛋白(ERK)、c-jun氨基末端蛋白(JNK)和p38。而当 ERK和JNK通路在RAS丝裂原信号转导中的重要作用 已经证明，p38通路的作用尚不清楚。它 这里提出RAS对p38的激活构成了一个负面的 反馈以抑制其有丝分裂信号。这一假设是基于我们的 初步结果表明，RAS激活了p38途径的几个分子， 它们中的每一个反过来又抑制RAS依赖的基因表达和 扩散。已发表的p38通路抗有丝分裂活性的证据 也支持这一模式。这一假设将通过以下方式进行检验 具体目的：1)检查p38通路是否在 MEK/ERK在RAS信号转导中的作用；2)研究其抗有丝分裂的特性 P38通路在RAS增殖信号中的作用；3)确定p38是否 通路通过拮抗JNK的激活来抑制RAS的活性。实验将会 通过对MAPK信号转导通路的分析，对MAPK的三条通路进行了剖析 信号转导机制以及RAS激活p38的结果 我们的NIH3T3细胞模型。所获得的知识随后将应用于肿瘤细胞 在这种情况下，增殖信号是结构性活跃的。加在一起， 这些研究将建立一种负反馈机制，通过这种机制 信号在MAPK级联的水平上受到调节。所获得的信息 将促进我们对癌基因信号网络的理解，并提供新的 开发以信号转导通路为导向的抗病毒策略 增殖性疾病。

DESCRIPTION: (Adapted from the investigator's abstract) Ras is known to active three mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. While the essential roles of the ERK and the JNK pathways in Ras mitogenic signaling have been demonstrated, the contribution of the p38 pathway remains unclear. It is proposed here that activation of the p38 by Ras constitutes a negative feedback to restrain its mitogenic signaling. This hypothesis is based on our preliminary results that Ras activates several molecules of the p38 pathway, and each of these in turn inhibits Ras-dependent gene expression and proliferation. Published evidence of anti-mitogenic activity of the p38 pathway also supports this model. This hypothesis will be tested by the following specific aims: 1) To examine whether the p38 pathway functions downstream of MEK/ERK in Ras signaling; 2) To characterize the anti-mitogenic property of the p38 pathway in Ras proliferative signaling; 3) To determine whether the p38 pathway inhibits Ras activity by antagonizing JNK activation. Experiments will be carried out to dissect three MAPK pathways by focusing on analyses of the signaling mechanism as well as the consequence of the p38 activation by Ras in our NIH3T3 cell model. Knowledge obtained will be then applied to tumor cells where the proliferative signaling is constitutively active. Taken together, these studies will establish a negative feedback mechanism by which Ras signaling is regulated at the level of MAPK cascades. The information gained will advance our understanding of oncogene signaling networks and provide a new angle to develop signaling transduction pathway-oriented strategies against proliferative diseases.