Inhibition of Ras mitogenic signaling by the P38 pathway

描述：（改编自研究者摘要）已知Ras具有活性 三种丝裂原活化蛋白激酶（MAPK）途径，包括细胞外 信号调节激酶（ERK）、c-Jun N-末端激酶（JNK）和p38。而 ERK和JNK通路在Ras促有丝分裂信号传导中的重要作用 虽然已经证实，但p38通路的作用仍不清楚。它 在此提出，Ras对p38的激活构成了一个负性的 反馈以抑制其促有丝分裂信号传导。这个假设是基于我们的 初步结果表明Ras激活p38通路的几个分子， 每一种都反过来抑制Ras依赖性基因的表达， 增殖已发表的p38通路抗有丝分裂活性的证据 也支持这种模式。这一假设将通过以下方式进行检验： 具体目的：1）检测p38通路是否在以下下游起作用： Ras信号转导中的MEK/ERK; 2）为了表征Ras的抗有丝分裂特性， p38通路在Ras增殖信号转导中的作用 信号通路通过拮抗JNK的激活抑制Ras活性。实验将 进行解剖三个MAPK途径，重点是分析 信号转导机制以及Ras激活p38的结果， 我们的NIH 3 T3细胞模型。获得的知识将应用于肿瘤细胞 其中增殖性信号传导是组成型活性的。综合起来看， 这些研究将建立一个负反馈机制， 在MAPK级联水平调节信号传导。获得的信息 将促进我们对癌基因信号网络的理解，并提供一个新的 角度发展信号转导途径为导向的战略， 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.