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.
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