Recent observations confirm that oncogenic Ras can cause transformation by Raf-independent signaling pathways. First, studies from the laboratories of the applicant as well as others showed that the activity of Rho family proteins is necessary for full oncogenic Ras transformation of NIH 3T3 cells. Second, the investigators determined that mutants of Ras that no longer activated the Raf>MEK>MAPK pathway still caused tumorigenic transformation of NIH 3T3 cells, possibly by activation of Rho family proteins. Finally, they observed that oncogenic Ras activation of the Raf/MAPK pathway alone was not sufficient to cause tumorigenic transformation of RIE-1 epithelial cells. Collectively, these observations provide the basis for their desire to decipher the complex nature of Ras mediated signal transduction pathways required to cause changes in cell growth and differentiation. Specifically, they propose to (1) determine if oncogenic Ras utilizes multiple effector-mediated pathways to trigger cellular transformation, (2) identify effector-mediated signaling pathways which determine why the Ras-related proteins Krev-1 and R-Ras display biological activities different from Ras, (3) establish whether Ras-mediated signaling events important for Ras transformation of fibroblasts are also important for Ras transformation of epithelial cells, and (4) determine if oncogenic Ras proteins modulate cellular differentiation via utilization of downstream effector pathways which are distinct from those that contribute to Ras transformation.
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