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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069577-02
Application #
2443227
Study Section
Special Emphasis Panel (ZRG2-MEP (01))
Project Start
1996-09-01
Project End
2001-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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