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 #
5R01CA069577-04
Application #
2895467
Study Section
Special Emphasis Panel (ZRG2-MEP (01))
Program Officer
Spalholz, Barbara A
Project Start
1996-09-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
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
Cha, Jiyoung Y; Maddileti, Savitri; Mitin, Natalia et al. (2009) Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. J Biol Chem 284:6227-40
Cha, Jiyoung Y; Lambert, Que T; Reuther, Gary W et al. (2008) Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis. Mol Cancer Res 6:435-45
Shields, Janiel M; Thomas, Nancy E; Cregger, Melissa et al. (2007) Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanoma. Cancer Res 67:1502-12
Hao, Honglin; Muniz-Medina, Vanessa M; Mehta, Heena et al. (2007) Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. Mol Cancer Ther 6:2220-9
Baines, Antonio T; Lim, Kian-Huat; Shields, Janiel M et al. (2006) Use of retrovirus expression of interfering RNA to determine the contribution of activated K-Ras and ras effector expression to human tumor cell growth. Methods Enzymol 407:556-74
Mitin, Natalia; Rossman, Kent L; Der, Channing J (2005) Signaling interplay in Ras superfamily function. Curr Biol 15:R563-74
Eckert, Lynn B; Repasky, Gretchen A; Ulku, Aylin S et al. (2004) Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res 64:4585-92
Collette, John; Ulku, Aylin S; Der, Channing J et al. (2004) Enhanced cathepsin L expression is mediated by different Ras effector pathways in fibroblasts and epithelial cells. Int J Cancer 112:190-9
Repasky, Gretchen A; Chenette, Emily J; Der, Channing J (2004) Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol 14:639-47
Cox, Adrienne D; Der, Channing J (2003) The dark side of Ras: regulation of apoptosis. Oncogene 22:8999-9006

Showing the most recent 10 out of 18 publications