The two primary goals of our previous proposal were to determine the contribution of multiple Ras-mediated effector signaling pathways to transformation and to determine whether different Ras signaling events are important for oncogenic Ras transformation of fibroblasts versus epithelial cells. In our continuation of these studies, we extend these analyses to emphasize two additional themes. First, we will evaluate the role of a novel effector pathway in Ras transformation We have identified Tiami as a novel effector of Ras. Tiami in turn can activation the Rac small GTPase. Rac has been shown to mediate Ras regulation of the p38 and JNK MAPK pathways. Therefore, we will assess the roles of these MAPK cascades as key components of Raf-independent signaling pathways important for Ras transformation. Second, the least understood aspect of Ras signaling involves the gene targets important for Ras-mediated oncogenesis. We describe studies to begin a delineation of the genes whose expression is deregulated by oncogenic Ras.
Four specific aims are proposed to accomplish these goals. First, we will characterize the role of Tiami as a critical effector of Ras transformation, and whether Tiami links Ras with Rac and p38/JNK signaling. Second, we will evaluate the distinct and opposing roles of the p38 and JNK MAPK cascades in Ras transformation, and determine whether these MAPKs mediate Ras regulation of gene expression. Third, we will determine the role of specific Ras-mediated signaling pathways involved in transformation of ROSE rat ovarian epithelial cells and define the gene targets that promote Ras transformation. Finally, we will employ microarray analyses to delineate the gene targets important for Ras transformation (in cooperation with telomerase and SV4O T antigen) of primary human embryonic kidney and mammary epithelial cells. These studies will evaluate our hypothesis that oncogenic Ras transformation of epithelial cells is critically dependent on activation of Raf-independent effector signaling pathways, in part, by deregulating the expression and function of key target genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069577-10
Application #
7023270
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
1996-09-01
Project End
2007-02-28
Budget Start
2006-03-13
Budget End
2007-02-28
Support Year
10
Fiscal Year
2006
Total Cost
$251,773
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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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

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