G-proteins are involved in the signal transduction processes ranging from sensory perception to cellular growth control mechanism. The impairment of G-protein function has been implicated in several pathological conditions such as pseudohypothyroidism, cardiac dysfunction, and oncogenesis. Constitutively activated G-protein pathways have been demonstrated to cause cellular transformation. The precise mechanism by which these mutations in G-proteins disrupt normal cell growth has not been fully understood. In addition, the growing list of G-protein of subunits has left several members of this class of signal-transducers without defined receptors or effectors. G-alpha12 and G-alpha13 are the members of G 12 family of G proteins. GTPase deficient mutants of G-alpha12 and G-alpha13 readily transform the fibroblast cell lines. Previously we have shown that these alpha-subunits activate Na+/H+ exchangers and unique set of primary response genes. Our recent studies indicate that these alpha-subunits also activate the newly identified Jun N-terminal Kinase (JNK) family of Mitogen Activated Protein Kinases (MAP kinases). Specifically this proposal will focus on identifying the signaling components regulated by G-alpha12 and G-alpha13 in relation to their oncogenicity of these alpha- subunits.
The specific aims of this proposal are 1. To define the role of G-alpha12 and G-alpha13 in activating growth factor-sensitive Na+/H+ exchanger; 2. To analyze the mechanism of G-alpha12 and G-alpha13 activation of specific set of primary response genes; and 3. To analyze the mechanism of G-alpha12 and G-alpha13 activation JNK. The long term objective of this project is to identify the role of G-protein regulated signal transduction pathways in relation to cell growth and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049897-02
Application #
2378267
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1996-03-01
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Temple University
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Ha, Ji Hee; Ward, Jeremy D; Varadarajalu, Lakshmi et al. (2014) The gep proto-oncogene G?12 mediates LPA-stimulated activation of CREB in ovarian cancer cells. Cell Signal 26:122-32