Oncogenic mutant of Gα12 stimulates cell proliferation through cycloxygenase-2 signaling pathway

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Abstract
Expression of the GTPase-deficient, activated mutant α-subunit of the heterotrimeric G protein G12 (Gα12QL) leads to the neoplastic transformation of fibroblast cell lines. The mitogenic pathway regulated by Gα12QL includes an extensive signaling network involving several small GTPases and various kinases. In addition, Gα12QL has been shown to potentiate the serum-induced phospholipase-A2 activity in NIH3T3 cells. In the present study, we demonstrate that cycloxygenase-2 (COX-2) pathway is involved in the mitogenic pathway activated by Gα12QL. Expression of Gα12QL and not Gα13QL, stimulates the serum-induced release of arachidonic acid in NIH3T3 cells. Furthermore, expression of Gα12QL or the stimulation of wild-type Gα12 induces the expression of COX-2. Our results also indicate that the COX-2 inhibitor acutely disrupts the DNA-synthesis stimulated by Gα12QL in NIH3T3 cells. These studies, for the first time, identify the crucial role of COX-2 in Gα12-mediated regulation of cell proliferation and suggest a role for prostaglandin-derived autocrine loop in Gα12-mediated signaling pathways.