A MUTANT ALPHA-SUBUNIT OF G(12) POTENTIATES THE EICOSANOID PATHWAY AND IS HIGHLY ONCOGENIC IN NIH-3T3 CELLS

The discovery of GTPase-inhibiting mutations in genes for alpha subunits of G(s) or G(i2) in certain human endocrine tumors has raised the possibility that heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) might contribute to neoplastic disease. Expression of GTPase-deficient alpha(s) or alpha(i2). polypeptides in rodent fibroblasts increases or decreases cAMP, respectively, and induces certain alterations in cell growth but only a few of the phenotypic changes associated with cellular transformation. In contrast, an analogous mutation in the alpha subunit of G(q), which activates phosphatidylinositol (PI)-specific phospholipase C, is fully oncogenic. However, activated alpha(q) is cytotoxic and several orders of magnitude less potent as an oncogene than certain G protein-coupled receptors. Thus, G proteins other than those inducing PI hydrolysis might possess high transforming efficiency. In the present study, we explored the G12 family of G proteins for their oncogenic potential. Our results show that whereas overexpression of wild-type alpha12 in NIH 3T3 cells is itself weakly transforming, an activated alpha12 behaves as a remarkably potent oncogene. Transformation by alpha12 correlates with alterations in the eicosanoid pathway but not with PI-specific phospholipase C or other G protein-linked second messengers.