A mutant alpha subunit of G12 potentiates the eicosanoid pathway and is highly oncogenic in NIH 3T3 cells.
The discovery of GTPase-inhibiting mutations in genes for alpha subunits of Gs 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 Gq, 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 alpha 12 in NIH 3T3 cells is itself weakly transforming, an activated alpha 12 behaves as a remarkably potent oncogene. Transformation by alpha 12 correlates with alterations in the eicosanoid pathway but not with PI-specific phospholipase C or other G protein-linked second messengers.
Laboratory of Cellular Development and Oncology, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
N
N
Xu
L
L
Bradley
I
I
Ambdukar
J S
JS
Gutkind
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000242:Cyclic AMP / Q000032:analysis; D015777:Eicosanoids / Q000378:metabolism*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000145:classification / Q000235:genetics*; D007295:Inositol Phosphates / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation; D009374:Neoplasms, Experimental; D009857:Oncogenes / Q000235:genetics*; D015290:Second Messenger Systems; D014162:Transfection
D015777:Eicosanoids; D007295:Inositol Phosphates; D000242:Cyclic AMP; D019204:GTP-Binding Proteins