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A Mutant α Subunit of G12 Potentiates the Eicosanoid Pathway and is Highly Oncogenic in NIH 3T3 Cells
Ningzhi Xu, Lorelle Bradley, Indu Ambdukar and J. Silvio Gutkind
Proceedings of the National Academy of Sciences of the United States of America
Vol. 90, No. 14 (Jul. 15, 1993), pp. 6741-6745
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2362582
Page Count: 5
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The discovery of GTPase-inhibiting mutations in genes for α subunits of Gs or Gi2 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 αs or αi2 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 α subunit of Gq, which activates phosphatidylinositol (PI)-specific phospholipase C, is fully oncogenic. However, activated αq 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 α12 in NIH 3T3 cells is itself weakly transforming, an activated α12 behaves as a remarkably potent oncogene. Transformation by α12 correlates with alterations in the eicosanoid pathway but not with PI-specific phospholipase C or other G protein-linked second messengers.
Proceedings of the National Academy of Sciences of the United States of America © 1993 National Academy of Sciences