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

被引:179
|
作者
XU, NZ
BRADLEY, L
AMBDUKAR, I
GUTKIND, JS
机构
[1] NIDR,CELLULAR DEV & ONCOL LAB,MOLEC SIGNALLING GRP,BETHESDA,MD 20892
[2] NIDR,CLIN INVEST & PATIENT CARE BRANCH,BETHESDA,MD 20892
关键词
D O I
10.1073/pnas.90.14.6741
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:6741 / 6745
页数:5
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