Xu N, Bradley L, Ambdukar I, Gutkind J S
Laboratory of Cellular Development and Oncology, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6741-5. doi: 10.1073/pnas.90.14.6741.
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.
在某些人类内分泌肿瘤中，Gs或G(i2)的α亚基基因中发现了GTP酶抑制性突变，这增加了异源三聚体鸟嘌呤核苷酸结合调节蛋白（G蛋白）可能导致肿瘤性疾病的可能性。在啮齿动物成纤维细胞中表达缺乏GTP酶活性的αs或αi2多肽，分别会增加或降低细胞内的环磷酸腺苷（cAMP）水平，并诱导细胞生长发生某些改变，但与细胞转化相关的表型变化只有少数几种。相比之下，Gq的α亚基中的类似突变，可激活磷脂酰肌醇（PI）特异性磷脂酶C，具有完全致癌性。然而，激活的αq具有细胞毒性，作为癌基因的效力比某些G蛋白偶联受体低几个数量级。因此，除了那些诱导PI水解的G蛋白外，其他G蛋白可能具有较高的转化效率。在本研究中，我们探讨了G蛋白的G12家族的致癌潜力。我们的结果表明，虽然在NIH 3T3细胞中过表达野生型α12本身的转化能力较弱，但激活的α12却表现为一种非常有效的癌基因。α12介导的转化与类花生酸途径的改变相关，但与PI特异性磷脂酶C或其他G蛋白偶联的第二信使无关。
