Kalinec G, Nazarali A J, Hermouet S, Xu N, Gutkind J S
Laboratory of Cellular Development and Oncology, National Institute of Dental Research, Bethesda, Maryland 20892.
Mol Cell Biol. 1992 Oct;12(10):4687-93. doi: 10.1128/mcb.12.10.4687-4693.1992.
The discovery of mutated, GTPase-deficient alpha subunits of Gs or Gi2 in certain human endocrine tumors has suggested that heterotrimeric G proteins play a role in the oncogenic process. Expression of these altered forms of G alpha s or G alpha i2 proteins in rodent fibroblasts activates or inhibits endogenous adenylyl cyclase, respectively, and causes certain alterations in cell growth. However, it is not clear whether growth abnormalities result from altered cyclic AMP synthesis. In the present study, we asked whether a recently discovered family of G proteins, Gq, which does not affect adenylyl cyclase activity, but instead mediates the activation of phosphatidylinositol-specific phospholipase C harbors transforming potential. We mutated the cDNA for the alpha subunit of murine Gq in codons corresponding to a region involved in binding and hydrolysis of GTP. Similar mutations unmask the transforming potential of p21ras or activate the alpha subunits of Gs or Gi2. Our results show that when expressed in NIH 3T3 cells, activating mutations convert G alpha q into a dominant acting oncogene.
在某些人类内分泌肿瘤中发现Gs或Gi2的α亚基发生突变且缺乏GTP酶活性，这表明异源三聚体G蛋白在致癌过程中发挥作用。在啮齿动物成纤维细胞中表达这些改变形式的Gαs或Gαi2蛋白，分别激活或抑制内源性腺苷酸环化酶，并导致细胞生长出现某些改变。然而，尚不清楚生长异常是否源于环磷酸腺苷合成的改变。在本研究中，我们探讨了最近发现的一类G蛋白Gq是否具有转化潜能，Gq不影响腺苷酸环化酶活性，而是介导磷脂酰肌醇特异性磷脂酶C的激活。我们将小鼠Gqα亚基的cDNA在对应于参与GTP结合和水解区域的密码子处进行突变。类似的突变可揭示p21ras的转化潜能或激活Gs或Gi2的α亚基。我们的结果表明，当在NIH 3T3细胞中表达时，激活突变可将Gαq转化为显性作用的癌基因。
