The small GTP-binding protein Rho links G protein-coupled receptors and G alpha(12) to the serum response element and to cellular transformation
The small GTP-binding protein Rho links G protein-coupled receptors and G alpha(12) to the serum response element and to cellular transformation
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DOI：
10.1073/pnas.94.19.10098
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发表时间：
1997-09-16
影响因子：
11.1
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Fromm, C;Coso, OA;Gutkind, JS
与异源三聚体G蛋白偶联的受体可以有效地刺激多种细胞类型中的生长促进途径，并且如果持续激活，这些受体也可以表现为显性作用的癌蛋白。然而，在人类肿瘤中发现了G α（s）和G α（i2）家族的G蛋白的激活突变;当在鼠成纤维细胞中表达时，G α（q）和G α（12）家族的成员完全转化。为了阐明通过异源三聚体G蛋白参与增殖信号传导的分子事件，我们最近集中在基因表达调控上，使用表达mi毒蕈碱乙酰胆碱受体的NIH 3 T3成纤维细胞作为模型系统，我们观察到这种转化G蛋白偶联受体的激活诱导多种早期应答基因的快速表达，包括c-fos原癌基因，c-fos启动子元件之一的血清反应元件（serum response element，SRE）起着中心调节作用，并且已经发现SRE依赖的转录的激活受到几种蛋白质的调节，包括血清反应因子和三元复合物因子，借助于报告质粒进行基因表达，我们在此观察到M1毒蕈碱乙酰胆碱受体的刺激在NIH 3 T3细胞中有效地诱导SRE驱动的报道基因活性，在这些细胞中，只有异三聚体G蛋白α亚基的G α（12）家族强烈诱导SRE，而G β（1）γ（2）二聚体在更有限的程度上激活SRE，此外，我们的研究提供了强有力的证据表明m1，G α（12）和小GTP结合蛋白RhoA是一种新的信号转导途径的组成部分，该途径导致SRE的三元复合因子非依赖性转录激活和细胞转化。
Receptors coupled to heterotrimeric G proteins can effectively stimulate growth promoting pathways in a large variety of cell types, and if persistently activated, these receptors can also behave as dominant-acting oncoproteins, Consistently, activating mutations for G proteins of the G alpha(s) and G alpha(i2) families were found in human tumors; and members of the G alpha(q) and G alpha(12) families are fully transforming when expressed in murine fibroblasts. In an effort aimed to elucidate the molecular events involved in proliferative signaling through heterotrimeric G proteins we have focused recently on gene expression regulation, Using NIH 3T3 fibroblasts expressing mi muscarinic acetylcholine receptors as a model system, we have observed that activation of this transforming G protein-coupled receptors induces the rapid expression of a variety of early responsive genes, including the c-fos protooncogene, One of the c-fos promoter elements, the serum response element (SRE), plays a central regulatory role, and activation of SRE-dependent transcription has been found to be regulated by several proteins, including the serum response factor and the ternary complex factor, With the aid of reporter plasmids for gene expression, we observed here that stimulation of m1 muscarinic acetylcholine receptors potently induced SRE-driven reporter gene activity in NIH 3T3 cells, In these cells, only the G alpha(12) family of heterotrimeric G protein alpha subunits strongly induced the SRE, while G beta(1) gamma(2) dimers activated SRE to a more limited extent, Furthermore, our study provides strong evidence that m1, G alpha(12) and the small GTP-binding protein RhoA are components of a novel signal transduction pathway that leads to the ternary complex factor-independent transcriptional activation of the SRE and to cellular transformation.