The gep oncogenes, Gα12 and Gα13, upregulate the transforming growth factor-β1 gene
The gep oncogenes, Gα12 and Gα13, upregulate the transforming growth factor-β1 gene
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DOI：
10.1038/onc.2008.488
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发表时间：
2009-03-05
期刊：
影响因子：
8
通讯作者：
Kim, S. G.
中科院分区：
文献类型：
--
作者：
Lee, S. J.;Yang, J. W.;Kim, S. G.
转化生长因子β 1（TGF β 1）在肿瘤转化和转分化中起作用。G α（12）和G α（13），被称为gep癌基因，刺激有丝分裂途径。然而，没有关于它们在TGF β 1基因调节中的作用以及将它们与基因转录连接的分子的信息。使用鼠胚胎成纤维细胞和肝星状细胞的敲除或敲除实验表明，G α（12）和G α（13）缺陷减少组成性、自刺激性或凝血酶诱导型TGF β 1基因表达。相反，G α（12）和G α（13）的激活突变体的转染使敲除细胞能够促进TGF β 1诱导。启动子缺失分析表明，激活蛋白1（AP-1）在TGF β 1基因反式激活中起作用，这一点通过观察到G蛋白的缺乏降低了AP-1活性，而它们的激活增强了AP-1活性而得到证实。此外，AP-1结合位点的突变消除了G α（12）和G α（13）诱导TGF β 1基因的能力。Rho或Rac的显性阴性突变体的转染，但不是Cdc 42，阻止基因反式激活和降低AP-1活性下游的G α 12和G α 13。总之，G α 12和G α 13通过增加Rho/Rac依赖性AP-1活性来调节TGF β 1基因的表达，这意味着G蛋白偶联受体（GPCR）-G α（12）途径参与了TGF β 1介导的转分化过程。
Transforming growth factor-beta 1 (TGF beta 1) plays a role in neoplastic transformation and transdifferentiation. G alpha(12) and G alpha(13), referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGF beta 1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a G alpha(12) and G alpha(13) deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGF beta 1 gene expression. In contrast, transfection of activated mutants of G alpha(12) and G alpha(13) enabled the knockout cells to promote TGF beta 1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGF beta 1 gene transactivation, which was corroborated by the observation that a deficiency of the G-proteins decreased the AP-1 activity, whereas their activation enhanced it. Moreover, mutation of the AP-1-binding site abrogated the ability of G alpha(12) and G alpha(13) to induce the TGF beta 1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of G alpha 12 and G alpha 13. In summary, G alpha 12 and G alpha 13 regulate the expression of the TGF beta 1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-G alpha(12) pathway is involved in the TGF beta 1-mediated transdifferentiation process.