Oncogenic mutant of Gα12 stimulates cell proliferation through cycloxygenase-2 signaling pathway
Oncogenic mutant of Gα12 stimulates cell proliferation through cycloxygenase-2 signaling pathway
复制标题
DOI：
10.1038/sj.onc.1203345
复制
发表时间：
1999-12-02
期刊：
影响因子：
8
通讯作者：
Dhanasekaran, N
中科院分区：
文献类型：
--
作者：
Dermott, JM;Reddy, MVR;Dhanasekaran, N
异源三聚体G蛋白G12（G α（12）QL）的GTP酶缺陷的、激活的突变体α亚基的表达导致成纤维细胞系的肿瘤转化。由G α（12）QL调节的促有丝分裂途径包括一个广泛的信号网络，涉及几种小GTP酶和各种激酶。此外，G α（12）QL已被证明可增强NIH 3 T3细胞中血清诱导的磷脂酶-A（2）活性。在本研究中，我们证明了环氧化酶-2（考克斯-2）通路参与了G α（12）QL激活的促有丝分裂通路。G α（12）QL而不是G α（13）QL的表达刺激了NIH 3 T3细胞中血清诱导的花生四烯酸的释放。此外，G α（12）QL的表达或野生型G α（12）的刺激诱导考克斯-2的表达。我们的研究结果还表明，考克斯-2抑制剂急性破坏了NIH 3 T3细胞中G α（12）QL刺激的DNA合成。这些研究首次确定了考克斯-2在步态介导的细胞增殖调节中的关键作用，并提示了在G α（12）介导的信号传导途径中，野牡丹素衍生的自分泌环的作用。
Expression of the GTPase-deficient, activated mutant alpha-subunit of the heterotrimeric G protein G12 (G alpha(12)QL) leads to the neoplastic transformation of fibroblast cell lines. The mitogenic pathway regulated by G alpha(12)QL includes an extensive signaling network involving several small GTPases and various kinases. In addition, G alpha(12)QL has been shown to potentiate the serum-induced phospholipase-A(2) activity in NIH3T3 cells. In the present study, we demonstrate that cycloxygenase-2 (COX-2) pathway is involved in the mitogenic pathway activated by G alpha(12)QL Expression of G alpha(12)QL and not G alpha(13)QL, stimulates the serum-induced release of arachidonic acid in NIH3T3 cells. Furthermore, expression of G alpha(12)QL or the stimulation of wild-type G alpha(12) induces the expression of COX-2. Our results also indicate that the COX-2 inhibitor acutely disrupts the DNA-synthesis stimulated by G alpha(12)QL in NIH3T3 cells. These studies, for the first time, identify the crucial role of COX-2 in Gait-mediated regulation of cell proliferation and suggest a role for prostaglandin-derived autocrine loop in G alpha(12)-mediated signaling pathways.