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首页> 外文期刊>Cellular Signalling >The gep proto-oncogene Gα_(12) mediates LPA-stimulated activation of CREB in ovarian cancer cells
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The gep proto-oncogene Gα_(12) mediates LPA-stimulated activation of CREB in ovarian cancer cells

机译：gep原癌基因Gα_（12）介导LPA刺激卵巢癌细胞中CREB的激活

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摘要

Lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers. Previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells via Gα_(12). The present study utilizing Protein/ DNA array analyses of LPA-stimulated HeyA8 cells in which the expression of Gα_(12) was silenced, demonstrates for the first time that Gα_(12)-dependent mitogenic signaling by LPA involves the atypical activation cAMPresponse element binding protein (CREB). Results indicate that the robust activation of CREB by LPA is an early event that can be monitored by the phosphorylation of SER133 of CREB as early as 3 min. The findings that the expression of the constitutively activated mutant of Gα_(12) stimulates CREB even in the absence of LPA inmultiple ovarian cancer cell lines confirmthe direct role of Gα_(12) in the activation of CREB. This is further substantiated by the observation that the silencing of Gα_(12) drastically attenuates LPA-stimulated phosphorylation of CREB. Our results also establish that LPA-Gα_(12)-dependent activation of CREB is through a cAMP-independent, but Ras-ERKdependent mechanism. More significantly, our findings indicate that the expression of the dominant negative S133A mutant of CREB leads to a reduction in LPA-stimulated proliferation of HeyA8 ovarian cancer cells. Thus, results presented here demonstrate for the first time that CREB is a critical signaling node in LPA-LPAR and Gα_(12)/gep proto-oncogene stimulated oncogenic signaling in ovarian cancer cells.
机译：溶血磷脂酸（LPA）在卵巢癌的病理生理中起着至关重要的作用。先前的研究表明，LPA通过Gα_（12）刺激卵巢癌细胞的增殖。本研究利用LPA刺激的HeyA8细胞的蛋白/ DNA阵列分析，其中Gα_（12）的表达被沉默，这首次证明了LPA依赖于Gα_（12）的有丝分裂信号涉及非典型激活cAMP响应元件的结合蛋白质（CREB）。结果表明，LPA对CREB的强烈激活是一个早期事件，可以通过早于3分钟的CREB的SER133磷酸化来监测。即使在没有LPA的情况下，在多个卵巢癌细胞系中，组成性活化的Gα_（12）突变体的表达也能刺激CREB，这一发现证实了Gα_（12）在CREB活化中的直接作用。观察到Gα_（12）的沉默会大大减弱LPA刺激的CREB磷酸化，这进一步证实了这一点。我们的研究结果还证实，LPA-Gα_（12）依赖性的CREB激活是通过cAMP依赖性的，但Ras-ERK依赖性的。更重要的是，我们的发现表明，CREB的显性阴性S133A突变体的表达导致LPA刺激的HeyA8卵巢癌细胞增殖的减少。因此，此处呈现的结果首次证明CREB是LPA-LPAR中的关键信号传导节点，而Gα_（12）/ gep原癌基因刺激了卵巢癌细胞中的致癌信号传导。

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