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首页> 外文期刊>Cellular Physiology and Biochemistry >Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation
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Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation

机译：Gq诱导的细胞凋亡由导致PKC诱导的JNK激活的AKT抑制介导。

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Background/Aims Gq protein-coupled receptors (GqPCRs) regulate various cellular processes including mainly proliferation and differentiation. In a previous study, we found that in prostate cancer cells, the GqPCR of GnRH induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Since it was thought that GqPCR induces mainly activation of AKT, we undertook to examine how general is this phenomenon and understand its signaling. Methods We used various cells to follow the phosphorylation of signaling components using western blotting. Results In a screen of 21 cell lines, we found that PKC activation results in the reduction of AKT activity, which correlates nicely to JNK activation and in some cases to apoptosis. To further understand the signaling pathways involved in this stimulation, we studied in detail the SVOG-4O and αT3-1 cells. We found that PGF2α and GnRH agonist (GnRH-a) indeed induce significant Gq- and PKC- dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists on c-Src activation of the JNK cascade and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3, to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. Conclusion Our results present a general mechanism that mediates a GqPCR-induced, death receptors-independent, apoptosis in physiological, as well as cancer-related systems.
机译：背景/目的Gq蛋白偶联受体（GqPCR）调节各种细胞过程，主要包括增殖和分化。在先前的研究中，我们发现在前列腺癌细胞中，GnRH的GqPCR通过降低PKC依赖的AKT活性并提高JNK磷酸化来诱导细胞凋亡。由于人们认为GqPCR主要诱导AKT活化，因此我们致力于研究这种现象的普遍性并了解其信号传导。方法我们使用蛋白质印迹法，使用各种细胞追踪信号转导成分的磷酸化。结果在21个细胞系的筛选中，我们发现PKC激活导致AKT活性降低，这与JNK激活以及某些情况下与凋亡密切相关。为了进一步了解这种刺激所涉及的信号传导途径，我们详细研究了SVOG-4O和αT3-1细胞。我们发现PGF2α和GnRH激动剂（GnRH-a）确实在这些细胞中诱导了显着的Gq和PKC依赖性细胞凋亡。这是由PKC下游的两个信号分支介导的，它们在JNK上游的MLK3的水平会聚。一个分支包括JNK级联的c-Src激活，第二个分支涉及AKT活性的降低，从而减轻了其对MLK3的抑制作用，从而允许c-Src信号流向JNK。在MAPKK级别，我们发现信号是由MKK7而不是MKK4传输的。结论我们的结果提出了介导生理和癌症相关系统中GqPCR诱导的，独立于死亡受体的细胞凋亡的一般机制。

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