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首页> 外文期刊>Endocrinology >Mechanisms of protein kinase C signaling in the modulation of 3',5'-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells.
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Mechanisms of protein kinase C signaling in the modulation of 3',5'-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells.

机译：蛋白激酶C信号传导在小鼠性腺细胞中调节3'，5'-环磷酸腺苷介导的类固醇生成的机制。

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The protein kinase C (PKC) signaling pathway plays integral roles in the expression of the steroidogenic acute regulatory (StAR) protein that regulates steroid biosynthesis in steroidogenic cells. PKC can modulate the activity of cAMP/protein kinase A signaling involved in steroidogenesis; however, its mechanism remains obscure. In the present study, we demonstrate that activation of the PKC pathway, by phorbol 12-myristate 13-acetate (PMA), was capable of potentiating dibutyryl cAMP [(Bu)(2)cAMP]-stimulated StAR expression, StAR phosphorylation, and progesterone synthesis in both mouse Leydig (MA-10) and granulosa (KK-1) tumor cells. The steroidogenic potential of PMA and (Bu)(2)cAMP was linked with phosphorylation of ERK 1/2; however, inhibition of the latter demonstrated varying effects on steroidogenesis. Transcriptional activation of the StAR gene by PMA and (Bu)(2)cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of the cAMP response element binding protein (CREB). An oligonucleotide probe containing a CREB/activating transcription factor binding region in the StAR promoter was found to bind nuclear proteins in PMA and (Bu)(2)cAMP-treated MA-10 and KK-1 cells. Chromatin immunoprecipitation studies revealed that the induction of phosphorylated CREB was tightly correlated with in vivo protein-DNA interactions and recruitment of CREB binding protein to the StAR promoter. Ectopic expression of CREB binding protein enhanced CREB-mediated transcription of the StAR gene, an event that was markedly repressed by the adenovirus E1A oncoprotein. Further studies demonstrated that the activation of StAR expression and steroid synthesis by PMA and (Bu)(2)cAMP was associated with expression of the nuclear receptor Nur77, indicating its essential role in hormone-regulated steroidogenesis. Collectively, these findings provide insight into the mechanisms by which PKC modulates cAMP/protein kinase A responsiveness involved in regulating the steroidogenic response in mouse gonadal cells.
机译：蛋白激酶C（PKC）信号通路在类固醇生成的急性调节（StAR）蛋白的表达中起着不可或缺的作用，该蛋白调节类固醇生成细胞中的类固醇生物合成。 PKC可以调节参与类固醇生成的cAMP /蛋白激酶A信号传导的活性;但是，其机制仍然不清楚。在本研究中，我们证明了由佛波12-肉豆蔻酸13-乙酸酯（PMA）激活PKC途径能够增强二丁酰cAMP [（Bu）（2）cAMP]刺激的StAR表达，StAR磷酸化和小鼠Leydig（MA-10）和granulosa（KK-1）肿瘤细胞中的孕酮合成。 PMA和（Bu）（2）cAMP的类固醇生成潜力与ERK 1/2的磷酸化有关。但是，抑制后者显示出对类固醇生成的不同影响。 PMA和（Bu）（2）cAMP对StAR基因的转录激活受多种因素影响，其上调取决于cAMP反应元件结合蛋白（CREB）的磷酸化。发现在StAR启动子中包含CREB ​​/活化转录因子结合区的寡核苷酸探针与PMA和（Bu）（2）cAMP处理的MA-10和KK-1细胞中的核蛋白结合。染色质的免疫沉淀研究表明，磷酸化CREB的诱导与体内蛋白质-DNA相互作用以及CREB结合蛋白向StAR启动子的募集紧密相关。 CREB结合蛋白的异位表达增强了StAR基因的CREB介导的转录，这一事件被腺病毒E1A癌蛋白显着抑制。进一步的研究表明，PMA和（Bu）（2）cAMP激活StAR表达和类固醇合成与核受体Nur77的表达有关，表明其在激素调节的类固醇生成中起重要作用。总的来说，这些发现提供了对PKC调节cAMP /蛋白激酶A反应性的机制的洞察力，而cAMP /蛋白激酶A反应性涉及调节小鼠性腺细胞中的类固醇生成反应。

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