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首页> 外文期刊>Molecular and Cellular Biology >p54nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation
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p54nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation

机译：p54nrb / NONO通过调节磷酸二酯酶mRNA的剪接和降解来调节依赖环AMP的糖皮质激素的产生

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Glucocorticoid production in the adrenal cortex is activated in response to an increase in cyclic AMP (cAMP) signaling. The nuclear protein p54nrb/NONO belongs to the Drosophila behavior/human splicing (DBHS) family and has been implicated in several nuclear processes, including transcription, splicing, and RNA export. We previously identified p54nrb/NONO as a component of a protein complex that regulates the transcription of CYP17A1, a gene required for glucocorticoid production. Based on the multiple mechanisms by which p54nrb/NONO has been shown to control gene expression and the ability of the protein to be recruited to the CYP17A1 promoter, we sought to further define the molecular mechanism by which p54nrb/NONO confers optimal cortisol production. We show here that silencing p54nrb/NONO expression in H295R human adrenocortical cells decreases the ability of the cells to increase intracellular cAMP production and subsequent cortisol biosynthesis in response to adrenocorticotropin hormone (ACTH) stimulation. Interestingly, the expression of multiple phosphodiesterase (PDE) isoforms, including PDE2A, PDE3A, PDE3B, PDE4A, PDE4D, and PDE11A, was induced in p54nrb/NONO knockdown cells. Investigation of the mechanism by which silencing of p54nrb/NONO led to increased expression of select PDE isoforms revealed that p54nrb/NONO regulates the splicing of a subset of PDE isoforms. Importantly, we also identify a role for p54nrb/NONO in regulating the stability of PDE transcripts by facilitating the interaction between the exoribonuclease XRN2 and select PDE transcripts. In summary, we report that p54nrb/NONO modulates cAMP-dependent signaling, and ultimately cAMP-stimulated glucocorticoid biosynthesis by regulating the splicing and degradation of PDE transcripts.
机译：响应于循环AMP（cAMP）信号的增加，激活肾上腺皮质糖皮质激素的产生。核蛋白p54 nrb / NONO属于果蝇行为/人类剪接（DBHS）家族，已参与多个核过程，包括转录，剪接和RNA输出。我们先前确定p54 nrb / NONO是调节CYP17A1转录的蛋白复合物的组成部分，而CYP17A1是糖皮质激素生产所需的基因。基于p54 nrb / NONO已显示出控制基因表达的多种机制以及该蛋白质被募集到CYP17A1启动子的能力，我们寻求进一步研究定义p54 nrb / NONO赋予皮质醇最佳生产的分子机制。我们在这里显示，沉默H295R人肾上腺皮质细胞中p54 nrb / NONO的表达会降低细胞增加细胞内cAMP产生以及随后对肾上腺皮质激素的响应的皮质醇生物合成的能力（ ACTH）刺激。有趣的是，在p54 nrb / NONO敲低细胞中诱导了多种磷酸二酯酶（PDE）亚型的表达，包括PDE2A，PDE3A，PDE3B，PDE4A，PDE4D和PDE11A。对p54 nrb / NONO沉默导致某些PDE亚型表达增加的机制的研究表明，p54 nrb sup> / NONO调节PDE亚型的子集剪接。重要的是，我们还确定了p54 nrb / NONO通过促进核酸外切酶XRN2与选择的PDE转录本之间的相互作用，在调节PDE转录本的稳定性中的作用。总之，我们报道p54 nrb / NONO调节cAMP依赖性信号传导，并最终通过调节PDE转录物的剪接和降解来最终刺激cAMP刺激的糖皮质激素的生物合成。

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