Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs
Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs
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DOI：
10.1515/bc.2008.026
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发表时间：
2008-03-01
影响因子：
3.7
通讯作者：
Regazzi, Romano
中科院分区：
文献类型：
--
作者：
Lovis, Pascal;Gattesco, Sonia;Regazzi, Romano
胰腺P细胞胰岛素分泌的微调参与血糖稳态。这一过程中的缺陷可能导致慢性高血糖症和糖尿病。已经鉴定了几种控制胰岛素胞吐作用的蛋白质，但对其表达的调节机制仍知之甚少。在这里，我们表明，两个非编码microRNA，miR 124 a和miR 96，调节参与胰岛素胞吐的蛋白质的表达，并影响P-细胞株MIN 6 B1的分泌。miR 124 a增加SNAP 25、Rab 3A和突触蛋白-1A的水平，并降低Rab 27 A和Noc 2的水平。Rab 27 A表达的抑制通过与Rab 27 A mRNA的3 '非翻译区直接结合介导。对其他基因的影响是间接的，与mRNA水平的变化有关。miR 124 a的过表达导致在基础条件下过度的激素释放和葡萄糖诱导的分泌减少。miR 96增加了颗粒蛋白（一种胰岛素胞吐的负调节剂）的mRNA和蛋白水平，并降低了Noc 2的表达，导致MIN 6 B1细胞对促分泌素应答的能力降低。我们的数据确定miR 124 a和miR 96作为蛋白质表达的新调节剂，在胰岛素胞吐和其他激素和神经递质的释放中发挥关键作用。
Fine-tuning of insulin secretion from pancreatic P-cells participates in blood glucose homeostasis. Defects in this process can lead to chronic hyperglycemia and diabetes mellitus. Several proteins controlling insulin exocytosis have been identified, but the mechanisms regulating their expression remain poorly understood. Here, we show that two non-coding microRNAs, miR124a and miR96, modulate the expression of proteins involved in insulin exocytosis and affect secretion of the P-cell line MIN6B1. miR124a increases the levels of SNAP25, Rab3A and synapsin-1A and decreases those of Rab27A and Noc2. Inhibition of Rab27A expression is mediated by direct binding to the 3'-untranslated region of Rab27A mRNA. The effect on the other genes is indirect and linked to changes in mRNA levels. Overexpression of miR124a leads to exaggerated hormone release under basal conditions and a reduction in glucose-induced secretion. miR96 increases mRNA and protein levels of granuphilin, a negative modulator of insulin exocytosis, and decreases the expression of Noc2, resulting in lower capacity of MIN6B1 cells to respond to secretagogues. Our data identify miR124a and miR96 as novel regulators of the expression of proteins playing a critical role in insulin exocytosis and in the release of other hormones and neurotransmitters.