MicroRNA-200 Is Induced by Thioredoxin-interacting Protein and Regulates Zeb1 Protein Signaling and Beta Cell Apoptosis
MicroRNA-200 Is Induced by Thioredoxin-interacting Protein and Regulates Zeb1 Protein Signaling and Beta Cell Apoptosis
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DOI：
10.1074/jbc.m114.592360
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发表时间：
2014-12-26
影响因子：
4.8
通讯作者：
Shalev, Anath
中科院分区：
文献类型：
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作者：
Filios, Stephen R.;Xu, Guanlan;Shalev, Anath
小的非编码microRNAs已经成为细胞过程的重要调节因子，但它们在胰岛β细胞中的作用才刚刚开始被阐明。胰岛β细胞缺失是糖尿病发病机制中的一个关键因素，我们已证实糖尿病患者胰岛β细胞硫氧还蛋白相互作用蛋白(TXNIP)表达增加，并导致胰岛β细胞凋亡，而TXNIP缺乏对糖尿病具有保护作用。最近，我们发现TXNIP还通过诱导microRNA(MiR)-204来损害β细胞的功能。有趣的是，使用INS-1β细胞和原代胰岛，我们现在发现另一种microRNA miR-200的表达是由TXNIP和糖尿病诱导的。此外，我们发现miR-200靶向并降低了ZEB1(锌指E盒结合同源盒1)，并通过切割caspase-3水平、Bax/Bcl2比率和TUNEL检测促进了β细胞的凋亡。此外，ZEB1基因敲除模拟了miR-200对β细胞凋亡的影响，提示ZEB1在介导miR-200效应中起重要作用。此外，miR-200增加了β细胞上皮标志物E-钙粘素的表达，这与抑制上皮-间充质转化一致，这一过程被认为参与了β细胞的扩张。因此，我们首次发现了一个新的TXNIP/miR-200/ZEB1/E-cadherin信号通路，它将miR-200与β细胞的凋亡和糖尿病联系起来，也将β细胞的TXNIP与上皮-间充质转化联系起来。此外，我们的结果揭示了miR-200在β细胞中的调节和功能，并表明TXNIP诱导的microRNAs控制着β细胞生物学的各种过程。
Small noncoding microRNAs have emerged as important regulators of cellular processes, but their role in pancreatic beta cells has only started to be elucidated. Loss of pancreatic beta cells is a key factor in the pathogenesis of diabetes, and we have demonstrated that beta cell expression of thioredoxin-interacting protein (TXNIP) is increased in diabetes and causes beta cell apoptosis, whereas TXNIP deficiency is protective against diabetes. Recently, we found that TXNIP also impairs beta cell function by inducing microRNA (miR)-204. Interestingly, using INS-1 beta cells and primary islets, we have now discovered that expression of another microRNA, miR-200, is induced by TXNIP and by diabetes. Furthermore, we found that miR-200 targeted and decreased Zeb1 (zinc finger E-box-binding homeobox 1) and promoted beta cell apoptosis as measured by cleaved caspase-3 levels, Bax/Bcl2 ratio, and TUNEL. In addition, Zeb1 knockdown mimicked the miR-200 effects on beta cell apoptosis, suggesting that Zeb1 plays an important role in mediating miR-200 effects. Moreover, miR-200 increased beta cell expression of the epithelial marker E-cadherin, consistent with inhibition of epithelial-mesenchymal transition, a process thought to be involved in beta cell expansion. Thus, we have identified a novel TXNIP/miR-200/Zeb1/E-cadherin signaling pathway that, for the first time, links miR-200 to beta cell apoptosis and diabetes and also beta cell TXNIP to epithelial-mesenchymal transition. In addition, our results shed new light on the regulation and function of miR-200 in beta cells and show that TXNIP-induced microRNAs control various processes of beta cell biology.