Menin Is Required for Optimal Processing of the MicroRNA let-7a*
Menin Is Required for Optimal Processing of the MicroRNA let-7a*
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DOI：
10.1074/jbc.m113.520692
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Hua, Xianxin
中科院分区：
文献类型：
--
作者：
Gurung, Buddha;Muhammad, Abdul Bari;Hua, Xianxin
背景：Menin抑制胰腺β细胞增殖。结果：Menin促进let-7a的加工，其靶点IRS2在胰岛素信号传导和β细胞增殖中起重要作用。结论：Menin部分通过调控miRNA生物发生抑制β细胞增殖。意义：了解menin如何抑制β细胞增殖将有助于改善针对内分泌肿瘤和代谢疾病（包括糖尿病）的治疗方法。多发性内分泌瘤I型（MEN1）是一种遗传性综合征，包括胰岛增生易感性。这种综合征是由编码menin蛋白的MEN1基因突变引起的。Menin与包括JunD在内的几个转录因子相互作用，并抑制它们的活性。然而，menin抑制基因表达的确切机制尚不清楚。在这里，我们发现menin与亚砷酸盐抗性蛋白2 （ARS2）相互作用，ARS2是核RNA cap结合复合物的一个组成部分，对包括let-7a在内的某些mirna的生物发生至关重要。primary-let-7a （pri-let-7a）的水平不受menin的影响；然而，成熟的let-7a水平在Men1切除后大幅下降。Let-7a靶点，包括Insr和Irs2，促增殖基因对胰岛素介导的信号传导至关重要，在men1切除的细胞中上调。在野生型细胞中使用抗mirna抑制let-7a足以将胰岛素受体底物2 （IRS2）的表达提高到men1切除细胞中观察到的水平。menin的缺失不影响Drosha和CBP80的表达，但严重损害了pri-miRNA向pre-miRNA的加工。Ars2敲低降低了menin表达细胞中的let-7a加工，但对menin切除细胞中的let-7a水平影响不大。由于已知IRS2介导胰岛素信号传导和胰岛素/丝裂原诱导的细胞增殖，这些发现共同揭示了menin抑制细胞增殖的新机制，至少部分是通过促进某些mirna的加工，包括let-7a，导致IRS2表达和胰岛素信号传导的抑制。
Background: Menin represses pancreatic beta cell proliferation. Results: Menin promotes processing of let-7a, whose target IRS2 plays an important role in insulin signaling and beta cell proliferation. Conclusion: Menin represses beta cell proliferation partly via regulation of miRNA biogenesis. Significance: Understanding how menin represses beta cell proliferation will aid toward improving therapies targeting endocrine tumors and metabolic diseases including diabetes.Multiple endocrine neoplasia type I (MEN1) is an inherited syndrome that includes susceptibility to pancreatic islet hyperplasia. This syndrome results from mutations in the MEN1 gene, which encodes menin protein. Menin interacts with several transcription factors, including JunD, and inhibits their activities. However, the precise mechanism by which menin suppresses gene expression is not well understood. Here, we show that menin interacts with arsenite-resistant protein 2 (ARS2), a component of the nuclear RNA CAP-binding complex that is crucial for biogenesis of certain miRNAs including let-7a. The levels of primary-let-7a (pri-let-7a) are not affected by menin; however, the levels of mature let-7a are substantially decreased upon Men1 excision. Let-7a targets, including Insr and Irs2, pro-proliferative genes that are crucial for insulin-mediated signaling, are up-regulated in Men1-excised cells. Inhibition of let-7a using anti-miRNA in wild type cells is sufficient to enhance the expression of insulin receptor substrate 2 (IRS2) to levels observed in Men1-excised cells. Depletion of menin does not affect the expression of Drosha and CBP80, but substantially impairs the processing of pri-miRNA to pre-miRNA. Ars2 knockdown decreased let-7a processing in menin-expressing cells but had little impact on let-7a levels in menin-excised cells. As IRS2 is known to mediate insulin signaling and insulin/mitogen-induced cell proliferation, these findings collectively unravel a novel mechanism whereby menin suppresses cell proliferation, at least partly by promoting the processing of certain miRNAs, including let-7a, leading to suppression of Irs2 expression and insulin signaling.