Glucocorticoid-Mediated Repression of the Oncogenic microRNA Cluster miR-17∼92 Contributes to the Induction of Bim and Initiation of Apoptosis
Glucocorticoid-Mediated Repression of the Oncogenic microRNA Cluster miR-17∼92 Contributes to the Induction of Bim and Initiation of Apoptosis
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DOI：
10.1210/me.2010-0402
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Distelhorst, Clark W.
中科院分区：
文献类型：
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作者：
Molitoris, Jason K.;McColl, Karen S.;Distelhorst, Clark W.
合成糖皮质激素是淋巴系统恶性肿瘤的最早有效治疗方法之一，因为它们能够诱导细胞凋亡，并且仍然与其他化疗药物联合使用。Bim是B细胞淋巴瘤-2家族的促凋亡成员，其上调是糖皮质激素诱导的细胞凋亡的重要介质。虽然已知糖皮质激素会升高Bim mRNA和蛋白，但对其机制知之甚少。在这里，我们报告糖皮质激素抑制microRNA簇miR-17的表达类似于92，这导致Bim蛋白表达升高，作为糖皮质激素诱导Bim的机制。我们使用一个双链酶-Bim 3'非翻译区构建体，证明糖皮质激素在miR-17类似于92抑制后转录后介导Bim诱导，导致Bim蛋白表达增加。与92 microRNA相似的miR-17过表达降低Bim诱导并减弱糖皮质激素介导的细胞凋亡。相反，类似于92的miR-17的敲低增加Bim蛋白表达和糖皮质激素介导的细胞凋亡。这些发现表明，与92相似的miR-17内源性水平抑制T细胞淋巴恶性肿瘤中的Bim表达，并且糖皮质激素通过下调与92相似的miR-17 microRNA簇诱导Bim表达。我们的研究结果提出了一种新的机制，有助于糖皮质激素治疗后Bim的上调和诱导淋巴细胞凋亡。此外，我们的工作表明，抑制类似于92的miR-17增加糖皮质激素诱导的细胞凋亡，突出了类似于92的miR-17作为白血病和淋巴瘤治疗靶点的潜在重要性。（分子内分泌学25：409-420，2011）
Synthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17 similar to 92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3' untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17 similar to 92 repression, resulting in increased Bim protein expression. Overexpression of miR-17 similar to 92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR-17 similar to 92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17 similar to 92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17 similar to 92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17 similar to 92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17 similar to 92 as a therapeutic target in leukemias and lymphomas. (Molecular Endocrinology 25: 409-420, 2011)