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首页> 外文期刊>Molecular and Cellular Biology >Regulation of Mucin Gene Expression by CREB via a Nonclassical Retinoic Acid Signaling Pathway
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Regulation of Mucin Gene Expression by CREB via a Nonclassical Retinoic Acid Signaling Pathway

机译：CREB通过非经典维甲酸信号通路调节粘蛋白基因表达。

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Vitamin A and its metabolite retinoic acid (RA) are essential elements for normal lung development and the differentiation of lung epithelial cells. We previously showed that RA rapidly activated cyclic AMP response element-binding protein (CREB) in a nonclassical manner in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated that this nonclassical signaling of RA on the activation of CREB plays a critical role in regulating the expression of airway epithelial cell differentiation markers, the MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase Cα isozyme and transmits the activation signal to CREB via the Raf/MEK/extracellular signal-regulated kinase/p90 ribosomal S6 kinase (RSK) pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a cis-acting replication element motif on the promoter (at nucleotides [nt] ?878 to ?871) of the MUC5AC gene. The depletion of CREB using small interfering RNA abolished not only the RA-induced MUC5AC but also RA-induced MUC2 and MUC5B. Taken together, our findings demonstrate that CREB activation via this nonclassical RA signaling pathway may play an important role in regulating the expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.
机译：维生素A及其代谢物视黄酸（RA）是正常肺发育和肺上皮细胞分化的必需元素。我们以前显示RA在正常人气管支气管上皮（NHTBE）细胞中以非经典方式快速激活了环状AMP反应元件结合蛋白（CREB）。在本研究中，我们进一步证明RA激活CREB的这种非经典信号在调节气道上皮细胞分化标志物 MUC2 ， MUC5AC 的表达中起着至关重要的作用。 em>和 MUC5B 基因。我们发现RA快速激活蛋白激酶Cα同工酶，并通过Raf / MEK /细胞外信号调节激酶/ p90核糖体S6激酶（RSK）途径将激活信号传递至CREB。活化的RSK从细胞质转移到细胞核，在这里磷酸化CREB。然后，活化的CREB与 MUC5AC 基因启动子（在核苷酸[nt] 878至871位）上的顺式作用复制元件基序结合。使用小的干扰RNA消耗CREB不仅消除了RA诱导的 MUC5AC ，而且消除了RA诱导的 MUC2 和 MUC5B 。综上所述，我们的研究结果表明，通过这种非经典的RA信号通路激活CREB可能在调节粘蛋白基因的表达和介导NHTBE细胞正常黏膜分化期间RA的早期生物学效应中起重要作用。

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