Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.
Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.
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张力反应性 microRNA 有助于最大限度地诱导渗透调节转录因子 OREBP 以响应高 NaCl 高渗性
DOI：
10.1093/nar/gkq818
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发表时间：
2011-01
影响因子：
14.9
通讯作者：
Yang JY
中科院分区：
文献类型：
--
作者：
Huang W;Liu H;Wang T;Zhang T;Kuang J;Luo Y;Chung SS;Yuan L;Yang JY
渗透反应元件结合蛋白（OREBP）是一种与细胞膜反应相关的Rel样转录因子。先前的研究表明，高渗诱导的OREBP蛋白的积累可能是通过转录激活以及转录后mRNA稳定或增加翻译介导的。然而，潜在的机制仍然不完全阐明。在这里，我们报告说，microRNAs（miRNA）在高渗诱导的OREBP的诱导中起着关键的调节作用。在肾髓质上皮mIMCD 3细胞中，高渗可显著刺激OREBP-3′UTR的活性。此外，OREBP-3′UTR的过表达或通过敲低Dicer去除miRNAs大大增加了OREBP蛋白的表达。另一方面，高NaCl暴露后，miRNA表达迅速发生显著变化，其中miR-200 b和miR-717下调最为显著。此外，增加miR-200 b或miR-717导致OREBP的mRNA、蛋白和转录活性显著下调，而抑制miRNA或破坏miRNA-3′UTR相互作用则消除了沉默效应。在体内小鼠肾髓质中，发现miR-200 b和miR-717响应于肾张力改变而起调节OREBP的作用。总之，我们的研究结果支持这样的观点，即miRNAs有助于最大限度地诱导OREBP参与哺乳动物肾细胞对渗透应激的细胞反应。
Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3′-untranslated region of OREBP (OREBP-3′UTR). Furthermore, overexpression of OREBP-3′UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR-717 being most significantly down-regulated. Moreover, increased miR-200b or miR-717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA–3′UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR-200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells.
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影响因子：
5.3
作者：
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通讯作者：
Schneider, RJ
影响因子：
3.7
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Drews-Elger K;Ortells MC;Rao A;López-Rodriguez C;Aramburu J
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小鼠子宫胚胎着床过程中MicroRNA的表达和调控
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Yang, Zeng-Ming
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7.3
作者：
Kino T;Takatori H;Manoli I;Wang Y;Tiulpakov A;Blackman MR;Su YA;Chrousos GP;DeCherney AH;Segars JH
通讯作者：
Segars JH
影响因子：
11.4
作者：
Pothof, Joris;Verkaik, Nicole S.;Persengiev, Stephan P.
通讯作者：
Persengiev, Stephan P.