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首页> 外文期刊>American Journal of Physiology >MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells.
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MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells.

机译：MEKK3介导的高渗应激肾脏细胞中p38激酶和TonE的信号传导。

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摘要

Mitogen-activated protein kinase (MAPK) cascades contain a trio of kinases, MAPK kinase kinase (MKKK) --> MAPK kinase (MKK) --> MAPK, that mediate a variety of cellular responses to different signals including hypertonicity. The signaling response to hypertonicity is conserved across evolution from yeast to mammals in that it involves activation of p38/SAPK. However, very little is known about which upstream protein kinases mediate activation of p38 by hypertonicity in mammals. The MKKKs, MEKK3 and MEKK4, are upstream regulators of p38 in many cells. To investigate these signaling proteins as potential activators of p38 in the hypertonicity response, we generated stably transfected MDCK cells that express activated versions of MEKK3 or MEKK4, utilized RNA interference to deplete MEKK3, and employed pharmacological inhibition of p38 kinase. MEKK3-transfected cells demonstrated increased betaine transporter (BGT1) mRNA levels and upregulated tonicity enhancer (TonE)-driven luciferase activity under isotonic (basal) and hypertonic conditions compared with empty vector-transfected controls; small-interference RNA-mediated depletion of MEKK3 downregulated the activity of p38 kinase and decreased the expression of BGT1 mRNA. p38 Kinase inhibition abolished the effects of MEKK3 activation on BGT1 induction. In contrast, the response to hypertonicity in MEKK4-kA-transfected cells was similar to that observed in empty vector-transfected controls. Our data are consistent with the existence of an input from MEKK3 -->--> p38 kinase -->--> TonE.
机译：丝裂原活化的蛋白激酶（MAPK）级联包含三类激酶，即MAPK激酶激酶（MKKK）-> MAPK激酶（MKK）-> MAPK，可介导多种细胞对不同信号的反应，包括高渗性。从酵母到哺乳动物的进化过程中，对高渗性的信号传导反应得以保留，因为它涉及p38 / SAPK的激活。然而，对于哺乳动物中的高渗介导上游蛋白激酶介导p38活化的了解很少。 MKKK，MEKK3和MEKK4是许多细胞中p38的上游调控因子。为了研究这些信号蛋白在高渗反应中作为p38的潜在激活剂，我们生成了稳定转染的MDCK细胞，它们表达MEKK3或MEKK4的激活版本，利用RNA干扰来消耗MEKK3，并采用p38激酶的药理抑制作用。与空载体转染的对照相比，MEKK3转染的细胞在等渗（基础）和高渗条件下显示出增加的甜菜碱转运蛋白（BGT1）mRNA水平和张力调节剂（TonE）驱动的荧光素酶活性。小干扰RNA介导的MEKK3耗竭下调了p38激酶的活性并降低了BGT1 mRNA的表达。 p38激酶抑制消除了MEKK3激活对BGT1诱导的影响。相反，MEKK4-kA转染的细胞对高渗的反应类似于在空载体转染的对照中观察到的反应。我们的数据与来自MEKK3->-> p38激酶->-> TonE的输入的存在是一致的。

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