Post-Transcriptional Regulation of the DUSP6/MKP-3 Phosphatase by MEK/ERK Signaling and Hypoxia
Post-Transcriptional Regulation of the DUSP6/MKP-3 Phosphatase by MEK/ERK Signaling and Hypoxia
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DOI：
10.1002/jcp.22339
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发表时间：
2011-01-01
影响因子：
5.6
通讯作者：
Gimond, Clotilde
中科院分区：
文献类型：
--
作者：
Bermudez, Olga;Jouandin, Patrick;Gimond, Clotilde
DUSP 6/MKP-3是对MAP激酶ERK 1/2具有特异性的细胞质双特异性磷酸酶。先前的数据表明，MEK/ERK轴通过DUSP 6的转录和翻译后调节对其自身的信号传导施加逆转录控制。我们首次证实了MEK/ERK在维持dusp 6 mRNA水平中的关键作用，而PI 3 K/mTOR、p38 MAPK和JNK信号通路没有显著影响。我们进一步表明，调节dusp 6 mRNA的稳定性在ERK依赖性调节dusp 6的表达中起着至关重要的作用。荧光素酶报告基因构建表明，MEK/ERK信号以3 '非翻译区（3' UTR）依赖的方式增加dusp 6 mRNA的半衰期。此外，发现缺氧（肿瘤生长的标志）以HIF-1依赖性方式增加dusp 6 mRNA的内源性水平和含有其3 'UTR的荧光素酶报告基因构建体的稳定性。然而，基础ERK活性需要对缺氧的反应。最后，TIS 11 CCCH锌指蛋白家族的成员Tristetraprolin（TTP）和果蝇的同源物DSP 2（调节mRNA稳定性的两种蛋白质）降低了内源性dusp 6 mRNA的水平和dusp 6/3 'UTR荧光素酶报告基因构建体的活性。这项研究表明，转录后调控是控制DUSP 6表达的关键过程。J.细胞。226：276-284，2010。(C)2010 Wiley-Liss，Inc.
DUSP6/MKP-3 is a cytoplasmic dual-specificity phosphatase specific for the MAP kinases ERK1/2. Previous data have shown that the MEK/ERK axis exerts a retro-control on its own signaling through transcriptional and post-translational regulation of DUSP6. We first confirm the key role of MEK/ERK in maintaining the levels of dusp6 mRNA, while PI3K/mTOR, p38 MAPK, and JNK signaling pathways had no significant effects. We further show that regulation of dusp6 mRNA stability plays a critical role in ERK-dependent regulation of dusp6 expression. Luciferase reporter constructs indicated that MEK/ERK signaling increased the half-life of dusp6 mRNA in a 3'untranslated region (3'UTR)-dependent manner. In addition, hypoxia, a hallmark of tumor growth, was found to increase both endogenous levels of dusp6 mRNA and the stability of the luciferase reporter constructs containing its 3'UTR, in a HIF-1-dependent manner. Nevertheless, a basal ERK activity was required for the response to hypoxia. Finally, Tristetraprolin (TTP), a member of the TIS11 CCCH zinc finger protein family, and PUM2, an homolog of drosophila pumilio, two proteins regulating mRNA stability reduced the levels of endogenous dusp6 mRNA and the activity of the dusp6/3'UTR luciferase reporter constructs. This study shows that post-transcriptional regulation is a key process in the control of DUSP6 expression. J. Cell. Physiol. 226: 276-284, 2010. (C) 2010 Wiley-Liss, Inc.