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Post‐transcriptional regulation of the DUSP6/MKP‐3 phosphatase by MEK/ERK signaling and hypoxia
Author(s) -
Bermudez Olga,
Jouandin Patrick,
Rottier Juliette,
Bourcier Christine,
Pagès Gilles,
Gimond Clotilde
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22339
Subject(s) - dusp6 , mapk/erk pathway , kinase , messenger rna , untranslated region , phosphatase , post translational regulation , luciferase , transcriptional regulation , pi3k/akt/mtor pathway , microbiology and biotechnology , biology , signal transduction , chemistry , phosphorylation , gene expression , protein phosphatase 2 , cell culture , gene , transfection , genetics
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. © 2010 Wiley‐Liss, Inc.