Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation

Mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) has been shown to play a critical role in mediating the feedback control of MAP kinase ca scades in a variety of cellular processes, including proliferation and stre ss responsiveness. Although MKP-1 expression is induced by a broad array of extracellular stimuli, the mechanisms mediating its induction remain poorl y understood. Here we show that MKP-1 mRNA was potently induced by arsenite and ultraviolet light and modestly increased by heat shock and hydrogen pe roxide. Interestingly, arsenite also dramatically induces phosphorylation-a cetylation of histone H3 at a global level which precedes the induction of MKP-1 mRNA. The transcriptional induction of MKP-1, histone H3 modification , and elevation in MKP-1 mRNA in response to arsenite are all partially pre vented by the p38 MAP kinase inhibitor SB203580, suggesting that the p38 pa thway is involved in these processes. Finally, analysis of the DNA brought down by chromatin immunoprecipitation (ChIP) reveals that arsenite induces phosphorylation-acetylation of histone H3 associated with the MKP-1 gene an d enhances binding of RNA polymerase II to MKP-1 chromatin. ChIP assays fol lowing exposure to other stress agents reveal various degrees of histone H3 modification at the MKP-1 chromatin. The differential contribution of p38 and ERK MAP kinases in mediating MKP-1 induction by different stress agents further illustrates the complexity and versatility of stress-induced MKP-1 expression. Our results strongly suggest that chromatin remodeling after s tress contributes to the transcriptional induction of MKP-1.