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Molecular and Cellular Biology, December 2001, p. 8213-8224, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8213-8224.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transcriptional Induction of MKP-1 in Response to Stress Is Associated with Histone H3 Phosphorylation-Acetylation

Ji Li,1 Myriam Gorospe,1 Dorothy Hutter,1,dagger Janice Barnes,1 Stephen M. Keyse,2 and Yusen Liu1,*

Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224,1 and ICRF Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital, Dundee, United Kingdom2

Received 13 August 2001/Accepted 7 September 2001

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 cascades in a variety of cellular processes, including proliferation and stress responsiveness. Although MKP-1 expression is induced by a broad array of extracellular stimuli, the mechanisms mediating its induction remain poorly understood. Here we show that MKP-1 mRNA was potently induced by arsenite and ultraviolet light and modestly increased by heat shock and hydrogen peroxide. Interestingly, arsenite also dramatically induces phosphorylation-acetylation 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 prevented by the p38 MAP kinase inhibitor SB203580, suggesting that the p38 pathway 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 and enhances binding of RNA polymerase II to MKP-1 chromatin. ChIP assays following 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 stress contributes to the transcriptional induction of MKP-1.


* Corresponding author. Mailing address: Box 12, Laboratory of Cellular and Molecular Biology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224. Phone: (410) 558-8442. Fax: (410) 558-8335. E-mail: yusen-liu{at}nih.gov.

dagger Present address: Department of Biology, Villanova University, Villanova, PA 19085.


Molecular and Cellular Biology, December 2001, p. 8213-8224, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8213-8224.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



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