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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,
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.

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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