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J. Biol. Chem., Vol. 281, Issue 32, 22446-22452, August 11, 2006

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Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide^*

Padma Kannan-Thulasiraman, Efstratios Katsoulidis, Martin S. Tallman, J. Simon C. Arthur, and Leonidas C. Platanias¹

From the Robert H. Lurie Comprehensive Cancer Center and the Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, and Lakeside VA Hospital Chicago, Illinois 60611 and the Medical Research Council Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom

Arsenic trioxide (As₂O₃) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As₂O₃ induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines. Such activation requires upstream engagement of p38 MAPK, as demonstrated by experiments using pharmacological inhibitors of p38 or p38 knock-out cells. Arsenic-induced apoptosis was enhanced in cells in which MSK1 expression was decreased using small interfering RNA and in Msk1 knock-out mouse embryonic fibroblasts, suggesting that this kinase is activated in a negative feedback regulatory manner to regulate As₂O₃ responses. Consistent with this, pharmacological inhibition of MSK1 enhanced the suppressive effects of As₂O₃ on the growth of primary leukemic progenitors from chronic myelogenous leukemia patients. Altogether, these findings indicate an important role for MSK1 downstream of p38 in the regulation of As₂O₃ responses.

Received for publication, March 31, 2006 , and in revised form, June 7, 2006.

^* This work was supported by United States Department of Defense Grant DAMD 17-03-1-0254, a merit review grant from the Department of Veterans Affairs, and National Institutes of Health Grant CA94079 (to L. C. P.) and Training Grant T32CA070085 (to P. K.-T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, Lurie 3-107, 303 East Superior St., Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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