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J. Biol. Chem., Vol. 283, Issue 18, 12034-12042, May 2, 2008

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Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2^*

Blazej Dolniak, Efstratios Katsoulidis, Nathalie Carayol, Jessica K. Altman, Amanda J. Redig, Martin S. Tallman, Takeshi Ueda, Rie Watanabe-Fukunaga, Rikiro Fukunaga, and Leonidas C. Platanias¹

From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611 and the Laboratory of Genetics, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan

Arsenic trioxide (As₂O₃) is a potent inducer of apoptosis of malignant 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 phosphorylation/activation of the MAPK signal-integrating kinases (Mnks) 1 and 2 in leukemia cell lines. Such activation is defective in cells with targeted disruption of the p38 MAPK gene, indicating that it requires upstream engagement of the p38 MAPK pathway. Studies using Mnk1^–/– or Mnk2^–/–, or double Mnk1^–/–Mnk2^–/– knock-out cells, establish that activation of Mnk1 and Mnk2 by arsenic trioxide regulates downstream phosphorylation of the eukaryotic initiation factor 4E at Ser-209. Importantly, arsenic-induced apoptosis is enhanced in cells with targeted disruption of the Mnk1 and/or Mnk2 genes, suggesting that these kinases are activated in a negative-feedback regulatory manner, to control generation of arsenic trioxide responses. Consistent with this, pharmacological inhibition of Mnk activity enhances the suppressive effects of arsenic trioxide on primary leukemic progenitors from patients with acute leukemias. Taken together, these findings indicate an important role for Mnk kinases, acting as negative regulators for signals that control generation of arsenic trioxide-dependent apoptosis and antileukemic responses.

Received for publication, October 25, 2007 , and in revised form, February 15, 2008.

^* This work was supported by National Institutes of Health Grants CA121192, CA77816, and CA100579 (to L. C. P.) and a merit review grant by the Dept. of Veterans Affairs (to L. C. P.). 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, Northwestern University Medical School, 303 East Superior St., Lurie 3-107, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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				L. C. Platanias Biological Responses to Arsenic Compounds J. Biol. Chem., July 10, 2009; 284(28): 18583 - 18587. [Abstract] [Full Text] [PDF]