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J. Biol. Chem., Vol. 279, Issue 10, 8608-8616, March 5, 2004

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Increased Myeloproliferation in Glutathione S-Transferase -deficient Mice Is Associated with a Deregulation of JNK and Janus Kinase/STAT Pathways^*

Laurent Gate, Rajrupa S. Majumdar, Alexandra Lunk, and Kenneth D. Tew

From the Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

It has been shown that glutathione S-transferase (GST) interacts with and suppresses the activity of c-Jun NH₂-terminal kinase (JNK). GST-deficient mice (GST^–/–) have higher levels of circulating white blood cells, with similar proportions of lymphocytes, monocytes, and granulocytes. Interestingly, a selective expansion of splenic B lymphocytes was observed in GST^–/– animals but no change in T lymphocytes or natural killer cells. A peptidomimetic inhibitor of GST that disrupts the interaction between GST and JNK mimics in wild type mice the increased myeloproliferation observed in GST^–/– animals. Until now, the molecular basis for this effect has not been defined. In an in vitro hematopoiesis assay, interleukin-3, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor were more effective at stimulating proliferation of hematopoietic cells in GST^–/– mice than in wild type. The JNK inhibitor SP600125 which caused little inhibition of cytokine-induced myeloproliferation in wild type mice, decreased the number of colonies in GST^–/– animals. A more sustained phosphorylation of the STAT family of proteins was also observed in GST^–/– bone marrow-derived mast cells exposed to interleukin-3. This was associated with an increased proliferation and a down-regulation of expression of negative regulators of the Janus kinase-STAT pathway SHP, Src homology 2 domain-containing tyrosine phosphatase-1 and -2. The increased activation of JNK and STATs in GST-deficient mice provides a viable mechanism for the increased myeloproliferation in these animals. These data also confirm the important role that GST plays in the regulation of cell signaling pathways in a myeloproliferative setting.

Received for publication, August 5, 2003 , and in revised form, December 3, 2003.

^* This work was supported by National Institutes of Health Grants CA06927 and CA85660 (to K. D. T.) and by an appropriation from the Commonwealth of Pennsylvania. 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.

To whom correspondence should be addressed: Dept. of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Tel.: 1-215-728-3137; Fax: 1-215-728-4333; E-mail: KD_Tew{at}fccc.edu.

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