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J. Biol. Chem., Vol. 281, Issue 42, 31222-31233, October 20, 2006

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Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase^*

Rachel B. Reinert, L. Morgan Oberle, Sheree A. Wek, Piyawan Bunpo, Xue Ping Wang^¶, Izolda Mileva^||, Leslie O. Goodwin^¶, Carla J. Aldrich^**, Donald L. Durden, Margaret A. McNurlan^||, Ronald C. Wek, and Tracy G. Anthony¹

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Evansville, Indiana 47712, the Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, the ^¶North Shore Long Island Jewish Research Institute, Manhasset, New York 11030, the ^**Department of Microbiology and Immunology, Indiana University School of Medicine, Evansville, Indiana 47712, the AFLAC Center for Cancer and Blood Disorders, Emory University School of Medicine, Atlanta, Georgia 30322, and the ^||Department of Surgery, State University of New York, Stony Brook, New York 11794

L-Asparaginase is important in the induction regimen for treating acute lymphoblastic leukemia. Cytotoxic complications are clinically significant problems lacking mechanistic insight. To reveal tissue-specific molecular responses to this drug, mice were administered asparaginase from either Escherichia coli (clinically used) or Wolinella succinogenes (novel, glutaminase-free form). Both enzymes abolished serum asparagine, but only the E. coli form reduced circulating glutamine. E. coli asparaginase reduced protein synthesis in liver and spleen but not pancreas via increased phosphorylation of the translation factor eIF2. In contrast, treatment with Wolinella caused no untoward changes in protein synthesis in any tissue examined. Treating mice deleted for the eIF2 kinase, GCN2, with the E. coli enzyme showed eIF2 phosphorylation to be GCN2-dependent, but only initially. Furthermore, although eIF2 phosphorylation was not increased in the pancreas or by Wolinella asparaginase, expression of the amino acid stress response genes, asparagine synthetase and CHOP/GADD153, increased as a result of both enzymes, even in tissues demonstrating no change in eIF2 phosphorylation. Finally, signaling downstream of the mammalian target of rapamycin kinase was repressed in liver and pancreas by E. coli but not Wolinella asparaginase. These data demonstrate that the nutrient stress response to asparaginase is tissue-specific and exacerbated by glutamine depletion. Importantly, increased expression of asparagine synthetase and CHOP does not require eIF2 phosphorylation, signifying alternate or auxiliary means of inducing gene expression under conditions of amino acid depletion in the whole animal.

Received for publication, May 11, 2006 , and in revised form, August 23, 2006.

^* This work was supported by National Institutes of Health Grants R01GM49164 (to R. C. W.) and R01AG17446 (to M. A. M.), the American Institute for Cancer Research (to T. G. A.), a Research Enhancement Grant by Indiana University School of Medicine (to T. G. A.), and an American Cancer Society Institutional Grant (to T. G. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Indiana University School of Medicine-Evansville, 8600 University Blvd., Evansville, IN 47712. Tel.: 812-465-1199; Fax: 812-465-1184; E-mail: tganthon{at}iupui.edu.

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