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J. Biol. Chem., Vol. 279, Issue 52, 53988-53993, December 24, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/52/53988    most recent M404809200v2 M404809200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tran, P. O. T. Articles by Robertson, R. P. Search for Related Content PubMed PubMed Citation Articles by Tran, P. O. T. Articles by Robertson, R. P. Social Bookmarking                      What's this?

Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress^*

Phuong Oanh T. Tran, Sarah M. Parker, Eric LeRoy, Christopher C. Franklin, Terrance J. Kavanagh¶, Tao Zhang, Huarong Zhou, Portia Vliet¶, Elizabeth Oseid, Jamie S. Harmon, and R. Paul Robertson||**

From the Pacific Northwest Research Institute, Seattle, Washington 98122 and Department of Pathology, ^¶NIEHS Center of Ecogenetics and Environmental Health, National Institutes of Health, Department of Environmental Health, ^||Departments of Medicine and Pharmacology, University of Washington, Seattle, Washington 98195, and Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Co 80262

The catalytic subunit of glutamylcysteine ligase (GCLC) primarily regulates de novo synthesis of glutathione (GSH) in mammalian cells and is central to the antioxidant capacity of the cell. However, GCLC expression in pancreatic islets has not been previously examined. We designed experiments to ascertain whether GCLC is normally expressed in islets and whether it is up-regulated by interleukin-1 (IL-1). GCLC expression levels were intermediate compared with other metabolic tissues (kidney, liver, muscle, fat, and lung). IL-1 up-regulated GCLC expression (10 ng/ml IL-1, 3.76 ± 0.86; 100 ng/ml IL-1, 4.22 ± 0.68-fold control) via the p38 form of mitogen-activated protein kinase and NFB and also increased reactive oxygen species levels (10 ng/ml IL-1, 5.41 ± 1.8-fold control). This was accompanied by an increase in intraislet GSH/GSSG ratio (control, 7.1 ± 0.1; 10 ng/ml IL-1, 8.0 ± 0.5; 100 ng/ml IL-1, 8.2 ± 0.5-fold control; p < 0.05). To determine whether overexpression of GCLC increases the antioxidant capacity of the islet and prevents the adverse effects of IL-1 on glucose-induced insulin secretion, islets were infected with an adenovirus encoding GCLC. IL-1 significantly decreased glucose-stimulated insulin secretion (control, 123.8 ± 17.7; IL-1, 40.2 ± 3.9 microunits/ml insulin/islet). GCLC overexpression increased intraislet GSH levels and partially prevented the decrease in glucose-stimulated insulin secretion caused by IL-1. These data provide the first report of GCLC expression in the islet and demonstrate that adenoviral overexpression of GCLC increases intracellular GSH levels and protects the beta cell from the adverse effects of IL-1.

Received for publication, April 30, 2004 , and in revised form, September 22, 2004.

^* This work was supported by a Juvenile Diabetes Research Foundation advanced postdoctoral fellowship (to P. O. T. T.) and National Institutes of Health Grants CA90473 (to C. C. F.) and RO1 DK38325 (to R. P. R.). 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: Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. Tel.: 206-726-1210; Fax: 206-726-1217; E-mail: rpr{at}pnri.org.

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