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Drak2 Is Upstream of p70S6 Kinase: Its Implication in Cytokine-Induced Islet Apoptosis, Diabetes, and Islet Transplantation¹

Jianning Mao^*, Hongyu Luo^*, Bing Han^*, Richard Bertrand and Jiangping Wu^2,*,

^* Laboratory of Immunology, Laboratory of Oncology, and Nephrology Service, Centre Hospitalier de l’Université de Montréal, Notre Dame Hospital, Montreal, Quebec, Canada

Drak2 is a member of the death-associated protein family and a serine threonine kinase. In this study, we investigated its role in β cell survival and diabetes. Drak2 mRNA and protein were rapidly induced in islet β cells after stimulation by inflammatory lymphokines known to be present in type 1 diabetes. Drak2 up-regulation was accompanied by increased β cell apoptosis. β cell apoptosis caused by the said stimuli was inhibited by Drak2 knockdown using small interfering RNA. Conversely, transgenic Drak2 overexpression led to aggravated β cell apoptosis triggered by the stimuli. Further in vivo experiments demonstrated that Drak2 transgenic islets were more vulnerable to streptozocin insult. We established that inducible NO synthase was upstream and caspase-9 was downstream of Drak2 in its signaling pathway. Purified Drak2 could phosphorylate ribosomal protein S6 (p70S6) kinase in an in vitro kinase assay. Drak2 overexpression in NIT-1 cells led to enhanced p70S6 kinase phosphorylation, whereas Drak2 knockdown in these cells reduced it. These mechanistic studies proved that p70S6 kinase was a bona fide Drak2 substrate.

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 This work was supported by grants from the Canadian Institutes of Health Research (MOP57697, MOP69089, and PPP85159 to J.W., and MOP79565 to H.L.), the Kidney Foundation of Canada, the Heart and Stroke Foundation of Quebec, the Juvenile Diabetes Research Foundation USA (1-2005-197), and the J.-Louis Levesque Foundation (to J.W.). Group grants from the Canadian Institutes of Health Research for New Emerging Teams in Transplantation, and from Fonds de la Recherche en Santé du Québec for Transfusional and Hemovigilance Medical Research, and Genome Canada/Genome Quebec are also acknowledged.

² Address correspondence and reprint requests to Dr. Jiangping Wu, Laboratory of Immunology, Research Centre, Centre Hospitalier de l’Université de Montréal, Notre-Dame Hospital, Pavilion DeSève, Room Y-5616, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. E-mail address: jianping.wu{at}umontreal.ca

³ Abbreviations used in this paper: DAP, death-associated protein; DAPK, DAP kinase; HA, hemagglutinin; iNOS, inducible NO synthase; L-NMMA, N^G-methyl-L-arginine; siRNA, small interfering RNA; STZ, streptozocin; Tg, transgenic; WT, wild type.