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Molecular and Cellular Biology, July 2004, p. 5721-5732, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5721-5732.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role for Activating Transcription Factor 3 in Stress-Induced ß-Cell Apoptosis{dagger}

Matthew G. Hartman,1,2 Dan Lu,1,2 Mi-Lyang Kim,1,2 Gary J. Kociba,3 Tala Shukri,4 Jean Buteau,5,{ddagger} Xiaozhong Wang,6,§ Wendy L. Frankel,7 Denis Guttridge,8 Marc Prentki,5 Shane T. Grey,9 David Ron,6 and Tsonwin Hai1,2*

Department of Molecular and Cellular Biochemistry,1 Center for Molecular Neurobiology,2 Department of Veterinary Biosciences,3 Department of Molecular Virology, Immunology, and Medical Genetics,8 Department of Pathology, Ohio State University, Columbus, Ohio,7 Immunology Research Center, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, Massachusetts,4 Department of Nutrition, University of Montreal, Montreal, Quebec, Canada,5 Skirball Institute, NYU School of Medicine, New York, New York,6 Arthritis and Inflammation Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia9

Received 30 March 2004/ Accepted 1 April 2004

Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced ß-cell apoptosis. First, ATF3 is induced in ß cells by signals relevant to ß-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-{kappa}B and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in ß cells develop abnormal islets and defects secondary to ß-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced ß-cell apoptosis.

* Corresponding author. Mailing address: 1060 Carmack Rd., Columbus, OH 43210. Phone: (614) 292-2910. Fax: (614) 292-5379. E-mail: hai.2{at}osu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: College of Physicians and Surgeons, Columbia University, New York, NY 10032.

§ Present address: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.

Molecular and Cellular Biology, July 2004, p. 5721-5732, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5721-5732.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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