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J. Biol. Chem., Vol. 279, Issue 29, 30133-30142, July 16, 2004

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Dynamic O-GlcNAc Modification of Nucleocytoplasmic Proteins in Response to Stress

A SURVIVAL RESPONSE OF MAMMALIAN CELLS^*

Natasha E. Zachara, Niall O'Donnell¶, Win D. Cheung, Jessica J. Mercer, Jamey D. Marth||, and Gerald W. Hart**

From the Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185 and The Howard Hughes Medical Institute, Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093

Cellular response to environmental, physiological, or chemical stress is key to survival following injury or disease. Here we describe a unique signaling mechanism by which cells detect and respond to stress in order to survive. A wide variety of stress stimuli rapidly increase nucleocytoplasmic protein modification by O-linked -N-acetylglucosamine (O-GlcNAc), an essential post-translational modification of Ser and Thr residues of metazoans. Blocking this post-translational modification, or reducing it, renders cells more sensitive to stress and results in decreased cell survival; and increasing O-GlcNAc levels protects cells. O-GlcNAc regulates both the rates and extent of the stress-induced induction of heat shock proteins, providing a molecular basis for these findings.

Received for publication, April 5, 2004 , and in revised form, May 11, 2004.

^* This work was supported in part by National Institutes of Health Grant CA42486 (to G. W. H.), NHLBI Grant N01-HV-28180 (to G. W. H.), National Institutes of Health Grant DK48247 (to J. D. M.), and the Howard Hughes Medical Institute (to J. D. M.). Under a licensing agreement between Covance Research Products and The Johns Hopkins University, Dr. Hart receives a share of royalties received by the university on sales of the CTD 110.6 antibody. 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.

^¶ Present address: Johnson & Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121.

^|| Recipient of support as an Investigator of the Howard Hughes Medical Institute.

^** To whom correspondence should be addressed: Dept. of Biological Chemistry, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185. Tel.: 410-614-1265; Fax: 410-614-8804; E-mail: gwhart{at}jhmi.edu.

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