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Molecular and Cellular Biology, November 2000, p. 8571-8579, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase Activity

Yu-Wen E. Chang,1,dagger Rolf Jakobi,2 Ann McGinty,1,3 Marco Foschi,1,4 Michael J. Dunn,1 and Andrey Sorokin1,*

Department of Medicine and Cardiovascular Research Center1 and Department of Pharmacology and Toxicology,2 Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Department of Surgery, The Queen's University of Belfast, Institute of Clinical Science, The Royal Group of Hospitals, Belfast, Northern Ireland, United Kingdom3; and Department of Internal Medicine, University of Florence, Florence 50134, Italy4

Received 1 January 2000/Returned for modification 29 February 2000/Accepted 22 August 2000

Cyclooxygenase 2 (COX-2) inhibits nerve growth factor (NGF) withdrawal apoptosis in differentiated PC12 cells. The inhibition of apoptosis by COX-2 was concomitant with prevention of caspase 3 activation. To understand how COX-2 prevents apoptosis, we used cDNA expression arrays to determine whether COX-2 regulates differential expression of apoptosis-related genes. The expression of dynein light chain (DLC) (also known as protein inhibitor of neuronal nitric oxide synthase [PIN]) was significantly stimulated in PC12 cells overexpressing COX-2. The COX-2-dependent stimulation of DLC expression was, at least in part, mediated by prostaglandin E2. Overexpression of DLC also inhibited NGF withdrawal apoptosis in differentiated PC12 cells. Stimulation of DLC expression resulted in an increased association of DLC/PIN with neuronal nitric oxide synthase (nNOS), thereby reducing nNOS activity. Furthermore, nNOS expression and activity were significantly increased in differentiated PC12 cells after NGF withdrawal. This increased nNOS activity as well as increased nNOS dimer after NGF withdrawal were inhibited by COX-2 or DLC/PIN overexpression. An nNOS inhibitor or a membrane-permeable superoxide dismutase (SOD) mimetic protected differentiated PC12 cells from NGF withdrawal apoptosis. In contrast, NO donors induced apoptosis in differentiated PC12 cells and potentiated apoptosis induced by NGF withdrawal. The protective effects of COX-2 on apoptosis induced by NGF withdrawal were also overcome by NO donors. These findings suggest that COX-2 promotes cell survival by a mechanism linking increased expression of prosurvival genes coupled to inhibition of NO- and superoxide-mediated apoptosis.

* Corresponding author. Mailing address: Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. Phone: (414) 456-4438. Fax: (414) 456-6515. E-mail: sorokin{at}mcw.edu.

dagger Present address: Molecular Biology Resources, Inc., Milwaukee, WI 53218.

Molecular and Cellular Biology, November 2000, p. 8571-8579, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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