Cyclooxygenase 2 promotes cell survival by stimulation of dynein light chain expression and inhibition of neuronal nitric oxide synthase activity. Mol Cell Biol 2000 Nov;20(22):8571-9
Date
10/25/2000Pubmed ID
11046152Pubmed Central ID
PMC102162DOI
10.1128/MCB.20.22.8571-8579.2000Scopus ID
2-s2.0-0033756160 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
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 E(2). 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.
Author List
Chang YW, Jakobi R, McGinty A, Foschi M, Dunn MJ, Sorokin AAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Carrier Proteins
Caspase 3
Caspases
Cell Differentiation
Cell Survival
Cyclooxygenase 2
Drosophila Proteins
Dyneins
Glomerular Mesangium
Humans
Isoenzymes
Membrane Proteins
Molecular Mimicry
Nerve Growth Factor
Neurons
Nitric Oxide Donors
Nitric Oxide Synthase
Nitric Oxide Synthase Type I
Organosilicon Compounds
PC12 Cells
Prostaglandin-Endoperoxide Synthases
Quaternary Ammonium Compounds
Rats
Superoxide Dismutase
