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J Biol Chem, Vol. 274, Issue 29, 20251-20258, July 16, 1999

Suppression of Apoptosis by All-trans-Retinoic Acid
DUAL INTERVENTION IN THE c-JUN N-TERMINAL KINASE-AP-1 PATHWAY

Victoria Moreno-Manzano^§, Yoshihisa Ishikawa, Javier Lucio-Cazana^§, and Masanori Kitamura

From the  Glomerular Bioengineering Unit, Department of Medicine, University College London Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom and the ^§ Department of Physiology and Pharmacology, University of Alcala de Henares, E-28871 Madrid, Spain

Retinoic acid induces apoptosis of various cells, whereas little is known about its anti-apoptotic potential. In this report, we describe an anti-apoptotic property of all-trans-retinoic acid (t-RA) in mammalian cells. Mesangial cells exposed to hydrogen peroxide (H₂O₂) exhibited shrinkage of the cytoplasm, membrane blebbing, condensation of nuclei, and DNA fragmentation. Pretreatment with t-RA attenuated the morphologic and biochemical hallmarks of apoptosis. t-RA also inhibited apoptosis of mesangial cells triggered by pyrrolidine dithiocarbamate, whereas it did not prevent tumor necrosis factor--induced apoptosis. The anti-apoptotic effect against H₂O₂ was similarly observed in NRK49F fibroblasts, but not in Madin-Darby canine kidney epithelial cells and ECV304 endothelial cells. Mesangial cells exposed to H₂O₂ undergo apoptosis via the activator protein 1 (AP-1)-dependent pathway. We found that t-RA abrogated the H₂O₂-induced expression of c-fos/c-jun and activation of AP-1. Furthermore, t-RA inhibited H₂O₂-triggered activation of c-Jun N-terminal kinase (JNK), and dominant-negative inhibition of JNK attenuated the H₂O₂-induced apoptosis. These data disclosed the novel potential of retinoic acid as an inhibitor of apoptosis. The anti-apoptotic action of t-RA was ascribed, at least in part, to dual suppression of the cell death pathway mediated by JNK and AP-1.

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