Suppression of apoptosis by all-trans-retinoic acid. Dual intervention in the c-Jun n-terminal kinase-AP-1 pathway.
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-alpha-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.[1]References
- Suppression of apoptosis by all-trans-retinoic acid. Dual intervention in the c-Jun n-terminal kinase-AP-1 pathway. Moreno-Manzano, V., Ishikawa, Y., Lucio-Cazana, J., Kitamura, M. J. Biol. Chem. (1999) [Pubmed]
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