title: Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly.
abstract: The effect of the immune regulator vitamin A on T cell death has been poorly characterized. In the present study, we demonstrate that an active metabolite of vitamin A, retinoic acid (RA), promotes cell death in Jurkat leukemic T cells by counteracting mitogen-mediated repression of Fas-induced apoptosis. The effect of RA was dose-dependent, and at the optimal concentration of 1 muM, repression of Fas-induced cell death by the mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) or Con A was reversed by approximately 50% and 30%, respectively. RA promoted apoptosis rather than necrosis, as judged by analysis of cell morphology, mitochondrial membrane depolarization, and DNA fragmentation. TPA-mediated protection from Fas-induced apoptosis is dependent on ERK and NF-kappaB. However, analyses of ERK and NF-kappaB activities and expression of target genes indicated that RA-mediated counteraction of the protective effect of TPA did not involve negative crosstalk with ERK or NF-kappaB survival pathways. RA-induced cell death was accompanied by enhanced cleavage of procaspase-3, -6, and -8, as well as enhanced cleavage of DNA fragmentation factor 45. Interestingly, RA-mediated cleavage of procaspase-8 occurred very early and before any effect of RA could be detected on procaspase-3 cleavage, suggesting that RA might act at the level of the Fas death-inducing signaling complex (DISC). Indeed, DISC immunoprecipitation studies revealed that RA treatment reversed the inhibitory effect of TPA on CH11-induced recruitment and processing of procaspase-8 at the DISC. In conclusion, we have identified a role of RA in abrogating mitogen-mediated repression of Fas DISC assembly, thus enhancing Fas-induced apoptosis in leukemic T cells.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. nikolai.engedal@rr-research.no
authors.forename: Nikolai
authors.initials: N
authors.lastname: Engedal
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Heidi Kiil
authors.initials: HK
authors.lastname: Blomhoff
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000517:prevention & control; D008934:Mitogens / Q000494:pharmacology; D016328:NF-kappa B; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D008934:Mitogens; D016328:NF-kappa B; D019014:fas Receptor; D014212:Tretinoin; D048049:Extracellular Signal-Regulated MAP Kinases; C505530:CASP8 protein, human; D053181:Caspase 8