title: Retinoids induce Nur77-dependent apoptosis in mouse thymocytes.
abstract: Nur77 is a transcription factor, which plays a determinant role in mediating T cell receptor-induced cell death of thymocytes. In addition to regulation of transcription, Nur77 contributes to apoptosis induction by targeting mitochondria, where it can convert Bcl-2, an anti-apoptotic protein into a proapoptotic molecule. Previous studies have demonstrated that retinoids are actively produced in the mouse thymus and can induce a transcription-dependent apoptosis in mouse thymocytes. Here we show that retinoic acids induce the expression of Nur77, and retinoid-induced apoptosis is completely dependent on Nur77, as retinoids were unable to induce apoptosis in Nur77 null thymocytes. In wild-type thymocytes retinoids induced enhanced expression of the apoptosis-related genes FasL, TRAIL, NDG-1, Gpr65 and Bid, all of them in a Nur77-dependent manner. The combined action of these proteins led to Caspase 8-dependent Bid cleavage in the mitochondria. In addition, we could demonstrate the Nur77-dependent induction of STAT1 leading to enhanced Bim expression, and the mitochondrial translocation of Nur77 leading to the exposure of the Bcl-2/BH3 domain. The retinoid-induced apoptosis was dependent on both Caspase 8 and STAT1. Our data together indicate that retinoids induce a Nur77-dependent cell death program in thymocytes activating the mitochondrial pathway of apoptosis.
authors.affiliation: Department of Dental Biochemistry, Signaling and Apoptosis Research Group, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Department of Dental Biochemistry, Signaling and Apoptosis Research Group, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Department of Biochemistry and Molecular Biology, Signaling and Apoptosis Research Group, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sarang
authors.affiliation: Department of Dental Biochemistry, Signaling and Apoptosis Research Group, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Garabuczi
authors.affiliation: Department of Dental Biochemistry, Signaling and Apoptosis Research Group, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary. Electronic address: szondy@med.unideb.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000502:physiology*; D012176:Retinoids / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D060168:Thymocytes / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012176:Retinoids; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse
keywords: Apoptosis; Nur77; Retinoid; Thymocyte