Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10801983 | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | 2015 | 11 Pages |
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.
Keywords
Bcl-29cRANUR77Retinoid X receptorRXRRARatRABH3 Interacting Domain Death AgonistStat1all-trans retinoic acid9-cis Retinoic AcidThymocyteApoptosisdouble positiveRALDHRetinaldehyde dehydrogenaseRetinoidFas LigandFasLsignal transducers and activators of transcription 1B cell lymphoma 2BIDRetinoic acid receptor
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Authors
Beáta Kiss, Katalin Tóth, Zsolt Sarang, Ãva Garabuczi, Zsuzsa Szondy,