In eukaryotic cells, liganded RARγ2/RXRα heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway. In this study, we dissected the role of the RARγ2 and RXRα partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RARγ2 is the "engine" initiating transcription and its own degradation subsequent to ligand binding. Integrity of its AF-2 domain and phosphorylation of its AF-1 domain are required for both the degradation and the transactivation of the receptor. Deletion of the whole AF-1 domain does not impair these processes but shifts the receptor toward other proteolytic pathways through RXRα. In contrast, RXRα plays only a modulatory role, cooperating with RARγ2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RARγ2/RXRα heterodimers. Our results underline that the AF-1 and AF-2 domains of each heterodimer partner cooperate with one other and that this cooperation is relevant for both the transcription and degradation processes.
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