The AF-1 and AF-2 domains of RAR gamma 2 and RXR alpha cooperate for triggering the transactivation and the degradation of RAR gamma 2/RXR alpha heterodimers.
In eukaryotic cells, liganded RAR gamma 2/RXR alpha 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 RAR gamma 2 and RXR alpha partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RAR gamma 2 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 RXR alpha. In contrast, RXR alpha plays only a modulatory role, cooperating with RAR gamma 2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RAR gamma 2/RXR alpha 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.
Gianní
Maurizio
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) CNRS INSERM ULP, UMR 7104, BP 10142, 67404 Illkirch Cedex, France.
Tarrade
Anne
A
Nigro
Elisa Agnese
EA
Garattini
Enrico
E
Rochette-Egly
Cécile
C
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D019281:Dimerization; D017930:Genes, Reporter; D015151:Immunoblotting; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry*; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000737:chemistry*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000097768:Retinoic Acid Receptor gamma
D015500:Chloramphenicol O-Acetyltransferase; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma