Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RAR gamma degradation and transactivation.
The nuclear retinoic acid receptor RAR gamma 2 undergoes proteasome-dependent degradation upon ligand binding. Here we provide evidence that the domains that signal proteasome-mediated degradation overlap with those that activate transcription, i.e. the activation domains AF-1 and AF-2. The AF-1 domain signals RAR gamma 2 degradation through its phosphorylation by p38MAPK in response to RA. The AF-2 domain acts via the recruitment of SUG-1, which belongs to the 19S regulatory subunit of the 26S proteasome. Blocking RAR gamma 2 degradation through inhibition of either the p38MAPK pathway or the 26S proteasome function impairs its RA-induced transactivation activity. Thus, the turnover of RAR gamma 2 is linked to transactivation.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, BP 163, 67404 Illkirch cedex, France.
Maurizio
M
Giannì
Annie
A
Bauer
Enrico
E
Garattini
Pierre
P
Chambon
Cécile
C
Rochette-Egly
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D014212:Tretinoin; D025801:Ubiquitin; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma; C092282:PSMC5 protein, human; C106843:SUG1 protein, mammalian