Dimerization with retinoid X receptors and phosphorylation modulate the retinoic acid-induced degradation of retinoic acid receptors alpha and gamma through the ubiquitin-proteasome pathway.
In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for targeted degradation of proteins. We show that, in F9 cells and in transfected COS-1 cells, the nuclear retinoid receptors, retinoic acid receptor gamma2 (RARgamma2), RARalpha1, and retinoid X receptor alpha1 (RXRalpha1) are degraded in a retinoic acid-dependent manner through the ubiquitin-proteasome pathway. The degradation of RARgamma2 is entirely dependent on its phosphorylation and on its heterodimerization with liganded RXRalpha1. In contrast, RARalpha1 degradation can occur in the absence of heterodimerization, whereas it is inhibited by phosphorylation, and heterodimerization reverses that inhibition. RXRalpha1 degradation is also modulated by heterodimerization. Thus, each partner of RARgamma/RXRalpha and RARalpha/RXRalpha heterodimers modulates the degradation of the other. We conclude that the ligand-dependent degradation of RARs and RXRs by the ubiquitin-proteasome pathway, which is regulated by heterodimerization and by phosphorylation, could be important for the regulation of the magnitude and duration of the effects of retinoid signals.
Kopf
E
E
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, BP 163, 67404 Illkirch Cedex, CU de Strasbourg, France.
Plassat
J L
JL
Vivat
V
V
de Thé
H
H
Chambon
P
P
Rochette-Egly
C
C
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D003546:Cysteine Endopeptidases / Q000502:physiology*; D019281:Dimerization; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014452:Ubiquitins / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
D003546:Cysteine Endopeptidases; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D014452:Ubiquitins; D000097768:Retinoic Acid Receptor gamma