Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) catabolism in acute promyelocytic leukemia (APL); we found that, in addition to caspase-mediated PML/RAR alpha cleavage, RA triggers degradation of both PML/RAR alpha and RAR alpha, Similarly, in non-APL cells, RA directly targeted RAR alpha and RAR alpha fusions to the proteasome degradation pathway. Activation of either RAR alpha or RXR alpha by specific agonists induced degradation of both proteins. Conversely, a mutation in RAR alpha that abolishes heterodimer formation and DNA binding, blocked both RAR alpha and RXR alpha degradation. Mutations in the RAR alpha DNA-binding domain or AF-2 transcriptional activation region also impaired RAR alpha catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation.