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

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic le ukemia/retinoic acid receptor alpha (PML/RAR alpha) catabolism in acute pro myelocytic leukemia (APL); we found that, in addition to caspase-mediated P ML/RAR alpha cleavage, RA triggers degradation of both PML/RAR alpha and RA R alpha, Similarly, in non-APL cells, RA directly targeted RAR alpha and RA R alpha fusions to the proteasome degradation pathway. Activation of either RAR alpha or RXR alpha by specific agonists induced degradation of both pr oteins. Conversely, a mutation in RAR alpha that abolishes heterodimer form ation and DNA binding, blocked both RAR alpha and RXR alpha degradation. Mu tations in the RAR alpha DNA-binding domain or AF-2 transcriptional activat ion region also impaired RAR alpha catabolism. Hence, our results link tran scriptional activation to receptor catabolism and suggest that transcriptio nal up-regulation of nuclear receptors by their ligands may be a feedback m echanism allowing sustained target-gene activation.