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

1999, Proceedings of the National Academy of Sciences

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor α (PML/RAR α ) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML/RAR α cleavage, RA triggers degradation of both PML/RAR α and RAR α . Similarly, in non-APL cells, RA directly targeted RAR α and RAR α fusions to the proteasome degradation pathway. Activation of either RAR α or RXR α by specific agonists induced degradation of both proteins. Conversely, a mutation in RAR α that abolishes heterodimer formation and DNA binding, blocked both RAR α and RXR α degradation. Mutations in the RAR α DNA-binding domain or AF-2 transcriptional activation region also impaired RAR α 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.