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

The nuclear retinoic acid receptor RARγ2 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 RARγ2 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 RARγ2 degradation through inhibition of either the p38MAPK pathway or the 26S proteasome function impairs its RA‐induced transactivation activity. Thus, the turnover of RARγ2 is linked to transactivation.