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

• DOI: 10.1073/pnas.96.26.14807
• Publication Date: 2002-07-26T14:41:48Z
• Authors: Jun Zhu; Maurizio Gianni; Eliezer Kopf; Nicole Honoré; Mounira Chelbi-Alix; Marcel Koken; Frédérique Quignon; Cécile Rochette-Egly; Hugues de Thé
• Keywords: 0301 basic medicine; Proteasome Endopeptidase Complex; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; DNA Mutational Analysis; Tretinoin; Neoplasm Proteins; Cysteine Endopeptidases; 03 medical and health sciences; Retinoid X Receptors; Leukemia, Promyelocytic, Acute; Multienzyme Complexes; Caspases; Dimerization; Transcription Factors

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.