Aryl Hydrocarbon Receptor Degradation-Promoting Factor (ADPF) and the Control of the Xenobiotic Response

Induction of Cyp1a1 and ADPF-controlled degradation of nuclear AhR. In the absence of an agonist, the quiescent AhR is in a complex with two molecules of hsp90 (yellow ovals) and the AIP protein (green oval) in the cytoplasm; B[a]P-binding activates AhR, which translocates into the nucleus and dimerizes with Arnt; the AhR-Arnt dimer binds to a dioxin responsive element (DRE) and initiates the transcription of Cyp1a1. B[a]P-activated AhR is degraded through the ubiquitin-26S proteasome pathway that is controlled by ADPF (as a probable E3) in the nucleus. Cyclohexmide (CHX) blocks the synthesis of ADPF and consequently the B[a]P-induced degradation of nuclear AhR, resulting in superinduction. ADPF, AhR degradation promoting factor; AhR, Aryl hydrocarbon receptor; AIP, AhR-interacting protein; B[a]P, benzo[a]pyrene; Arnt, Aryl hydrocarbon receptor nuclear translocator; ER, endoplasmic reticulum.