Fig. 1
Canonical and non-canonical signaling pathways of AhR. a Schematic representation of the canonical signaling pathways of AhR. In the absence of ligand, AhR is retained in the cytoplasm in an inactive complex containing chaperone proteins, such as HSP90 and XAP2. After ligand binding, AhR translocates into the nucleus, where it dimerizes with ARNT. The AhR/ARNT dimer binds genomic regions containing DRE that regulate expression of several phase I and phase II metabolizing enzymes, as well as several other genes, such as Cyp1a1, Cyp1b1, AhRR, Il-22, and GSTA. AhR activity is tightly controlled by three different negative feedback loops, including: (i) proteosomal degradation of AhR initiated by the ubiquitin ligase complex, (ii) metabolism clearance of ligands by CYP1A1, and (iii) disruption of the AhR/ARNT complex by AhRR. AhRR, AhR repressor; ARNT, AhR nuclear translocator; Cyp1a1, cytochrome P450 1A1; Cyp1b1, cytochrome P450 1B1; DRE, dioxin response element; GSTA, glutathione-S-transferase A; HSP90, heat shock protein 90; Il-22, interleukin 22; XAP2, HBV X-associated protein 2. b–e Schematic representation of examples of non-canonical AhR signaling. b AhR activation by ligands may lead to a direct interaction with pRb, which blocks cell cycle progression by suppressing the expression of S-phase genes. pRb, hypophosphorylated retinoblastoma protein. c Through an interaction with NF-κB, AhR induces the expression of cytokines and chemokines, such as BAFF, BLC, CCL1, and IFR3. The AhR/NF-κB interaction also induces decreased expression of Cyp1A1. BAFF, B-cell-activating factor of the tumor necrosis factor family; BLC, B-lymphocyte chemoattractant; CCL1, CC-chemokine ligand 1; IFR3, interferon responsive factor; NF-κB, nuclear factor-κB. d Ligand-activated AhR binds ER and promotes the proteolysis of ER by assembling a ubiquitin ligase complex. ER, estrogen receptor. e After ligand binding, AhR dimerizes with KLF6 and binds genomic regions containing NC-DRE that regulate the expression of target genes, such as p21cip1, which mediate cell cycle control. KLF6, tumor suppressor Kruppel-like factor 6; NC-DRE, non-consensus DRE
