Aryl Hydrocarbon Receptor Signaling

Exposure to halogenated and polycyclic aromatic hydrocarbons results in a wide range of toxic and carcinogenic responses. Most of these exposure effects are mediated by the aryl hydrocarbon receptor (AhR). AHR is a cytosolic protein associated with chaperone and immunophilin-like proteins (HSP90, XAP2, TEBP). Upon ligand activation, AHR dissociates from the complex, translocates into the nucleus, dimerizes with the aryl hydrocarbon nuclear translocator (ARNT), recruits several classes of co-activators, and binds to the xenobiotic response element (XRE). This AhR complex induces transcriptional activation of genes encoding xenobiotic metabolizing enzymes (CYP1A1, CYP1A2, CYP1B1), phase II metabolizing enzymes (GST, NADPH-quinone oxidoreductase, UDP-glucuronyl-S-transferase) and other growth factors and proteins, involved in cell cycle progression (p27Kip1, p21Cip1) and apoptosis (Bax, Fas, Fasl). AHR is also known to interact with different signaling pathways involved in cell cycle progression, cell proliferation, apoptosis and tumorigenesis. AhR mediates these effects through interactions with various proteins: 1. Retinoblastoma protein (RB). Interaction of AHR with RB promotes active repression of E2F-responsive genes, thereby cooperating in the inhibition of cell cycle progression. 2. Transforming growth factor-β (TGF-β). AHR enhances the metabolism of retinoic acid which attenuates TGF-β-mediated apoptosis. 3. Estrogen receptor (ER). In the presence of estrogen, AHR represses estrogen receptor (ER) signaling through a number of different mechanisms: direct interaction between ligand-activated AHR and ER at the estrogen response element (ERE) of ER target genes, binding of the AhR complex to adjacent inhibitory xenobiotic response element (iXRE), increased proteasome-dependent degradation of ER. By contrast, in absence of estrogen, ligand-activated AHR complex associates with ER resulting in transcriptional activation of ERE-dependent genes. 4. NF-κB. Direct interaction between AhR and RelA induce transactivation of c-Myc protein involved in cell proliferation and tumorigenesis.