title: Selective suppression of the human aryl hydrocarbon receptor function can be mediated through binding interference at the C-terminal half of the receptor.
abstract: The human aryl hydrocarbon receptor is a cytosolic signaling molecule which affects immune response and aberrant cell growth. Canonical signaling of the receptor requires the recruitment of coactivators to the promoter region to remodel local chromatin structure. We predicted that interference of this recruitment would block the aryl hydrocarbon receptor function. To prove that, we employed phage display to identify nine peptides of twelve-amino-acid in length which target the C-terminal half of the human aryl hydrocarbon receptor, including the region where coactivators bind. Eight 12mer peptides, in the form of GFP fusion, suppressed the ligand-dependent transcription of six AHR target genes (cyp1a1, cyp1a2, cyp1b1, ugt1a1, nqo1, and ahrr) in different patterns in Hep3B cells, whereas the AHR antagonist CH-223191 suppressed all these target genes similarly. Three of the 12mer peptides (namely 11-3, 1-7, and 7-3) suppressed the 3MC-induced, CYP1A1-dependent EROD activity and the ROS production caused by benzo[a]pyrene. These 12mer peptides suppressed the AHR function synergistically with CH-223191. In conclusion, we provide evidence that targeting the C-terminal half of the human aryl hydrocarbon receptor is a viable, new approach to selectively block the receptor function.
authors.affiliation: Harbin Center for Disease Control and Prevention, Harbin, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Thompson
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Ngo
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sung
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Leong
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, United States. Electronic address: wchan@pacific.edu.
authors.forename: William K
authors.initials: WK
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001391:Azo Compounds / Q000819:agonists / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D054730:Protein Interaction Domains and Motifs; D011720:Pyrazoles / Q000819:agonists / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D051792:Basic Helix-Loop-Helix Proteins; D002273:Carcinogens; D049452:Green Fluorescent Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D011993:Recombinant Fusion Proteins; C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; C111235:AHR protein, human
keywords: AHR suppression; ARNT; Aryl hydrocarbon receptor; Phage display