title: The aryl hydrocarbon receptor nuclear translocator (Arnt) is required for tumor initiation by benzo[a]pyrene.
abstract: Benzo[a]pyrene (B[a]P) is a ligand for the aryl hydrocarbon receptor (Ahr). After binding ligand, Ahr dimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) protein, and the dimer upregulates the transcription of Cyp1a1, Cyp1b1 and other enzymes involved in the metabolic activation of B[a]P. Arnt null mice die in utero. Mice in which Arnt deletion occurs constitutively in the epidermis die perinatally. In the current study, mice were developed in which the Arnt gene could be deleted specifically in adult skin epidermis. This deletion had no overt pathological effect. Homozygosity for a null reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase allele was introduced into the above mouse strain to render it more susceptible to tumor initiation by B[a]P. Deletion of Arnt in the epidermis of this strain completely prevented the induction of skin tumors in a tumor initiation-promotion protocol in which a single topical application of B[a]P acted as the tumor-initiating event, and tumor promotion was provided by repeated topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA). In contrast, deletion of Arnt did not prevent the induction of skin tumors in a protocol also using TPA as the promoter but using as the initiator N-methyl-N'-nitro-N-nitrosoguanidine, whose activity is unlikely to be affected by the activity of Ahr, Arnt or their target genes. These observations demonstrate that Arnt is required for tumor initiation by B[a]P in this system.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Shengli
authors.initials: S
authors.lastname: Shi
authors.forename: Diana Y
authors.initials: DY
authors.lastname: Yoon
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Hodge-Bell
authors.forename: Ilona G
authors.initials: IG
authors.lastname: Bebenek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whitekus
authors.forename: Ruixue
authors.initials: R
authors.lastname: Zhang
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Yim
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
authors.forename: Oliver
authors.initials: O
authors.lastname: Hankinson
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D002273:Carcinogens; D018336:Receptors, Aryl Hydrocarbon; D008769:Methylnitronitrosoguanidine; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D013755:Tetradecanoylphorbol Acetate