Phorbol ester treatment to mice inhibits DNA binding of the TCDD inducible nuclear dioxin-receptor to Cyp1A1 enhancer elements

Conference · Fri Mar 15 04:00:00 EST 1991 · FASEB Journal (Federation of American Societies for Experimental Biology); (United States)

OSTI ID:5173553

Okino, S T; Tukey, R H ^[1]

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1. Univ. of California, San Diego, La Jolla (United States)

The treatment of C57BL/6 mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in transcriptional activation of the Cyp1A1 and Cyp1A2 genes. Quantitation of mRNA levels and transcription rates demonstrate that post-transcriptional mechanisms are not involved in TCDD induction of the Cyp1A genes. The induction of the Cyp1A genes by TCDD occurs following ligand binding to the dioxin-receptor and accumulation of the ligand-receptor complex in the nucleus. The administration of the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) before or in combination with the administration of TCDD inhibits transcriptional activation of the Cyp1A genes. To analyze the mechanism of this inhibition, methods were developed to determine if the DNA binding potential of the nuclear dioxin-receptor was impaired. Using an oligonucleotide covering the Cyp1A1 xenobiotic responsive element (XRE), gel retardation assays demonstrated that within 1 hour, TCDD induces a nuclear DNA binding protein. This bonding is completely inhibited when incubated with excess XRE. Transcriptional increases in the Cyp1A1 and Cyp1A2 gene follow the appearance of the nuclear dioxin-receptor. When TPA is administered together with TCDD, the ligand dependent accumulation of the nuclear dioxin-receptor is abolished. Similar results are observed if TPA is administered prior to treatment with TCDD. These results indicate that TPA inhibits TCDD induced activation of the Cyp1A genes through a receptor mediated mechanism.

• OSTI ID: 5173553
• Report Number(s): CONF-9104107--
• Conference Information: Journal Name: FASEB Journal (Federation of American Societies for Experimental Biology); (United States) Journal Volume: 5:5
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
CARCINOGENS
CELL CONSTITUENTS
CELL NUCLEI
DIOXIN
ESTERS
GENES
HETEROCYCLIC COMPOUNDS
INHIBITION
KINETICS
MAMMALS
MEMBRANE PROTEINS
MICE
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PHORBOL ESTERS
PROTEINS
REACTION KINETICS
RECEPTORS
RODENTS
TRANSCRIPTION
VERTEBRATES