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2,3,7,8-Tetrachlorodibenzo-p-dioxin receptors regulate transcription of the cytochrome P1-450 gene. 1987

L K Durrin, and P B Jones, and J M Fisher, and D R Galeazzi, and J P Whitlock
Department of Pharmacology, Stanford University School of Medicine, California 94305.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dioxin, produces a diverse set of biological responses which, in some cases, reflects the altered expression of specific genes. An intracellular receptor protein binds TCDD saturably and with high affinity and mediates several of TCDD's biological effects. In mouse hepatoma cells, TCDD induces aryl hydrocarbon hydroxylase activity by activating the transcription of the cytochrome P1-450 gene. Studies of receptor-defective variant cells indicate that the activation of cytochrome P1-450 gene transcription requires functional TCDD receptors. Analysis of the DNA that flanks the 5'-end of the mouse cytochrome P1-450 gene reveals at least three control regions: a promoter, an inhibitory element, and a dioxin-responsive element (DRE). Therefore, expression of the cytochrome P1-450 gene represents a balance between negative and positive control. The DRE contains two discrete, non-overlapping DNA domains that respond to TCDD. Each TCDD-responsive domain acts independently of the other, each requires TCDD receptors for function, and each has the properties of a transcriptional enhancer. For example, the function of the DREs is relatively independent of both their location and their orientation with respect to the promoter. Together, the DREs and the TCDD-receptor complex constitute a dioxin-responsive enhancer system. Exposure of cells to TCDD results in the protection of a specific DNA domain from exonuclease digestion. This protection requires TCDD receptors. The protected domain maps to a DRE. This observation implies that the TCDD-receptor complex interacts with the DRE to activate the transcription of the cytochrome P1-450 gene.

UI MeSH Term Description Entries
D011955 Receptors, Drug Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified. Drug Receptors,Drug Receptor,Receptor, Drug
D002843 Chromatin The material of CHROMOSOMES. It is a complex of DNA; HISTONES; and nonhistone proteins (CHROMOSOMAL PROTEINS, NON-HISTONE) found within the nucleus of a cell. Chromatins
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004147 Dioxins A family of compounds that contain the 1,4-dioxin structure. Many specific dioxin derivatives are listed as CARCINOGENS; TERATOGENS; or MUTAGENS. Dioxin
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004742 Enhancer Elements, Genetic Cis-acting DNA sequences which can increase transcription of genes. Enhancers can usually function in either orientation and at various distances from a promoter. Enhancer Elements,Enhancer Sequences,Element, Enhancer,Element, Genetic Enhancer,Elements, Enhancer,Elements, Genetic Enhancer,Enhancer Element,Enhancer Element, Genetic,Enhancer Sequence,Genetic Enhancer Element,Genetic Enhancer Elements,Sequence, Enhancer,Sequences, Enhancer
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072317 Polychlorinated Dibenzodioxins Dibenzodioxin derivatives that contain multiple chloride atoms bound to the benzene ring structures. TCDD,Tetrachlorodibenzodioxin,2,3,7,8-Tetrachlorodibenzo-p-dioxin,Chlorinated Dibenzo-p-dioxins,Dibenzo(b,e)(1,4)dioxin, 2,3,7,8-tetrachloro-,PCDD,Polychlorinated Dibenzo-p-dioxins,Polychlorinated Dibenzodioxin,Polychlorodibenzo-4-dioxin,Polychlorodibenzo-p-dioxin,Tetrachlorodibenzo-p-dioxin,Chlorinated Dibenzo p dioxins,Dibenzo-p-dioxins, Chlorinated,Dibenzo-p-dioxins, Polychlorinated,Dibenzodioxin, Polychlorinated,Dibenzodioxins, Polychlorinated,Polychlorinated Dibenzo p dioxins,Polychlorodibenzo 4 dioxin,Polychlorodibenzo p dioxin,Tetrachlorodibenzo p dioxin
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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