Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element

Journal Article · Wed Aug 01 00:00:00 EDT 1990 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.87.16.6258· OSTI ID:5841801

Friling, R S; Bensimon, A; Tichauer, Y; Daniel, V ^[1]

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1. The Weizmann Institute of Science, Rehovot (Israel)

Glutathione S-transferase (GST) Ya subunit gene expression is induced in mammalian tissues by two types of chemical agents: (i) planar aromatic compounds (e.g., 3-methylcholanthrene, {beta}-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin) and (ii) electrophiles (e.g., trans-4-phenyl-3-buten-2-one and dimethyl fumarate) or compounds easily oxidized to electrophiles (e.g., tert-butylhydroquinone). To study the mechanism of this induction, the authors have introduced deletions in the 5{prime} flanking region of a mouse GST Ya subunit gene, fused it to the coding sequence for chloramphenicol acetyltransferase (CAT) activity, and transfected the Ya-CAT genes for expression into hepatoma cells. They show that a single cis-regulatory element, between nucleotides {minus}754 and {minus}713 from the start of transcription, is responsible for the induction by both planar aromatic and electrophilic compounds. Using murine hepatoma cell mutants defective in either the Ah-encoded aryl hydrocarbon receptor (BP{sup r}c1 mutant) or in cytochrome P{sub 1}-450 gene (c1 mutant), they show that induction by planar aromatic but not by electrophilic inducers requires a functional Ah receptor and cytochrome P{sub 1}-450 activity. From this it is concluded that Ya gene activation by planar aromatic compounds involves metabolism of these inducers by the phase I xenobiotic-metabolizing cytochrome P{sub 1}-450 system into electrophilic compounds. Therefore, the regulatory sequence of the Ya gene should be considered an electrophile-responsive element (EpRE) activated exclusively by inducers containing an electrophilic center.

• OSTI ID: 5841801
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 87:16; ISSN PNASA; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

3-METHYLCHOLANTHRENE
550200* -- Biochemistry
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
AROMATICS
BIOLOGICAL EFFECTS
CARBOXYLIC ACIDS
CYTOCHROMES
DICARBOXYLIC ACIDS
DIOXIN
DRUGS
ELECTROPHORESIS
ENZYME ACTIVITY
ENZYMES
FLAVENOIDS
FLAVONES
FUMARIC ACID
GENE REGULATION
GLUTATHIONE
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
MAMMALS
MICE
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PEPTIDES
PIGMENTS
POLYCYCLIC AROMATIC HYDROCARBONS
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RODENTS
TRANSFERASES
TUMOR CELLS
VERTEBRATES
XENOBIOTICS