The human glutathione S-transferase P1-1 gene: modulation of expression by retinoic acid and insulin.
Glutathione S-transferases (GSTs) are a group of enzymes which play an important role in the detoxication of xenobiotics. It is shown that the expression of human glutathione S-transferase P1-1 (GSTP1-1) is suppressed by retinoic acid (RA) as the result of decreased transcription from its gene, GSTP1. Chloramphenicol acetyltransferase (CAT) assays indicate that the effect of RA on the transcription of a GSTP1 promoter-CAT fusion gene is mediated by the region -99 to +72 of GSTP1. A consensus activator protein 1-binding site, located at nucleotide position -59 to -65 of GSTP1, is suggested to be responsible for RA repression. This effect of RA on GSTP1 expression is mediated by the human beta-type RA receptor, hRAR beta, but not the chicken retinoid X receptor, cRXR. The retinoid X receptor does not augment the action of hRAR beta on GSTP1. In addition, it is shown that GSTP1-1 expression is enhanced by insulin as a result of increased transcription of GSTP1. Assay of CAT activity indicates that the effect of insulin on the transcription of GSTP1 is also mediated by the region -99 to +72 of GSTP1. Comparison with sequences of other insulin-responsive genes, suggests that insulin enhancement of GSTP1 expression is effected by an eight-base-pair sequence, 'CCCGCGTC', located at +48 to +55 in intron 1 of the gene. These results are discussed in relation to the increased expression of GSTP1-1 in many tumour cells.
Department of Biochemistry and Molecular Biology, University College and Middlesex School of Medicine, London, U.K.
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Xia
J B
JB
Taylor
S R
SR
Spencer
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Ketterer
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002645:Chickens; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000378:metabolism; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms
D002352:Carrier Proteins; D007328:Insulin; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase