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, hRARbeta, but not the chicken retinoid X receptor, cRXR. The retinoid X receptor does not augment the action of hRARbeta 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 GSTP]. 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.