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 t he expression of human glutathione S-transferase P1-1 (GSTP1-1) is sup pressed 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 promote r-CAT fusion gene is mediated by the region - 99 to + 72 of GSTP1. A c onsensus activator protein 1-binding site, located at nucleotide posit ion - 59 to - 65 of GSTP1, is suggested to be responsible for RA repre ssion. This effect of RA on GSTP1 expression is mediated by the human beta-type RA receptor, hRARbeta, but not the chicken retinoid X recept or, cRXR. The retinoid X receptor does not augment the action of hRARb eta on GSTP1. In addition, it is shown that GSTP1-1 expression is enha nced by insulin as a result of increased transcription of GSTP1. Assay of CAT activity indicates that the effect of insulin on the transcrip tion of GSTP1 is also mediated by the region - 99 to + 72 of GSTP]. Co mparison with sequences of other insulin-responsive genes, suggests th at insulin enhancement of GSTP1 expression is effected by an eight-bas e-pair sequence, 'CCCGCGTC', located at + 48 to + 55 in intron 1 of th e gene. These results are discussed in relation to the increased expre ssion of GSTP1-1 in many tumour cells.