TURNOVER OF GLUTATHIONE-S-TRANSFERASE-ALPHA MESSENGER-RNAS IS ACCELERATED BY 12-O-TETRADECANOYL PHORBOL-13-ACETATE IN HUMAN HEPATOMA AND COLON-CARCINOMA CELL-LINES

The phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (TPA), known to induce murine glutathione S-transferase (GST) Ya, was examined for its effect on the expression of human GST alpha. Unexpectedly, 24-h tr eatment of the human hepatoma cell line HepG2 with 100 nmol/l TPA caus ed a decrease of the GST alpha mRNA level to below 5% of controls, i.e . opposite to the known response in the mouse. The level of mRNA for G ST Mu was also decreased, but the mRNAs of c-jun and jun-B were elevat ed after 2 h. The decrease of GST alpha mRNAs was inhibited by stauros porine, suggesting an involvement of protein kinase C. Inhibition of t ranscription and translation by actinomycin D and cycloheximide also p artially inhibited the effect of TPA on the expression of GST alpha. I n the presence of actinomycin D, GST alpha mRNA halflife was 14.5 h, c ompared to 3.5 h in the presence of TPA. The calcium ionophore A23187 caused a loss of GST alpha mRNAs to levels almost as low as those obta ined with TPA. The effects of TPA and the calcium ionophore were also observed in CaCo2 colon carcinoma cells. As a consequence of the decre ase of mRNA levels, GST alpha protein levels and total GST enzyme acti vity were also diminished. Also, the morphology of the cells was chang ed after 3 h exposure to TPA. These data suggest that human GST alpha expression can be regulated at the level of mRNA stability by a pathwa y involving protein kinase C.