Phorbol ester mediated inhibition of tyrosine aminotransferase gene expression

We have investigated the effect of a tumor promoting phorbol ester, TPA, on the expression of the gene for tyrosine aminotransferase. It had been reported that exposure of cells to TPA inhibits insulin mediated induction of TAT activity. We subsequently reported that TPA inhibits not only the insulin mediated induction of TAT activity, but also the induction caused by glucocorticoids and cAMP analogs. To determine the basis for this inhibition of induction caused by three different hormones which are believed to act through separate mechanisms, we investigated the effect of TPA on TAT mRNA levels. TPA causes a time and concentration dependent loss of TAT mRNA from the cells. There is no change in the first hour after addition of 1.6 uM TPA. At two hours, there is a dramatic decrease in the transcript. The level then remains below the original basal level up to 8 hours. The maximal effect is observed at a concentration of 1 uM. The EC50 is approximately 7 nM. In the presence of the dexamethasone, TAT mRNA was increased by 6 fold. In the same experiment TPA did not inhibit dexamethasone -mediated induction of the TAT mRNA level, rather TPA inhibited TAT mRNA basal levels. Results of TAT enzyme assays indicated that TPA did inhibit dexamethasone-induced TAT enzyme activity. These studies suggest that TPA may regulate TAT gene expression post-transcriptionally.