Heavy metals induce expression of the TPA-inducible sequence (TIS) genes.

We previously cloned a set of primary response genes, which we call TIS (TPA-Inducible Sequence) genes, from a cDNA library prepared from Swiss 3T3 cells treated with tetradecanoyl phorbol acetate (TPA) and cycloheximide. TPA, polypeptide growth factors, and serum induce TIS gene expression in 3T3 cells. We now report that cadmium and zinc elevate mRNA levels for the TIS genes, including TIS28 (c-fos), in Swiss 3T3 cells. The time-course of TIS gene mRNA accumulation after metal exposure is delayed in comparison to the accumulation of TIS gene mRNA after treatment with TPA and growth factors. Cadmium induction of the TIS gene message accumulation is blocked by actinomycin D. Moreover, cadmium treatment does not significantly stabilize TIS gene messages. TIS gene induction by metal is a primary response; TIS8, which encodes a zinc-finger transcription factor, and TIS28 (c-fos) can be induced in the presence of cadmium and cycloheximide, an inhibitor of protein synthesis. Down-regulation of protein kinase C does not attenuate TIS gene induction by heavy metals.