Synergistic induction of gene 33 expression by retinoic acid and insulin.

The expression of gene 33 in rat liver and hepatoma cells is regulated by multiple hormones and other bioactive agents. Previous studies have demonstrated a 15-fold increase in gene 33 mRNA after 1 h of insulin treatment. We demonstrate in this report that retinoic acid (RA) also controls the expression of this gene. Gene 33 mRNA levels are rapidly elevated by RA, with maximal accumulation (19-fold over control) attained after just 1 h of RA treatment. The transcription rate of gene 33 was increased by RA to a maximum level 6-fold greater than control values. Studies with inhibitors of RNA synthesis demonstrated no increase in the stability of gene 33 mRNA in response to RA or insulin. In addition, a synergistic induction of both gene 33 mRNA levels and the transcription rate of gene 33 was observed when both RA and insulin were added together. In the presence of both hormones, the transcription rate was induced almost 20-fold in 30 min, followed by a 49-fold increase in mRNA levels after 1 h. Thus, gene 33 represents the first example of a gene whose transcription rate is elevated directly by both insulin and RA, and synergistically elevated by treatment with both hormones together.