Triiodothyronine Rapidly Reverses Inhibition of S14 Gene Transcription by Glucagon*

The rapid response of hepatic mRNA-S14 to T3 has made this sequence an important model for studying the mechanism of hormonal induction of gene expression. In previous studies we showed, in the intact rat, that glucagon administration during the peak of the mRNA S14 diurnal rhythm causes a monoexponential fall in the level of mRNA-S14, and that T3 reverses this effect. We have now defined more precisely the mechanism governing this interaction. Measurement of in vitro nuclear transcriptional rates shows that T3 can reverse the glucagon-induced reduction of mRNA-S14 transcription. Reversal can be demonstrated within 5 min after the iv injection of T3. Further, the reversal appears to be related to the occupation of specific nuclear receptors, as inferred from the calculated nuclear occupancy and the effects of various iodothyronine analogs of T3. These results suggest that the effects of T3 are mediated by varying rates of production of the nuclear precursor and not by its stabilization, as previously proposed. Ancillary evidence supporting this conclusion came from the demonstration that the apparent t1/2 of the 4.5-kilobase precursor was not prolonged by T3.