Multihormonal regulation and kinetics of induction of a hepatic mRNA sequence which is slowly responsive to triiodothyronine.

In contrast to the rapid response of mRNA-S14 which occurs within 20 min after L-triiodothyronine (T3) administration, the induction of other rat hepatic mRNA sequences exhibits a lag time of several hours. We have studied the induction of mRNA-S11 which codes for a protein of pI 6.1 and an Mr of 22,500 as a model of such a slowly responsive gene. In addition to T3, both glucocorticoids and growth hormone regulate the expression of this gene. For each of these stimuli, the response exhibits a lag time of approximately 6 h. Following this lag time, there is a linear increase in the level of mRNA-S11 induced by a single maximal dose of T3, dexamethasone, and growth hormone to levels of 15-, 6-, and 3-fold, respectively, in excess of the hypothyroid base-line levels. The similarity in the lag time and the differences in maximal responses effectively argues against the possibility that the effect of one hormone is mediated exclusively by a change in the secretion or metabolism of another. Support for a direct action of T3 and glucocorticoids on the hepatic cell comes from the observation that these hormones stimulate mRNA-S11 in rat hepatocytes under primary culture. The increases in in vitro nuclear transcription measured following T3 and dexamethasone administration were clearly insufficient to account for the observed increases in mRNA. Furthermore, the hormonal induction of mRNA-S11 was promptly abrogated by cycloheximide (10 mg/kg) injected 6 h after the administration of T3 or dexamethasone at the time of the expected mRNA increase. The post-transcriptional control of the mRNA-S11 and its sensitivity to cycloheximide are similar to previously documented responses of the rapidly induced mRNA-S14 and suggest for both sequences a requirement for ongoing synthesis of rapidly turning over proteins. We speculate that the lag time of response of a given gene to T3 or glucocorticoid may be an intrinsic characteristic of the gene and may represent a common set of molecular events involved in the activation of that gene by diverse stimuli.