Kinetic model of the response of precursor and mature rat hepatic mRNA-S14 to thyroid hormone.

We found in preliminary experiments that multiple daily injections of triiodothyronine (T3) resulted in an apparent prolongation in the half time (t1/2) of mRNA-S14 decay. To appropriately interpret these observations, we developed a mathematical model of the fluctuations of mRNA-S14 and its nuclear precursor after a single injection or multiple daily injections of T3. The model parameters include 1) the effect of plasma protein binding and metabolic clearance rates on receptor-bound nuclear T3, 2) the threefold circadian variation in mRNA-S14, 3) a 12-min t1/2 for the nuclear precursor and a 1.5-h t1/2 for the mature mRNA-S14, 4) previously derived relationships between the level of plasma T3 and nuclear occupancy, and 5) direct proportionality between nuclear transcription of the S14 gene and T3 nuclear occupancy. The model faithfully predicted the excursions of the mature mRNA-S14 and its nuclear precursor. Nuclear retention of T3 and the effects of circadian variation on S14 gene transcription explain the apparent prolongation in the t1/2 of decay of mature mRNA. Our findings illustrate the feasibility of incorporating parameters at the molecular level into a comprehensive kinetic analysis of hormone action.