KINETIC-MODEL OF THE RESPONSE OS PRECURSOR AND MATURE RAT HEPATIC MESSENGER-RNA-S14 TO THYROID-HORMONE

We found in preliminary experiments that multiple daily injections of triiodothyronine (T-3) resulted in an apparent prolongation in the hal f time (t(1/2)) of mRNA-S14 decay. To appropriately interpret these ob servations, we developed a mathematical model of the fluctuations of m RNA-S14 and its nuclear precursor after a single injection or multiple daily injections of T-3. The model parameters include 1) the effect o f plasma protein binding and metabolic clearance rates on receptor-bou nd nuclear T-3, 2) the threefold circadian variation in mRNA-S14, 3) a 12-min t(1/2) for the nuclear precursor and a 1.5-h t(1/2) for the ma ture mRNA-S14, 4) previously derived relationships between the level o f plasma T-3 and nuclear occupancy, and 5) direct proportionality betw een nuclear transcription of the S14 gene and T-3 nuclear occupancy. T he model faithfully predicted the excursions of the mature mRNA-S14 an d its nuclear precursor. Nuclear retention of T-3 and the effects of c ircadian variation on S14 gene transcription explain the apparent prol ongation in the t(1/2) of decay of mature mRNA. Our findings illustrat e the feasibility of incorporating parameters at the molecular level i nto a comprehensive kinetic analysis of hormone action.