Triiodothyronine (T3) regulation of thyrotropin subunit gene transcription is proportional to T3 nuclear receptor occupancy.

We have investigated the relationship between T3 nuclear receptor occupancy and the T3-mediated responses of TSH subunit gene expression. Hypothyroid mice bearing TtT 97 thyrotropic tumors were injected daily for 12 days with 0-10 micrograms T3/100 g BW, ip. T3 levels were measured in plasma and in tumor nuclei, and the maximal T3-binding capacity of tumor nuclei and the fractional occupancy of T3 nuclear receptors at each dose were calculated. T3-mediated decreases in TSH secretion were half-maximal at a dose of 0.2-0.3 micrograms/100 g BW, which resulted in plasma T3 levels of 0.98-1.2 ng/ml. Responses at the TSH subunit gene levels followed a similar pattern. Transcription of TSH beta and alpha-subunit genes was decreased maximally from 384 to 26 ppm for TSH beta and from 424 to 112 ppm for alpha-subunit. Inhibition of transcription was half-maximal at plasma T3 concentrations of 0.8 and 1.0 ng/ml for TSH beta and alpha-subunit, respectively. The half-maximal effective doses of T3 for decreases in TSH gene transcription were in good agreement with the amount of T3 necessary to saturate 50% of nuclear T3 receptors in the tumor, calculated at 1.07 ng/ml T3. A plot of fractional decrease in TSH subunit gene transcription vs. fractional T3 nuclear receptor occupancy demonstrated a straight line relationship for both TSH beta and alpha-subunit. Thus, the response of both TSH subunit genes to T3, a decrease in TSH beta and alpha-subunit gene transcription, is directly proportional to nuclear T3 receptor occupancy.