Excess Production of Free Alpha Subunits by Mouse Pituitary Thyrotropic Tumor Cellsin Vitro*

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Abstract
Primary cultures from 3 serially transplanted mouse pituitary thyrotropic tumors. Furth 97A, 97B and 97C, and 1 newly generated tumor; NIH 101A, secreted free .alpha.-subunits and a .beta.-subunit (TSH[thyroid stimulating hormone]-.beta.) in addition to intact TSH. The 3 glycopeptides were measured in specific, heterologous radioimmunoassays. Basal secretion of .alpha.-subunit was in excess in all 4 thyrotropic tumor cultures, ranging from 5.7- to 8.9-fold higher than that of intact TSH and 30- to 35-fold higher than that of free TSH-.beta.. In cultures from 97A, TRH [thyrotropin releasing hormone] (10-7 M) stimulated the secretion of TSH, .alpha. subunit, and TSH-.beta. by 175-185% and T4 [thyroxine] 10-5 M) inhibited TSH to 19%, .alpha. subunit to 68% and TSH-.beta. to 58% of control Secretion of TSH and its subunits in cultures from 97B was not consistently affected by TRH or T4. In cultures from 97C, TSH and .alpha.-secretion were inhibited in a dose-dependent fashion by Ta [triiodothyronine] from 2.5 .times. 10-9-1.6 .times. 10-7 M. Gel chromatography of incubation media from tumor 97A revealed elution volumes of TSH and .alpha. similar to those of purified rat glycopeptides and confirmed the excess secretion of free .alpha.-subunit. The .alpha. to TSH ratios in media from cultures of pituitary cells from normal and thyroidectomized rats were 1.6 and 0.8, respectively. The total production of TSH and its subunits was measured in cultures from tumor 97A and confirmed that .alpha.-subunit was synthesized excessively. The ratio of the plasma concentrations of 2 to TSH in tumor-bearing mice was 1.6 compared to 1.3 in thyroidectomized mice, and 0.36 in thyroidectomized rats. The .alpha. to TSH ratios in extracts of the corresponding thyrotropic tissues (tumor or pituitary) were 2.7, 1.7 and 0.40, respectively. These data are analogous to those reported in humans with thyrotropic and certain other pituitary tumors, and support the hypothesis that the subunits of glycoprotein hormones are independently synthesized.