Regulation of de Novo Biosynthesis of Thyrotropin in Normal, Hyperplastic, and Neoplastic Thyrotrophs*

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Abstract
We have studied the in vitro regulation of de novo biosynthesis of TSH and a-subunit in normal and hyperplastic rat pituitary cells and mouse thyrotropic tumor cells. Twenty-four-hour cell cultures were exposed to a variety of stimulatory and inhibitory agents. Total (intracellular plus extracellular) unlabeled TSH and α-subunit were measured by RIA, and [35S]methionine-labeled products were measured by immunoprecipitation. TRH (10 nin) and potassium (K+; 60 HIM) were found to stimulate total unlabeled TSH (40–86% increments above control levels) and a-subunit (13–86%) as well as labeled TSH (25–45%) and a-subunit (18–119%). Responses to TRH and K+ were greater for secreted products than intracellular products. TRH and K+ also caused increases in [35S]methionine- labeled total proteins, but not to statistical significance. In long term cultures of thyrotropic tumor cells, the response of secreted TSH to TRH increased with time. A peak response of a 180% increase in TSH was reached after 6 days of culture. Other stimulatory and growth factors, including sodium butyrate (2 × 10-lJ M), epidermal growth factor (20 ng/ml), and a combination of estradiol (10 nM) and hydrocortisone (10 nM), caused no stimulation of TSH production. All TRH-mediated effects were blunted by T3 and somatostatin. There were quantitative but no major qualitative differences in the regulation of TSH biosynthesis among the three different cell types. Normal rat pituitary cells from young rats showed greater basal production of TSH and greater response to TRH than cells from older rats. Mouse thyrotropic tumors yielded a much larger number of thyrotrophs than rat pituitary glands and the thyrotropic tumor cells exhibited a higher ratio of labeled TSH to labeled total protein production. Thus, mouse thyrotropic tumors provide a particularly useful model for future studies of de novo biosynthesis of TSH.

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