Pituitary Insulin-Like Growth Factor-I Gene Expression: Regulation by Triiodothyronine and Growth Hormone*

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Abstract
Most of the growth-promoting effects of GH are mediated through insulin-like growth factor-I (IGF-I). Pituitary GH gene expression is, in turn, inhibited by IGF-I. Since rat pituitary tissue and GH3 pituitary tumor cells express both the GH and the IGF-I genes, we have attempted to clarify their potential interactions in the somatotroph by examining hormonal factors involved in the regulation of pituitary IGF-I gene expression. IGF-I mRNA was measured in GH3 cells by a solution hybridization/RNase protection assay, using riboprobes to differentially protect the IGF-I variant mRNAs arising by alternative splicing at both the 5'' untranslated (UT) and 3'' ends of the primary transcript. GH3 cells contained both class A and class C 5'' UT variant mRNAs, with a relative abundance similar to that found in the liver. Sixty-five percent of the total IGF-I mRNA in GH3 cells was processed at the 3'' end to IGF-Ia, and 35% to IGF-Ib mRNAs, whereas in the liver the proportions were 85% and 15%, respectively. GH3 cells grown in thyroid hormone-depleted medium for 4 days contained low levels of IGF-I mRNA. T3 and human (h) GH induced total IGF-I mRNA content in thyroid hormone-depleted cells, with both 5'' and 3'' alternative transcripts regulated coordinately, an effect that was maximal at 48-72 h. T3 stimulation of GH3 IGF-I mRNA over 48 h was dose dependent (0.01-5 nM). Similarly, hGH (0.5-10 .mu.g/ml) evoked a dose-dependent induction of IGF-I mRNA in the thyroid hormone-deficient GH3 cells. The effects of T3 (5 nM) and hGH (10 .mu.g/ml) on IGF-I mRNA were not additive. Furthermore, the effects of both T3 and hGH were selective for IGF-I mRNA, as neither of these treatments stimulated PRL mRNA, and treatment with hGH decreased GH3 cell GH and mRNA content. This model does not discriminate whether T3 has an independent effect on IGF-I gene expression or if its action is mediated solely through induction of GH. In conclusion, IGF-I mRNA transcripts are present in GH3 cells and are modulared by T3 and GH. Local paracrine or autocrine interactions may, therefore, be involved in the feedback control of GH secretion.