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Molecular Mechanisms of the Negative Effect of Insulin-Like Growth Factor-I on Growth Hormone Gene Expression in MtT/S Somatotroph Cells

First Department of Internal Medicine (A.N.-O., M.N., Y.O., H.S.), Department of Clinical Laboratory Medicine (Y.I.), Nagoya University School of Medicine, Nagoya 466-8550; Department of Cell Regulation, Saitama University (K.I.), Saitama 338-0825, Japan

Address all correspondence and requests for reprints to: Yasumasa Iwasaki, M.D., Department of Clinical Laboratory Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: iwasakiy{at}mb.infoweb.ne.jp

Although insulin-like growth factor-I (IGF-I) is shown to have a suppressive effect on GH gene expression at the pituitary level, its molecular mechanism has not yet been clarified. To study the issue, we established a new in vitro system using MtT/S, a recently established rat somatotroph tumor cell line that retains the basic characteristics of somatotroph function. Plasmids containing the GH 5' promoter (1.75 kb or shorter)-luciferase fusion gene were transfected stably or transiently into the cells, and the effect of IGF-I on the GH promoter activity was estimated by a luciferase assay. The results showed that IGF-I inhibited GH promotor activity (more than 50% suppression) in a time- and dose-related manner. IGF-I also inhibited GH secretion. A study using deletion mutants of the GH promoter revealed that the negative effect was maintained in the shortest construct (-80 to +6), suggesting that IGF-I-related factor is acting at the region very close to the minimal promoter. Interestingly, the negative effect was completely eliminated by a PI₃ kinase inhibitor wortmannin (1 µM), whereas a MAP kinase inhibitor PD98059 (20 µM) or S6 kinase inhibitor rapamycin (10 nM) did not influence the effect. Our results suggest that IGF-I suppresses GH gene expression at the transcriptional level and that the PI₃ kinase-mediated signaling pathway plays a major role in the negative effect of IGF-I. We believe that our system using MtT/S cells is an excellent experimental model system for studying the cellular and molecular mechanisms of the transcriptional regulation of GH in vitro.

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