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The Thyrotropin ß-Subunit Gene Is Repressed by Thyroid Hormone in a Novel Thyrotrope Cell Line, Mouse TT1 Cells¹

Departments of Reproductive Medicine and Neurosciences and the Center for Molecular Genetics, University of California-San Diego (B.Y., E.T.A., P.L.M.), La Jolla, California 92093-0674; and the Department of Medicine, University of Colorado Health Sciences Center (D.F.G., E.C.R.), Denver, Colorado 80262

Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine 0674, 2057 CMM-E, University of California-San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}uscd.edu

TSH is expressed in two populations of thyrotropes in the pituitary: one in the pars distalis and a second in the pars tuberalis. Pars distalis thyrotropes exhibit classical endocrine inhibition of TSH by thyroid hormone, whereas pars tuberalis thyrotropes do not. The majority of our understanding of TSH subunit gene regulation has come from studies conducted in dispersed pituitary, dispersed thyrotropic tumors, or the GH₃ somatolactotrope cell line. However, the dispersed pituitary model is limited because of its inherent heterogeneity, thyrotropic tumors are difficult to grow and maintain, and the GH₃ cells lack endogenous TSH expression. The recent derivation of a clonal thyrotrope cell line, TT1, that expresses thyrotrope-specific markers, overcomes these limitations. However, because it was not possible to distinguish whether the tumor from which the TT1 cells are derived originated in the pars distalis or the pars tuberalis, it was necessary to define their cellular origin and thereby establish their status as representative thyrotrope cells for future molecular studies. In this study, we demonstrate that the TT1 cells express thyroid hormone receptors (ß1 and ß2) and their heterodimeric partner, retinoid X receptor-. Treatment with T₃ causes a dose- and time-dependent decrease in the expression of the TSH ß-subunit messenger RNA. In contrast to previous reports in rat pituitary cultures, T₃ does not alter TSH ß-subunit messenger RNA stability in the TT1 cells. Based on these data and the presence of thyrotrope-specific isoforms of the transcription factor Pit-1, we conclude that the TT1 cells represent differentiated thyrotropes of the pars distalis and will be a useful model system for future analysis of the cis- and trans-acting factors necessary for thyrotrope-specific and thyroid hormone-regulated TSH gene expression.

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