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Molecular and Cellular Biology, December 1998, p. 7410-7422, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Thyroid Transcription Factor 1 Is Calcium Modulated and Coordinately Regulates Genes Involved in Calcium Homeostasis in C Cells

Koichi Suzuki,1,2 Stefano Lavaroni,1 Atsumi Mori,1 Fumikazu Okajima,1,3 Shioko Kimura,4 Ryohei Katoh,2 Akira Kawaoi,2,* and Leonard D. Kohn1,*

Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases,1 and Laboratory of Metabolism, National Cancer Institute,4 National Institutes of Health, Bethesda, Maryland 20892, and Department of Pathology, Yamanashi Medical University, Nakakoma, Yamanashi 409-38,2 and Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371,3 Japan

Received 6 May 1998/Returned for modification 24 July 1998/Accepted 27 August 1998

Thyroid transcription factor 1 (TTF-1) was identified for its critical role in thyroid-specific gene expression; its level in the thyroid is regulated by thyrotropin-increased cyclic AMP levels. TTF-1 was subsequently found in lung tissue, where it regulates surfactant expression, and in certain neural tissues, where its function is unknown. Ligands or signals regulating TTF-1 levels in lung or neural tissue are unknown. We recently identified TTF-1 in rat parafollicular C cells and parathyroid cells. In this report, we show that TTF-1 is present in the parafollicular C cells of multiple species and that it interacts with specific elements on the 5'-flanking regions of the extracellular Ca2+-sensing receptor (CaSR), calmodulin, and calcitonin genes in C cells. When intracellular Ca2+ levels are increased or decreased in C cells, by the calcium ionophore A23187, by physiologic concentrations of the P2 purinergic receptor ligand ATP, or by changes in extracellular Ca2+ levels, the promoter activity, RNA levels, and binding of TTF-1 to these genes are, respectively, decreased or increased. The changes in TTF-1 inversely alter CaSR gene and calcitonin gene expression. We show, therefore, that TTF-1 is a Ca2+-modulated transcription factor that coordinately regulates the activity of genes critical for Ca2+ homeostasis by parafollicular C cells. We hypothesize that TTF-1 similarly coordinates Ca2+-dependent gene expression in all cells in which TTF-1 and the CaSR are expressed, i.e., parathyroid cells, neural cells in the anterior pituitary or hippocampus, and keratinocytes.

* Corresponding author. Mailing address: Metabolic Diseases Branch, NIDDK, Bldg. 10, Room 9C101B, NIH, Bethesda, MD 20892-1360. Phone: (301) 496-3564. Fax: (301) 496-0200. E-mail: lenk{at}bdg10.niddk.nih.gov.

Molecular and Cellular Biology, December 1998, p. 7410-7422, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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