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

ABSTRACT

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.

ACKNOWLEDGMENTS

We thank Taka-aki Koshimizu, ERRB, NICHD, NIH, for helping in the measurement of intracellular calcium and for helpful discussions. We also acknowledge Stephen Marx and Alan Spiegel, as well as members of their groups in the Metabolic Diseases Branch, for helpful discussions and for critical reading of the manuscript.