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

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 Ca(2+)-sensing receptor (CaSR), calmodulin, and calcitonin genes in C cells. When intracellular Ca(2+) levels are increased or decreased in C cells, by the calcium ionophore A23187, by physiologic concentrations of the P(2) purinergic receptor ligand ATP, or by changes in extracellular Ca(2+) 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 Ca(2+)-modulated transcription factor that coordinately regulates the activity of genes critical for Ca(2+) homeostasis by parafollicular C cells. We hypothesize that TTF-1 similarly coordinates Ca(2+)-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.