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Molecular and Cellular Biology, December 1998, p. 7410-7422, Vol. 18, No. 12
Cell Regulation Section,
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.
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
*
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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