Ca2+-dependent regulation of calcitonin gene expression by the transcriptional repressor DREAM

Miho Matsuda, Tada Aki Yamamoto, Masato Hirata

Research output: Contribution to journalArticle

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Abstract

Calcitonin (CT), whose secretion from thyroid glands is regulated by increases in the concentration of extracellular Ca2+, is a well-known hormone that regulates calcium homeostasis. However, the molecular mechanisms underlying the gene expression dependent on Ca2+ have not been clarified. The downstream regulatory element (DRE) antagonist modulator (DREAM) was recently identified as a Ca2+-dependent transcriptional repressor. In the present study, we investigated the possible involvement of DREAM in the regulation of CT gene expression and secretion. A luciferase assay using TT cells, a thyroid carcinoma cell line, showed that a particular region in the CT gene promoter repressed the promoter activity under basal conditions but induced the activity when the Ca2+ concentration was increased. We found two DRE sequences in a region located upstream from the transcription start site. Gel retardation assay confirmed that DREAM bound to the CT-DRE and also indicated that DREAM bound to the DRE in a Ca2+-dependent manner. We generated stable transfectants of TT cells with wild-type or mutant DREAM, which lacked the responsiveness to Ca2+ changes. In contrast to the wild type, overexpression of the mutant DREAM inhibited the increase in CT secretion induced by a calcium ionophore. The addition of forskolin to increase cAMP activated the CT promoter, probably by the interaction of DREAM with cAMP-responsive element binding proteins, independent on the activation by Ca2+. Together, these results suggest that DREAM plays an important role in human CT gene expression in a Ca2+- and cAMP-dependent manner.

Original languageEnglish
Pages (from-to)4608-4617
Number of pages10
JournalEndocrinology
Volume147
Issue number10
DOIs
Publication statusPublished - Sep 22 2006

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Calcitonin
Gene Expression Regulation
Cyclic AMP Response Element Modulator
Kv Channel-Interacting Proteins
Gene Expression
Calcium Ionophores
Transcription Initiation Site
Electrophoretic Mobility Shift Assay
Colforsin
Luciferases
Thyroid Neoplasms
Carrier Proteins
Thyroid Gland
Homeostasis
Hormones
Calcium
Cell Line
Genes

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Ca2+-dependent regulation of calcitonin gene expression by the transcriptional repressor DREAM. / Matsuda, Miho; Yamamoto, Tada Aki; Hirata, Masato.

In: Endocrinology, Vol. 147, No. 10, 22.09.2006, p. 4608-4617.

Research output: Contribution to journalArticle

Matsuda, Miho ; Yamamoto, Tada Aki ; Hirata, Masato. / Ca2+-dependent regulation of calcitonin gene expression by the transcriptional repressor DREAM. In: Endocrinology. 2006 ; Vol. 147, No. 10. pp. 4608-4617.
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