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Ca²⁺-Dependent Regulation of Calcitonin Gene Expression by the Transcriptional Repressor DREAM

Laboratory of Molecular and Cellular Biochemistry (M.M., M.H.), and Department of Orthodontics (T.Y.), Faculty of Dental Science, and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan

Address all correspondence and requests for reprints to: Masato Hirata, Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. E-mail: hirata1{at}dent.kyushu-u.ac.jp.

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.