Calcitonin, a regulator of the 25-hydroxyvitamin D3 1α-hydroxylase gene

Abstract

Although parathyroid hormone (PTH) induces 25-hydroxyvitamin D3 (25(OH)D3) 1α-hydroxylase (1α(OH)ase) under hypocalcemic conditions, previous studies showed that calcitonin, not PTH, has an important role in the maintenance of serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) under normocalcemic conditions. In this study we report that 1α(OH)ase transcription is strongly induced by calcitonin in kidney cells and indicate mechanisms that underlie this regulation. The transcription factor C/EBPβ is up-regulated by calcitonin in kidney cells and results in a significant enhancement of calcitonin induction of 1α(OH)ase transcription and protein expression. Mutation constructs of the 1α(OH)ase promoter demonstrate the importance of the C/EBPβ binding site at-79/-73 for activation of the 1α(OH)ase promoter by calcitonin. The SWI/SNF chromatin remodeling complex was found to cooperate with calcitonin in the regulation of 1α(OH)ase. Chromatin immunoprecipitation analysis showed that calcitonin recruits C/EBPβ to the 1α(OH)ase promoter, and Re-chromatin immunoprecipitation analysis (sequential chromatin immunoprecipitations using different antibodies) showed that C/EBPβ and BRG1, an ATPase that is a component of the SWI/SNF complex, bind simultaneously to the 1a(OH)ase promoter. These findings are the first to address the dynamics between calcitonin, C/ EBPβ, and SWI/SNF in the regulation of 1α(OH)ase and provide a mechanism, for the first time, for calcitonin induction of 1α(OH)ase. Because plasma calcitonin as well as 1,25(OH)2D3 have been reported to be increased during pregnancy and lactation and in early development, these findings suggest a mechanism that may account, at least in part, for the increase in plasma 1,25(OH)2D3 during these times of increased calcium requirement.