Calcitonin, a Regulator of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene

Abstract

Although parathyroid hormone (PTH) induces 25-hydroxyvitamin D(3) (25(OH)D(3)) 1alpha-hydroxylase (1alpha(OH)ase) under hypocalcemic conditions, previous studies showed that calcitonin, not PTH, has an important role in the maintenance of serum 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) under normocalcemic conditions. In this study we report that 1alpha(OH)ase transcription is strongly induced by calcitonin in kidney cells and indicate mechanisms that underlie this regulation. The transcription factor C/EBPbeta is up-regulated by calcitonin in kidney cells and results in a significant enhancement of calcitonin induction of 1alpha(OH)ase transcription and protein expression. Mutation constructs of the 1alpha(OH)ase promoter demonstrate the importance of the C/EBPbeta binding site at -79/-73 for activation of the 1alpha(OH)ase promoter by calcitonin. The SWI/SNF chromatin remodeling complex was found to cooperate with calcitonin in the regulation of 1alpha(OH)ase. Chromatin immunoprecipitation analysis showed that calcitonin recruits C/EBPbeta to the 1alpha(OH)ase promoter, and Re-chromatin immunoprecipitation analysis (sequential chromatin immunoprecipitations using different antibodies) showed that C/EBPbeta and BRG1, an ATPase that is a component of the SWI/SNF complex, bind simultaneously to the 1alpha(OH)ase promoter. These findings are the first to address the dynamics between calcitonin, C/EBPbeta, and SWI/SNF in the regulation of 1alpha(OH)ase and provide a mechanism, for the first time, for calcitonin induction of 1alpha(OH)ase. Because plasma calcitonin as well as 1,25(OH)(2)D(3) 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)(2)D(3) during these times of increased calcium requirement.