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

Although parathyroid hormone (PTH) induces 25-hydroxyvitamin D-3 (25(OH)D-3) 1 alpha-hydroxylase (1 alpha(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 1 alpha(OH) ase transcription is strongly induced by calcitonin in kidney cells and indicate mechanisms that underlie this regulation. The transcription factor C/EBP beta is up-regulated by calcitonin in kidney cells and results in a significant enhancement of calcitonin induction of 1 alpha(OH) ase transcription and protein expression. Mutation constructs of the 1 alpha(OH) ase promoter demonstrate the importance of the C/EBP beta binding site at -79/-73 for activation of the 1 alpha(OH) ase promoter by calcitonin. The SWI/SNF chromatin remodeling complex was found to cooperate with calcitonin in the regulation of 1 alpha(OH) ase. Chromatin immunoprecipitation analysis showed that calcitonin recruits C/EBP beta to the 1 alpha(OH) ase promoter, and Re-chromatin immunoprecipitation analysis (sequential chromatin immunoprecipitations using different antibodies) showed that C/EBP beta and BRG1, an ATPase that is a component of the SWI/SNF complex, bind simultaneously to the 1 alpha(OH)ase promoter. These findings are the first to address the dynamics between calcitonin, C/EBP beta, and SWI/SNF in the regulation of 1 alpha(OH) aseandprovideamechanism, forthefirsttime, for calcitonin induction of 1 alpha(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.