title: Calmodulin-dependent kinase IV stimulates vitamin D receptor-mediated transcription.
abstract: 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] promotes intestinal absorption of calcium primarily by binding to the vitamin D receptor (VDR) and regulating gene expression. 1,25-(OH)2D3 also exerts rapid actions at the cell membrane that include increasing intracellular calcium levels and activating protein kinase cascades. To explore potential cross talk between calcium signaling elicited by the nongenomic actions of 1,25-(OH)2D3 and the genomic pathway mediated by VDR, we examined the effects of activated Ca2+/calmodulin-dependent kinases (CaMKs) on 1,25-(OH)2D3/VDR-mediated transcription. Expression of a constitutively active form of CaMKIV dramatically stimulated 1,25-(OH)2D3-activated reporter gene expression in COS-7, HeLa, and ROS17/2.8 cell lines. Metabolic labeling studies indicated that CaMKIV increased VDR phosphorylation levels. In addition, CaMKIV increased the independent transcription activity of the VDR coactivator SRC (steroid receptor coactivator) 1, and promoted ligand-dependent interaction between VDR and SRC coactivator proteins in mammalian two-hybrid studies. The functional consequences of this multifaceted mechanism of CaMKIV action were revealed by reporter gene studies, which showed that CaMKIV and select SRC coactivators synergistically enhanced VDR-mediated transcription. These studies support a model in which CaMKIV signaling stimulates VDR-mediated transcription by increasing phosphorylation levels of VDR and enhancing autonomous SRC activity, resulting in higher 1,25-(OH)2D3-dependent interaction between VDR and SRC coactivators.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors.forename: Tara I
authors.initials: TI
authors.lastname: Ellison
authors.forename: Diane R
authors.initials: DR
authors.lastname: Dowd
authors.forename: Paul N
authors.initials: PN
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D056920:Nuclear Receptor Coactivator 1; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018167:Receptors, Calcitriol; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; C517683:CAMK4 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517686:Camk4 protein, rat; D002117:Calcitriol