title: Tight junction CLDN2 gene is a direct target of the vitamin D receptor.
abstract: The breakdown of the intestinal barrier is a common manifestation of many diseases. Recent evidence suggests that vitamin D and its receptor VDR may regulate intestinal barrier function. Claudin-2 is a tight junction protein that mediates paracellular water transport in intestinal epithelia, rendering them "leaky". Using whole body VDR(-/-) mice, intestinal epithelial VDR conditional knockout (VDR(ΔIEC)) mice, and cultured human intestinal epithelial cells, we demonstrate here that the CLDN2 gene is a direct target of the transcription factor VDR. The Caudal-Related Homeobox (Cdx) protein family is a group of the transcription factor proteins which bind to DNA to regulate the expression of genes. Our data showed that VDR-enhances Claudin-2 promoter activity in a Cdx1 binding site-dependent manner. We further identify a functional vitamin D response element (VDRE) 5΄-AGATAACAAAGGTCA-3΄ in the Cdx1 site of the Claudin-2 promoter. It is a VDRE required for the regulation of Claudin-2 by vitamin D. Absence of VDR decreased Claudin-2 expression by abolishing VDR/promoter binding. In vivo, VDR deletion in intestinal epithelial cells led to significant decreased Claudin-2 in VDR(-/-) and VDR(ΔIEC) mice. The current study reveals an important and novel mechanism for VDR by regulation of epithelial barriers.
authors.affiliation: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors.forename: Yong-guo
authors.initials: YG
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Rush University, Chicago, Illinois, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Pathology, University of Rochester, Rochester, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Kansas City University of Medicine and Bioscience, Kansas City, Missouri, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Lab of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Department of Medicine, GI Diseases Research Unit and Division of Infectious Diseases, Queen's University, Ontario, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: Petrof
authors.affiliation: Departments of Pediatrics and Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.
authors.forename: Erika C
authors.initials: EC
authors.lastname: Claud
authors.affiliation: 1] Department of Biochemistry, Rush University, Chicago, Illinois, USA [2] Department of Pathology, University of Rochester, Rochester, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D057167:Claudins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism*; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; C113371:Cldn2 protein, mouse; D018167:Receptors, Calcitriol; D062725:Tight Junction Proteins