期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep10642
关键词
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资金
- Brian Piccolo Cancer Award
- Swim Across America Cancer Research Award
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 Delta IEC) 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 Delta IEC mice. The current study reveals an important and novel mechanism for VDR by regulation of epithelial barriers.
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