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MUCOSAL BIOLOGY

Control of differentiation-induced calbindin-D_9k gene expression in Caco-2 cells by cdx-2 and HNF-1

¹Interdepartmental Nutrition Program, Purdue University, West Lafayette, Indiana 47907; ²Institute National de la Sante et de la Recherche Medicale, Unite 381, 67200 Strasbourg, France; ³Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115; and ⁴Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts 02111

Submitted 19 March 2004 ; accepted in final form 21 June 2004

Calbindin D_9k (CaBP) is critical for intestinal calcium absorption; its in vivo expression is restricted to differentiated enterocytes of the small intestine. Our goal was to identify factors controlling the transcriptional regulation of this gene in the human intestine. Both the natural gene and a 4600-bp promoter construct were strongly regulated by differentiation (>100-fold) but not by treatment with 1,25(OH)₂ vitamin D (<2-fold) in the Caco-2 clone TC7. Deletion-mutation studies revealed that conserved promoter sequences for cdx-2 (at –3158 bp) and hepatocyte nuclear factor (HNF)-1 (at –3131 and at –98 bp) combined to control CaBP expression during differentiation. Other putative response elements were not important for CaBP regulation in TC7 cells (CCAAT enhancer binding protein, pancreatic duodenal homebox-1 (pdx-1), a proximal cdx-2 element). Mutation of the distal HNF-1 site had the greatest impact on CaBP gene expression through disruption of HNF-1 binding; both basal and differentiation-mediated CaBP expression was reduced by 80%. In contrast, mutation of the distal cdx-2 element reduced only basal CaBP expression. Whereas a 60% reduction of CaBP mRNA in the duodenum of HNF-1 null mice confirmed the physiological importance of HNF-1 for CaBP gene regulation, additional studies showed that maximal CaBP expression requires the presence of both HNF-1 and cdx-2. Our data suggest that cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1 modulates CaBP gene expression during cellular differentiation.

intestine; enterocyte; 1,25 dihydroxyvitamin D

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