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1 Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN, USA
2 Unite 381, Institute National de la Recherche Medicale, Strasbourg, France
3 Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital, Boston, MA, USA
4 Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: fleet{at}purdue.edu.
Calbindin D9k (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 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: e.g. C/EBP, 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. While a 60% reduction of CaBP mRNA in
the duodenum of HNF-1 null mice confirmed the physiologic 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.
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