Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 287, Issue 5, Pages G943-G953Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00121.2004
Keywords
intestine; enterocyte; 1,25 dihydroxyvitamin D
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Funding
- NIDDK NIH HHS [DK-54111, R01 DK054111-10, R01 DK054111] Funding Source: Medline
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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 alpha 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 alpha null mice confirmed the physiological importance of HNF-1 alpha for CaBP gene regulation, additional studies showed that maximal CaBP expression requires the presence of both HNF-1 alpha and cdx-2. Our data suggest that cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1 alpha modulates CaBP gene expression during cellular differentiation.
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