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Department of Medicine, Section of Digestive and Liver Diseases, University of Illinois at Chicago and Chicago Veterans Affairs Westside Division, Chicago, Illinois 60612
Na+/H+ exchanger
(NHE) isoforms NHE2 and NHE3, colocalized to the brush border membrane
of the epithelial cells, exhibit differences in their pattern of tissue
expression and regulation by various molecular signals. To investigate
the mechanisms involved in regulation of NHE3 gene expression, the
human NHE3 promoter region was cloned and characterized. Primer
extension experiments located the transcription start site to a
position 116 nucleotides upstream from the translation start codon. The
5'-flanking region lacked a CCAAT box but contained a TATA-like
sequence. Nucleotide sequencing of the 5'-flanking region revealed the
presence of a number of cis elements including Sp1, AP-2,
MZF-1, CdxA, Cdx-2, steroid and nonsteroid hormone receptor half sites,
and a phorbol 12-myristate 13-acetate-response element. Transient
transfection experiments using C2/bbe cell line defined a maximal
promoter activity in 
95/+5 region. The regulatory response elements
clustered within this region include a potential transcription factor
IID (TF IID), a CACCC, two Sp1, and two AP-2 motifs. Deletion
of a fragment containing the AP-2 and Sp1 motifs resulted in a drastic
decrease in promoter activity. In gel mobility shift assays, an
oligonucleotide spanning from 78 to 56 bp bound a recombinant AP-2,
and the corresponding binding activity in nuclear extracts was
supershifted with anti-AP2
antibody. Our studies suggest that the
NHE3 expression is regulated by a combination of cis
elements and their cognate transcription factors that include the AP-2
and Sp1 family members.
nucleotide sequence; transcription factor binding sites; deletion analysis; c2/bbe; transfection
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