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Submitted on June 24, 2003
Accepted on November 11, 2003
1 Department of Zoology, University of Hong Kong, People's Republic of China; Department of Physiology, The Chinese University of Hong Kong, People's Republic of China
* To whom correspondence should be addressed. E-mail: bkcc{at}hkusua.hku.hk.
The human secretin receptor (hSR) is an important glycoprotein receptor for regulating the secretion of pancreatic bicarbonate, water and electrolytes. In this study we investigated the transcriptional regulation of the hSR gene. A minimal 106-bp promoter was identified and it contains two GC boxes (GC box-A, -240 to -226 and GC box-B, -203 to -194, from the translation start site). Electrophoretic mobility shift and supershift analyses showed that both GC boxes interact with Sp1 and Sp3 transcription factors. Transient transfection in pancreas-derived PANC-1 and BPD-1 cells showed that mutation of either GC box-A or B reduced the promoter strength by 56-67%, while mutation of both GC boxes caused more than 90% reduction of promoter activity. Co-transfections of the hSR promoter with Sp1 and Sp3 expression vectors in Sp-deficient Drosophila SL-2 Schneider cells further demonstrated that the ratio of Sp1 to Sp3 is the key mechanism to modulate hSR gene expression. The methylation statuses of 27 CpG sites within the promoter region (-400 to -151 bp) were assessed in various human pancreas and liver cell lines. The hSR promoter is unmethylated (CAPAN-1) or partially methylated (PANC-1 and HPAC) in hSR-expressing cell lines but is completely methylated in hSR non-expressing HepG2 cells. Methyltransferase inhibitor 5-azaC increased hSR gene expression level in PANC-1 cells and induced hSR gene expression in HepG2 cells. Together, our study shows that in addition to Sp1 and Sp3, promoter methylation also plays a role in the regulation of hSR gene expression.
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