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1 School of Medicine and Medical Science, University College Dublin, UCD Conway Institute, Belfield, Dublin 4, Ireland
2 Centre de Recherche en Rhumatologie et Immunologie du CHUL, Quebec, Canada
3 Genetics of Development and Disease Branch, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: cormac.tyalor{at}ucd.ie.
Hypoxia occurs during a number of conditions where altered epithelial proliferation is critical including tumor development. Microarray analysis of colon-derived epithelial cells revealed a hypoxia-dependent increase in the expression of amphiregulin, an epidermal growth factor receptor (EGFR) ligand which activates epithelial proliferation and has been associated with the development of colonic tumors. Amphiregulin expression was also induced in tissues from mice exposed to whole animal hypoxia. The hypoxic upregulation of amphiregulin was independent of the classical transcriptional response mediated via the hypoxia inducible factor (HIF-1
). Transfection of HeLa cells with truncated amphiregulin promoter reporter constructs revealed that a 37bp segment upstream from the TATA box retained hypoxic sensitivity. This sequence contains an evolutionarily conserved cAMP response element (CRE) which constitutively binds the CRE binding protein (CREB). Deletion of the CRE abolished sensitivity to hypoxia. Thus, hypoxia promotes intestinal epithelial amphiregulin expression in a CRE-dependent manner, an event which may contribute to increased proliferation. These data also further support a role for CREB as an HIF-independent hypoxia-responsive transcription factor in the regulation of intestinal epithelial gene expression.
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