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dc.contributor.authorXiao, Linen
dc.contributor.authorKovac, Suzanaen
dc.contributor.authorChang, Mikeen
dc.contributor.authorShulkes, Arthuren
dc.contributor.authorBaldwin, Graham Sen
dc.contributor.authorPatel, Oneelen
dc.identifier.citationEndocrinology 2012; 153(7): 3006-16en
dc.description.abstractGastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.en
dc.subject.otherAryl Hydrocarbon Receptor Nuclear Translocator.metabolismen
dc.subject.otherCell Line, Tumoren
dc.subject.otherColorectal Neoplasms.metabolismen
dc.subject.otherGastrointestinal Neoplasms.metabolismen
dc.subject.otherGastrointestinal Tract.cytologyen
dc.subject.otherHypoxia-Inducible Factor 1.physiologyen
dc.subject.otherHypoxia-Inducible Factor 1, alpha Subunit.metabolismen
dc.subject.otherModels, Biologicalen
dc.subject.otherPromoter Regions, Geneticen
dc.subject.otherRNA, Messenger.metabolismen
dc.subject.otherSp1 Transcription Factor.metabolismen
dc.titleInduction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF).en
dc.typeJournal Articleen
dc.identifier.affiliationThe University of Melbourne, Department of Surgery, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australiaen
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