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Title: Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF).
Austin Authors: Xiao, Lin;Kovac, Suzana;Chang, Mike;Shulkes, Arthur;Baldwin, Graham S;Patel, Oneel
Affiliation: The University of Melbourne, Department of Surgery, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia
Issue Date: 16-May-2012
Publication information: Endocrinology 2012; 153(7): 3006-16
Abstract: Gastrin 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.
Gov't Doc #: 22593272
DOI: 10.1210/en.2011-2069
Type: Journal Article
Subjects: Anoxia
Aryl Hydrocarbon Receptor Nuclear Translocator.metabolism
Cell Line, Tumor
Colorectal Neoplasms.metabolism
Gastrointestinal Neoplasms.metabolism
Gastrointestinal Tract.cytology
Hypoxia-Inducible Factor 1.physiology
Hypoxia-Inducible Factor 1, alpha Subunit.metabolism
Models, Biological
Promoter Regions, Genetic
RNA, Messenger.metabolism
Sp1 Transcription Factor.metabolism
Appears in Collections:Journal articles

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