| Functional analysis of the 5' flanking region of the human G6PC3 gene: Regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway. | |
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MedLine Citation:
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PMID: 21474354 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453bp segment of the G6PC3 promoter, from -455 to -3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5mM glucose, and was not elevated further by glucose concentrations up to 25mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (-274 to -279 and -299 to -304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140bp (-140 to -306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo. |
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Authors:
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Kimberley Ann Bennett; Laura Forsyth; Ann Burchell |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-21 |
Journal Detail:
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Title: Molecular genetics and metabolism Volume: - ISSN: 1096-7206 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-4-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9805456 Medline TA: Mol Genet Metab Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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