Glucose response elements in a gene that codes for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.
We have shown previously that rat hepatoma FTO-2B cells express two mRNAs, called F (fetal) and L (liver), from distinct promoters of the same gene coding for 6-phosphofructo-2-kinase (PFK-2). This enzyme catalyzes the synthesis of fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis. We have now found that glucose, as well as lactate and pyruvate, increases the concentration of the F and L mRNAs. The effect of glucose was mimicked by xylitol, a precursor of xylulose 5-phosphate, and hence of intermediates of the pentose phosphate and glycolytic pathways, and was inhibited by okadaic acid, an inhibitor of protein phosphatases. Transfection experiments showed that the F promoter region is a target of the glucose effect, with glucose stimulating F promoter activity in a way probably similar to mitogens. Another region of the gene, located between the F and L promoters, also behaved as a glucose-sensitive element. This region corresponds to a cluster of DNase I-hypersensitive sites that were induced in chromatin following glucose treatment. The sequence organization of this region is very similar to the functional architecture of the glucose-sensitive insulin gene promoter. We propose a model for the concerted regulation by glucose metabolites of three pathways that lead to increased PFK-2 activity.
Dupriez
V J
VJ
Hormone and Metabolic Research Unit, Louvain University Medical School and International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
Rousseau
G G
GG
D000818:Animals; D006528:Carcinoma, Hepatocellular; D003609:Dactinomycin / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005796:Genes / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D019344:Lactic Acid / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D025481:Phosphofructokinase-2; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019289:Pyruvic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D014993:Xylitol / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007328:Insulin; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D019319:Okadaic Acid; D019344:Lactic Acid; D019289:Pyruvic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); D025481:Phosphofructokinase-2; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D005947:Glucose; D014993:Xylitol