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.