Dupriez V J, Rousseau G G
Hormone and Metabolic Research Unit, Louvain University Medical School and International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
DNA Cell Biol. 1997 Sep;16(9):1075-85. doi: 10.1089/dna.1997.16.1075.
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.
我们之前已经表明，大鼠肝癌FTO-2B细胞从编码6-磷酸果糖-2-激酶（PFK-2）的同一基因的不同启动子表达两种mRNA，分别称为F（胎儿型）和L（肝脏型）。这种酶催化果糖2,6-二磷酸的合成，果糖2,6-二磷酸是糖酵解的变构激活剂。我们现在发现，葡萄糖以及乳酸和丙酮酸会增加F和L mRNA的浓度。木糖醇（木酮糖5-磷酸的前体，因此也是磷酸戊糖途径和糖酵解途径中间体的前体）模拟了葡萄糖的作用，而冈田酸（一种蛋白磷酸酶抑制剂）则抑制了这种作用。转染实验表明，F启动子区域是葡萄糖作用的靶点，葡萄糖以可能类似于有丝分裂原的方式刺激F启动子活性。该基因位于F和L启动子之间的另一个区域也表现为葡萄糖敏感元件。该区域对应于葡萄糖处理后在染色质中诱导产生的一组DNA酶I超敏感位点。该区域的序列组织与葡萄糖敏感的胰岛素基因启动子的功能结构非常相似。我们提出了一个由葡萄糖代谢物协同调节导致PFK-2活性增加的三条途径的模型。
