Kahn A
ICGM, INSERM U129, CHU Cochin-Port-Royal, Paris, France.
Biochimie. 1997 Feb-Mar;79(2-3):113-8. doi: 10.1016/s0300-9084(97)81501-5.
Numerous hepatic and adipocytic genes are transcriptionally controlled by glucose and insulin. It is the case, for example, of the pyruvate kinase L (L-PK) gene in the liver and of the spot 14 gene in adipocytes, coding for proteic factors of glycolysis and lipogenesis, respectively. At the hepatic level, the role of insulin is mainly to stimulate the synthesis of glucokinase, needed for phosphorylation of glucose to glucose 6-phosphate. An efficient regulation of the L-PK gene by glucose also needs the synthesis of the glucose transporter (Glut2): in its absence, transcription of the gene is independent of the presence of glucose in the medium. The role of Glut2 can be to enhance the depletion of gluconeogenic cells into glucose-6-phosphate (G6-P) when cultivated without glucose. G6-P seems to act by one of its metabolites in the pentose phosphate pathway, probably a pentose phosphate, maybe xylulose 5-phosphate. The active metabolites of this pathway could control the activity of protein kinase and protein phosphatase cascades, leading to a modification of the phosphorylation state of the glucose response complex. This complex is assembled by so-called glucose/carbohydrate response elements (GIRE, ChoRE) that are composed of E boxes of the CACGTG type, more or less modified, forming a palindrome whose both parts are separated by five bases. These sequences are able to bind USF1 and USF2 proteins, which seem to be necessary to the glucose response. However, the binding of USF proteins to the GIRE of the L-PK gene, appreciated by in vivo footprints, is not modulated by nutritional conditions. Therefore, these USF proteins could interact with different partners which are targets of regulating cues: transcription factors bound in the immediate vicinity of the glucose response complex, notably the HNF4 factor, and, maybe, other proteins interacting with the USF factors assembled to the GIRE. The actually ongoing experiments try to appreciate the nature and the role of these partners, and to evaluate the metabolic response of mice whose USF genes were disabled by homologous recombination.
许多肝脏和脂肪细胞基因受葡萄糖和胰岛素的转录调控。例如，肝脏中的丙酮酸激酶L（L-PK）基因以及脂肪细胞中的spot 14基因就是如此，它们分别编码糖酵解和脂肪生成的蛋白质因子。在肝脏水平，胰岛素的作用主要是刺激葡萄糖激酶的合成，葡萄糖激酶是将葡萄糖磷酸化为葡萄糖6-磷酸所必需的。葡萄糖对L-PK基因的有效调控也需要葡萄糖转运蛋白（Glut2）的合成：在没有Glut2的情况下，该基因的转录与培养基中葡萄糖的存在无关。Glut2的作用可能是在无糖培养时增强糖异生细胞中葡萄糖-6-磷酸（G6-P）的消耗。G6-P似乎通过其在磷酸戊糖途径中的一种代谢产物起作用，可能是一种磷酸戊糖，也许是木酮糖5-磷酸。该途径的活性代谢产物可以控制蛋白激酶和蛋白磷酸酶级联反应的活性，导致葡萄糖反应复合物磷酸化状态的改变。这种复合物由所谓的葡萄糖/碳水化合物反应元件（GIRE，ChoRE）组装而成，这些元件由或多或少经过修饰的CACGTG型E盒组成，形成一个回文结构，其两部分由五个碱基隔开。这些序列能够结合USF1和USF2蛋白，这似乎是葡萄糖反应所必需的。然而，通过体内足迹法评估，USF蛋白与L-PK基因的GIRE的结合不受营养条件的调节。因此，这些USF蛋白可能与不同的伙伴相互作用，这些伙伴是调节信号的靶标：紧邻葡萄糖反应复合物结合的转录因子，特别是HNF4因子，也许还有其他与组装到GIRE上的USF因子相互作用的蛋白。目前正在进行的实验试图了解这些伙伴的性质和作用，并评估通过同源重组使USF基因失活的小鼠的代谢反应。
