Philippe J, Morel C, Cordier-Bussat M
Department of Genetics and Microbiology, University of Geneva Medical School, Switzerland.
J Biol Chem. 1995 Feb 17;270(7):3039-45. doi: 10.1074/jbc.270.7.3039.
Glucagon gene expression is negatively regulated by insulin at the transcriptional level. G3, a DNA control element located in the 5'-flanking sequence of the rat glucagon gene mediates the inhibition of transcription, which occurs in response to insulin. We show here that two islet-specific protein complexes C1A and C1B, bind to the A domain of G3, which is critical for the insulin response. These two complexes bind to overlapping sequences of the A domain and display very similar binding specificities. Point mutations in the A domain that affect binding of C1A and C1B result in both decreased G3 enhancer activity and insulin-mediated inhibitory effects with a close correlation between diminution of binding and function. One of the two complexes, C1A, is similar or identical to B1, a protein complexes interacting with the upstream promoter element of the glucagon gene, G1, implicated in the A cell-specific expression of the glucagon gene. Our data indicate that islet-specific proteins are involved in glucagon gene regulation by insulin.
胰高血糖素基因表达在转录水平受到胰岛素的负调控。G3是位于大鼠胰高血糖素基因5'侧翼序列中的一个DNA控制元件，介导了对转录的抑制，这种抑制是对胰岛素的反应。我们在此表明，两种胰岛特异性蛋白复合物C1A和C1B与G3的A结构域结合，该结构域对胰岛素反应至关重要。这两种复合物与A结构域的重叠序列结合，并显示出非常相似的结合特异性。A结构域中影响C1A和C1B结合的点突变导致G3增强子活性降低以及胰岛素介导的抑制作用，结合减少与功能之间存在密切相关性。两种复合物之一C1A与B1相似或相同，B1是一种与胰高血糖素基因上游启动子元件G1相互作用的蛋白复合物，与胰高血糖素基因的A细胞特异性表达有关。我们的数据表明，胰岛特异性蛋白参与了胰岛素对胰高血糖素基因的调控。
