Jin T, Drucker D J
Department of Medicine, Banting and Best Diabetes Center, University of Toronto, Ontario, Canada.
Mol Cell Biol. 1996 Jan;16(1):19-28. doi: 10.1128/MCB.16.1.19.
The proglucagon gene is expressed in a highly restricted tissue-specific manner in the A cells of the pancreatic islet and the L cells of the small and large intestines. The results of previous experiments indicate that cell-specific expression of the proglucagon gene is mediated by proteins that interact with the proximal G1 promoter element. We show here that the G1 element contains several AT-rich subdomains that bind proteins present in islet and enteroendocrine cell extracts. Electrophoretic mobility shift assay experiments using specific antisera identified the homeobox protein cdx-2/3 (which designates the same homeobox protein called cdx-2 for mice and cdx-3 for hamsters) as a major component of the G1-Gc2 complex in islet and intestinal cells. Mutations of the Gc element that decreased cdx-2/3 binding also resulted in decreased proglucagon promoter activity in islet and intestinal cell lines. The finding that cdx-2/3 mediates activation of the proglucagon promoter in both islet and enteroendocrine cells is consistent with the common endodermal lineage of these tissues and provides new insight into the coordinate regulation of genes expressed in both pancreatic and intestinal endocrine cell types.
胰高血糖素原基因在胰岛A细胞以及小肠和大肠的L细胞中以高度受限的组织特异性方式表达。先前实验的结果表明，胰高血糖素原基因的细胞特异性表达是由与近端G1启动子元件相互作用的蛋白质介导的。我们在此表明，G1元件包含几个富含AT的亚结构域，这些亚结构域可结合胰岛和肠内分泌细胞提取物中存在的蛋白质。使用特异性抗血清进行的电泳迁移率变动分析实验确定，同源框蛋白cdx-2/3（对于小鼠而言，它与称为cdx-2的同源框蛋白相同，对于仓鼠而言则称为cdx-3）是胰岛和肠细胞中G1-Gc2复合物的主要成分。降低cdx-2/3结合的Gc元件突变也导致胰岛和肠细胞系中胰高血糖素原启动子活性降低。cdx-2/3介导胰岛和肠内分泌细胞中胰高血糖素原启动子激活这一发现与这些组织共同的内胚层谱系一致，并为胰腺和肠内分泌细胞类型中表达的基因的协调调控提供了新的见解。
