Vallejo M, Miller C P, Habener J F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston 02114.
J Biol Chem. 1992 Jun 25;267(18):12868-75.
The insulin-, glucagon-, and somatostatin-producing cells in the pancreatic islets derive from a common precursor stem cell and differentiate sequentially during embryonic development, thereby providing an informative model for the study of the transcriptional mechanisms involved in the control of cell-specific gene expression. Relative to the early expression of the glucagon and insulin genes on embryonic days 10 and 12, respectively, the expression of the somatostatin gene is delayed (day 17). The relatively late expression of the somatostatin gene indicates the involvement of both negative and positive transcriptional control mechanisms. We show that the expression of the somatostatin gene in pancreatic islet cells is accomplished by the interplay of both positive and negative cis-regulatory DNA elements. We have characterized the functional properties of one of these positive control elements, the somatostatin gene upstream enhancer element (SMS-UE). The SMS-UE is a pancreatic islet D-cell-specific transcriptional regulator that acts synergistically with the cyclic AMP response element. Mutation-expression and cell-free transcription analyses show that the SMS-UE is a bipartite element with two interdependent functional domains. Our results indicate that the SMS-UE is part of a functional unit that includes other transcriptional control elements of the somatostatin gene proximal promoter, and that they act together to regulate the D-cell-specific transcription of the somatostatin gene in the islet cells of the pancreas.
胰岛中产生胰岛素、胰高血糖素和生长抑素的细胞源自共同的前体干细胞，并在胚胎发育过程中依次分化，从而为研究参与细胞特异性基因表达控制的转录机制提供了一个信息丰富的模型。相对于胰高血糖素基因和胰岛素基因分别在胚胎第10天和第12天的早期表达，生长抑素基因的表达延迟（第17天）。生长抑素基因相对较晚的表达表明其涉及负性和正性转录控制机制。我们发现，胰岛细胞中生长抑素基因的表达是由正性和负性顺式调控DNA元件相互作用完成的。我们已经对其中一个正性控制元件——生长抑素基因上游增强子元件（SMS-UE）的功能特性进行了表征。SMS-UE是一种胰岛D细胞特异性转录调节因子，它与环磷酸腺苷反应元件协同作用。突变-表达和无细胞转录分析表明，SMS-UE是一个具有两个相互依赖功能域的二分元件。我们的结果表明，SMS-UE是一个功能单元的一部分，该功能单元包括生长抑素基因近端启动子的其他转录控制元件，并且它们共同作用以调节胰腺胰岛细胞中生长抑素基因的D细胞特异性转录。
