Swift G H, Liu Y, Rose S D, Bischof L J, Steelman S, Buchberg A M, Wright C V, MacDonald R J
Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Mol Cell Biol. 1998 Sep;18(9):5109-20. doi: 10.1128/MCB.18.9.5109.
HOX proteins and some orphan homeodomain proteins form complexes with either PBX or MEIS subclasses of homeodomain proteins. This interaction can increase the binding specificity and transcriptional effectiveness of the HOX partner. Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic homeodomain protein PDX1 and switch the nature of its transcriptional activity. The two activities of PDX1 are exhibited through the 10-bp B element of the transcriptional enhancer of the pancreatic elastase I gene (ELA1). In pancreatic acinar cells the activity of the B element requires other elements of the ELA1 enhancer; in beta-cells the B element can activate a promoter in the absence of other enhancer elements. In acinar cell lines the activity is mediated by a complex comprising PDX1, PBX1b, and MRG1 (MEIS2). In contrast, beta-cell lines are devoid of PBX1b and MRG1, so that a trimeric complex does not form, and the beta-cell-type activity is mediated by PDX1 without PBX1b and MRG1. The presence of specific nuclear isoforms of PBX and MEIS is precisely regulated in a cell-type-specific manner. The beta-cell-type activity can be detected in acinar cells if the B element is altered to retain binding of PDX1 but prevent binding of the PDX1-PBX1b-MRG1 complex. These observations suggest that association with PBX and MEIS partners controls the nature of the transcriptional activity of the organ-specific PDX1 transcription factor in exocrine versus endocrine cells.
HOX蛋白和一些孤儿同源结构域蛋白与同源结构域蛋白的PBX或MEIS亚类形成复合物。这种相互作用可以增加HOX伙伴的结合特异性和转录效率。在此我们表明，PBX和MEIS亚类的特定成员与胰腺同源结构域蛋白PDX1形成多聚体复合物，并改变其转录活性的性质。PDX1的两种活性通过胰腺弹性蛋白酶I基因（ELA1）转录增强子的10碱基对B元件表现出来。在胰腺腺泡细胞中，B元件的活性需要ELA1增强子的其他元件；在β细胞中，B元件在没有其他增强子元件的情况下可以激活启动子。在腺泡细胞系中，该活性由包含PDX1、PBX1b和MRG1（MEIS2）的复合物介导。相反，β细胞系缺乏PBX1b和MRG1，因此不会形成三聚体复合物，β细胞类型的活性由没有PBX1b和MRG1的PDX1介导。PBX和MEIS的特定核异构体的存在以细胞类型特异性方式受到精确调控。如果改变B元件以保留PDX1的结合但阻止PDX1-PBX1b-MRG1复合物的结合，则可以在腺泡细胞中检测到β细胞类型的活性。这些观察结果表明，与PBX和MEIS伙伴的结合控制着外分泌细胞与内分泌细胞中器官特异性PDX1转录因子转录活性的性质。
