Rosmarin A G, Caprio D G, Kirsch D G, Handa H, Simkevich C P
Brown University School of Medicine, Division of Hematology, Miriam Hospital, Providence, Rhode Island 02906, USA.
J Biol Chem. 1995 Oct 6;270(40):23627-33. doi: 10.1074/jbc.270.40.23627.
CD18 (beta 2 leukocyte integrin) is a leukocyte-specific adhesion molecule that plays a crucial role in immune and inflammatory responses. A 79-nucleotide fragment of the CD18 promoter is sufficient to direct myeloid transcription. The CD18 promoter is bound by the B lymphocyte- and myeloid-restricted ets factor, PU.1, and disruption of the PU.1-binding sites significantly reduces promoter activity. However, PU.1 alone cannot fully account for the leukocyte-specific and myeloid-inducible transcription of CD18. We identified a ubiquitously expressed nuclear protein complex of extremely low electrophoretic mobility that also binds to this region of the CD18 promoter. This binding complex is a heterotetramer composed of GABP alpha, and ets factor, and GABP beta, a subunit with homology to Drosophila Notch. GABP alpha competes with the lineage restricted factor, PU.1, for the same critical CD18 ets sites. The CD18 promoter is activated in myeloid cells by transfection with both GABP alpha and GABP beta together, but not by either factor alone. Transfection of non-hematopoietic cells with the two GABP subunits together with PU.1 is sufficient to activate CD18 transcription in otherwise non-permissive cells. Thus, GABP and PU.1 compete for the same binding sites but cooperate to activate CD18 transcription.
CD18（β2白细胞整合素）是一种白细胞特异性黏附分子，在免疫和炎症反应中起关键作用。CD18启动子的一个79个核苷酸的片段足以指导髓系转录。CD18启动子与B淋巴细胞和髓系限制性ets因子PU.1结合，破坏PU.1结合位点会显著降低启动子活性。然而，单独的PU.1不能完全解释CD18的白细胞特异性和髓系诱导性转录。我们鉴定出一种普遍表达的核蛋白复合物，其电泳迁移率极低，也与CD18启动子的这一区域结合。这种结合复合物是一种异源四聚体，由GABPα（一种ets因子）和GABPβ（一种与果蝇Notch具有同源性的亚基）组成。GABPα与谱系限制性因子PU.1竞争相同的关键CD18 ets位点。通过同时转染GABPα和GABPβ可在髓系细胞中激活CD18启动子，但单独转染任何一个因子都不行。将两个GABP亚基与PU.1一起转染非造血细胞足以在原本不允许的细胞中激活CD18转录。因此，GABP和PU.1竞争相同的结合位点，但协同激活CD18转录。
