López-Rodríguez C, Chen H M, Tenen D G, Corbí A L
Instituto de Parasitología López-Neyra, C.S.I.C., Granada, Spain.
Eur J Immunol. 1995 Dec;25(12):3496-503. doi: 10.1002/eji.1830251243.
The leukocyte integrins LFA-1 (CD11a/CD18) and p150,95 (CD11c/CD18) mediate cell-cell and cell-extracellular matrix interactions during inflammatory responses and signal transduction into the cytoplasm. While the CD11a integrin subunit is expressed on all leukocytes, CD11c is almost exclusively expressed on cells of the myeloid lineage and on activated B lymphocytes. Its expression is regulated during cell activation and differentiation by transcriptional mechanisms. We have previously demonstrated that the proximal region of the CD11c promoter directs tissue-restricted and developmentally-regulated expression of reporter genes. Structural studies by electrophoretic mobility shift assays have demonstrated the presence of two Sp1-binding sites at -70 (Sp1-70) and -120 (Sp1-120) which mediate the Sp1 transactivation of the CD11c promoter in Sp1-defective SL2 cells, and which are involved in cell lineage-specific DNA-protein interactions, as demonstrated by footprinting in vivo. More importantly, mutation of either Sp1 site inhibited the activity of the CD11c promoter both in myeloid U937 cells and the CD11c-expressing B lymphoblastoid JY cell line, while the opposite effect was observed in the CD11c-negative epithelial HeLa cell line, demonstrating the involvement of both Sp1-binding sites in the basal and the tissue-restricted expression of the CD11c integrin subunit gene. Interestingly, the analysis of the CD11a proximal promoter also revealed the existence of an Sp1-binding site at -70, indicating a common role for these cis-acting elements in the transcription of the leukocyte integrin alpha subunit genes. The binding of Sp1 to the regulatory regions of the leukocyte integrin genes raises the possibility that the retinoblastoma susceptibility gene product is implicated in integrin expression through its functional interaction with Sp1, thus establishing a link between integrin-dependent leukocyte adhesiveness and the state of cellular differentiation/proliferation.
白细胞整合素LFA-1（CD11a/CD18）和p150,95（CD11c/CD18）在炎症反应过程中介导细胞间和细胞与细胞外基质的相互作用，并将信号转导至细胞质中。虽然CD11a整合素亚基在所有白细胞上均有表达，但CD11c几乎仅在髓系谱系细胞和活化的B淋巴细胞上表达。其表达在细胞活化和分化过程中受转录机制调控。我们之前已证明，CD11c启动子的近端区域指导报告基因的组织限制性和发育调控性表达。通过电泳迁移率变动分析进行的结构研究表明，在-70（Sp1-70）和-120（Sp1-120）处存在两个Sp1结合位点，它们介导Sp1缺陷型SL2细胞中CD11c启动子Sp1的反式激活，并且参与细胞谱系特异性DNA-蛋白质相互作用，如体内足迹实验所示。更重要的是，任一Sp1位点的突变均抑制了髓系U937细胞和表达CD11c的B淋巴母细胞系JY细胞系中CD11c启动子的活性，而在不表达CD11c的上皮性HeLa细胞系中观察到相反的效果，这表明两个Sp1结合位点均参与CD11c整合素亚基基因的基础表达和组织限制性表达。有趣的是，对CD11a近端启动子的分析还揭示在-70处存在一个Sp1结合位点，表明这些顺式作用元件在白细胞整合素α亚基基因转录中具有共同作用。Sp1与白细胞整合素基因调控区域的结合增加了视网膜母细胞瘤易感基因产物通过与Sp1的功能相互作用而参与整合素表达的可能性，从而在整合素依赖性白细胞黏附与细胞分化/增殖状态之间建立了联系。
