CELL-TYPE-SPECIFIC TRANSACTIVATION OF THE VCAM-1 PROMOTER THROUGH AN NF-KAPPA-B ENHANCER MOTIF
CELL-TYPE-SPECIFIC TRANSACTIVATION OF THE VCAM-1 PROMOTER THROUGH AN NF-KAPPA-B ENHANCER MOTIF
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DOI：
10.1074/jbc.270.15.8976
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发表时间：
1995-04-14
影响因子：
4.8
通讯作者：
MEDFORD, RM
中科院分区：
文献类型：
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作者：
AHMAD, M;MARUI, N;MEDFORD, RM
细胞因子激活血管细胞黏附分子-1(VCAM-1)基因的表达是多种血管炎症反应的重要特征。细胞因子通过转录激活内皮细胞中的血管细胞黏附分子-1启动子，至少部分是通过两个紧密相连的核因子-kappaB增强子基序，kappa L-kappa R(位置-77和-63)。然而，几乎所有的细胞类型都可以激活二聚体核因子-kappaB转录因子(p50+p65亚基)，而VCAM-1基因的表达呈现细胞类型特异性的表达模式。在传代的人血管内皮细胞中，肿瘤坏死因子-α显著反式激活了瞬时转染的最小kappa L-kappa R基序驱动的血管细胞间黏附分子-1启动子p85VCAMCAT，而在人上皮细胞系中则没有。提示细胞类型特异性因子可能通过kappa L-kappa R基序发挥作用。两种细胞对核因子-kappaB DNA结合活性和转录活性的诱导作用相似。然而，将p65和p50表达载体与HeLa细胞共转染后发现，最小的VCAM-1启动子可被p65单独反式激活，但p50的共同表达抑制了这一活性。此外，通过使用反义寡核苷酸抑制p50的表达，恢复了HeLa细胞中最小VCAM-1启动子的细胞因子激活。这些研究表明，核因子-kappa B(p50+p65异源二聚体)不支持VCAM-1启动子的反式激活，p50亚基可能在抑制VCAM-1的细胞因子激活方面发挥重要的抑制作用。此外，除了核因子-kappaB外，p65相关的转录因子可能是VCAM-1基因表达的阳性的、细胞因子诱导的、细胞类型特异性的调节因子。
Cytokine activation of vascular cell adhesion molecule-1 (VCAM-1) gene expression by endothelial cells is an important feature in a variety of vascular inflammatory responses. Cytokines transcriptionally activate the VCAM-1 promoter in endothelial cells at least in part through two closely linked NF-kappa B enhancer motifs, kappa L-kappa R (positions -77 and -63). However, cytokine activation of the dimeric NF-kappa B transcriptional factor (p50+p65 subunits) occurs in almost all cell types, whereas VCAM-1 gene expression exhibits a cell type-specific pattern of expression. Tumor necrosis factor-alpha markedly transactivated a transiently transfected minimal kappa L-kappa R motif-driven VCAM-1 promoter, p85VCAMCAT, in passaged human vascular endothelial cells but not in the human epithelial cell line, HeLa suggesting that cell type-specific factors may function through the kappa L-kappa R motif. Both cell types exhibited similar inductions of NF-kappa B DNA binding activity and transcriptional activity. However, co-transfection of HeLa cells with p65 and p50 expression vectors demonstrated that the minimal VCAM-1 promoter was effectively transactivated by p65 alone but that additional co-expression of p50 blocked this activity. Furthermore, cytokine activation of the minimal VCAM-1 promoter in HeLa cells was recovered by inhibition of p50 expression using antisense oligonucleotide. These studies suggest that the NF-kappa B(p50+p65 heterodimer) does not support transactivation of the VCAM-1 promoter with the p50 subunit potentially playing a significant inhibitory role in suppressing cytokine activation of VCAM-1. In addition, p65 associated transcriptional factors other than NF-kappa B may serve as positive, cytokine-inducible, cell type specific regulators of VCAM-1 gene expression.