HUMAN TUMOR-NECROSIS-FACTOR-ALPHA GENE-REGULATION BY VIRUS AND LIPOPOLYSACCHARIDE
HUMAN TUMOR-NECROSIS-FACTOR-ALPHA GENE-REGULATION BY VIRUS AND LIPOPOLYSACCHARIDE
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DOI：
10.1073/pnas.87.24.9769
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发表时间：
1990-12-01
影响因子：
11.1
通讯作者：
MANIATIS, T
中科院分区：
文献类型：
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作者：
GOLDFELD, AE;DOYLE, C;MANIATIS, T
我们已经鉴定了人肿瘤坏死因子α的一个区域。（TNF-α）最大组成型、病毒诱导和脂多糖（LPS）诱导的转录所必需的基因启动子。该区域含有与NF-κ B B结合位点共有序列匹配的三个位点。我们表明这三个位点在体外特异性结合NF-κ B，但这些位点中的每一个都可以从TNF-α中缺失。启动子，对病毒或LPS诱导该基因的作用很小。此外，当将这三个位点的多聚体置于截短的TNF-α的上游时，当使用启动子或异源启动子时，观察到受序列背景和细胞类型影响的基础转录水平的增加。然而，这些多聚体不足以用于病毒或LPS诱导任一启动子。因此，与含有NF-κ B结合位点的其它病毒-和LPS-诱导型启动子不同，这些来自TNF-α B的位点是由LPS诱导的。启动子对于病毒或LPS诱导既不是必需的，也不是充分的。人TNF-α的病毒诱导的序列要求的比较小鼠L929和P388 D1细胞中的基因显示出显著差异，表明病毒诱导该基因的序列要求是细胞类型特异性的。然而，在单个细胞类型P388 D1中病毒和LPS诱导基因所需的序列重叠。
We have identified a region of the human tumor necrosis factor .alpha. (TNF-.alpha.) gene promoter that is necessary for maximal constitutive, virus-induced, and lipopolysaccharide (LPS)-induced transcription. This region contains three sites that match an NF-.kappa.B binding-site consensus sequence. We show that these three sites specifically bind NF-.kappa.B in vitro, yet each of these sites cn be deleted from the TNF-.alpha. promoter with little effect on the induction of the gene by virus or LPS. Moreover, when multimers of these three sites are placed upstream from a truncated TNF-.alpha. promoter, or a heterologous promoter, an increase in the basal level of transcription is observed that is influenced by sequence context and cell type. However, these multimers are not sufficient for virus or LPS induction of either promoter. Thus, unlike other virus- ad LPS-inducible promoters that contain NF-.kappa.B binding sites, these sites from the TNF-.alpha. promoter are neither required nor sufficient for virus or LPS induction. Comparison of the sequence requirements of virus induction of the human TNF-.alpha. gene in mouse L929 and P388D1 cells reveals significant differences, indicating that the sequence requirements for virus induction of the gene are cell type-specific. However, the sequences required for virus and LPS induction of the gene in a single cell type, P388D1, overlap.