Identification of Direct Genomic Targets Downstream of the Nuclear Factor-κB Transcription Factor Mediating Tumor Necrosis Factor Signaling
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that controls expression of inflammatory genetic networks. Although the nuclear factor-κB (NF-κB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-κB-dependent genes is unknown. In this study, we used a te...
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| Veröffentlicht in: | The Journal of biological chemistry 2005-04, Vol.280 (17), p.17435-17448 |
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| container_title | The Journal of biological chemistry |
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| creator | Tian, Bing Nowak, David E. Jamaluddin, Mohammad Wang, Shaofei Brasier, Allan R. |
| description | Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that controls expression of inflammatory genetic networks. Although the nuclear factor-κB (NF-κB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-κB-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-κB inhibitor to systematically identify NF-κB-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-κB signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F) |
| doi_str_mv | 10.1074/jbc.M500437200 |
| format | Article |
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Although the nuclear factor-κB (NF-κB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-κB-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-κB inhibitor to systematically identify NF-κB-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-κB signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F) <0.001) and demonstrated a change in signal intensity of ± 3-fold relative to control. Of these, 28 were NF-κB-dependent, encoding proteins involved in diverse cellular activities. Quantitative real-time PCR assays of eight characterized NF-κB-dependent genes and five genes not previously known to be NF-κB-dependent (Gro-β and-γ, IκBϵ, interleukin (IL)-7R, and Naf-1) were used to determine whether they were directly or indirectly NF-κB regulated. Expression of constitutively active enhanced green fluorescent·NF-κB/Rel A fusion protein transactivated all but IL-6 and IL-7R in the absence of TNF stimulation. Moreover, TNF strongly induced all 12 genes in the absence of new protein synthesis. High probability NF-κB sites in novel genes were predicted by binding site analysis and confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays show the endogenous IκBα/ϵ, Gro-β/γ, and Naf-1 promoters directly bound NF-κB/Rel A in TNF-stimulated cells. Together, these studies systematically identify the direct NF-κB-dependent gene network downstream of TNF signaling, extending our knowledge of biological processes regulated by this pathway.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M500437200</identifier><language>eng</language><publisher>Elsevier Inc</publisher><ispartof>The Journal of biological chemistry, 2005-04, Vol.280 (17), p.17435-17448</ispartof><rights>2005 © 2005 ASBMB. 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Although the nuclear factor-κB (NF-κB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-κB-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-κB inhibitor to systematically identify NF-κB-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-κB signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F) <0.001) and demonstrated a change in signal intensity of ± 3-fold relative to control. Of these, 28 were NF-κB-dependent, encoding proteins involved in diverse cellular activities. Quantitative real-time PCR assays of eight characterized NF-κB-dependent genes and five genes not previously known to be NF-κB-dependent (Gro-β and-γ, IκBϵ, interleukin (IL)-7R, and Naf-1) were used to determine whether they were directly or indirectly NF-κB regulated. Expression of constitutively active enhanced green fluorescent·NF-κB/Rel A fusion protein transactivated all but IL-6 and IL-7R in the absence of TNF stimulation. Moreover, TNF strongly induced all 12 genes in the absence of new protein synthesis. High probability NF-κB sites in novel genes were predicted by binding site analysis and confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays show the endogenous IκBα/ϵ, Gro-β/γ, and Naf-1 promoters directly bound NF-κB/Rel A in TNF-stimulated cells. 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| title | Identification of Direct Genomic Targets Downstream of the Nuclear Factor-κB Transcription Factor Mediating Tumor Necrosis Factor Signaling |
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