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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of a human NF-κB-activating protein, TAB3
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Identification of a human NF-κB-activating protein, TAB3

机译：鉴定人NF-κB激活蛋白TAB3

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The NF-κB pathway plays a critical role in regulating cellular processes such as immune responses, stress responses, apoptosis, proliferation and differentiation, whereas dysfunction of this pathway has been associated with numerous cancer and immune disorders. We have applied our Random Activation of Gene Expression technology to an NF-κB reporter cell line to facilitate the discovery of positive regulators of NF-κB activation. A small protein expression library, corresponding to ≈0.1 x genome coverage, was generated and screened for clones exhibiting constitutive activation of NF-κB. After isolation of cellular clones displaying the relevant phenotypes, we identified two known components of the NF-κB pathway and a hypothetical gene that we have designated the human ortholog of Xenopus TAK1-binding protein 3 (TAB3). Overexpression of human TAB3 was found to activate both NF-κB and AP-1 transcription factors. Furthermore, the activation of NF-κB by TAB3 was blocked by the NF-κB inhibitor, SN50, and by expression of dominant-negative forms of tumor necrosis factor α-associated factor 6 and transforming growth factor β-activated kinase. Taken together, these data demonstrate that TAB3 transforming growth factor is a constituent of the NF-κB pathway functioning upstream of tumor necrosis factor α-associated factor 6 transforming growth factor β-activated kinase. Interestingly, increased expression of TAB3 was found in some cancer tissues, and its overexpression in NIH 3T3 cells resulted in cellular transformation, thus establishing a causative link between elevated TAB3 expression, constitutive NF-κB activation, and oncogenesis.
机译：NF-κB途径在调节细胞过程（如免疫反应，应激反应，细胞凋亡，增殖和分化）中起关键作用，而该途径的功能障碍与许多癌症和免疫疾病有关。我们已将我们的基因表达随机激活技术应用于NF-κB报道细胞系，以促进NF-κB激活的正调节剂的发现。产生了一个小蛋白质表达文库，相当于≈0.1x基因组覆盖率，并筛选了展示NF-κB组成型激活的克隆。分离显示相关表型的细胞克隆后，我们鉴定了NF-κB通路的两个已知成分和一个假设基因，我们将其指定为非洲爪蟾TAK1结合蛋白3（TAB3）的人类直系同源基因。发现人TAB3的过表达激活NF-κB和AP-1转录因子。此外，TAB3对NF-κB的激活被NF-κB抑制剂SN50阻断，并被肿瘤坏死因子α相关因子6和转化生长因子β活化激酶的显性阴性形式表达。综上所述，这些数据表明TAB3转化生长因子是在肿瘤坏死因子α相关因子6转化生长因子β激活激酶上游起作用的NF-κB途径的组成部分。有趣的是，在某些癌症组织中发现了TAB3的表达增加，并且它在NIH 3T3细胞中的过表达导致细胞转化，因此在升高的TAB3表达，组成型NF-κB活化和肿瘤发生之间建立起因果关系。

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