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首页> 外文期刊>Molecular and Cellular Biology >Human T-Cell Lymphotropic Virus Type 1 Tax Represses c-Myb-Dependent Transcription through Activation of the NF-κB Pathway and Modulation of Coactivator Usage
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Human T-Cell Lymphotropic Virus Type 1 Tax Represses c-Myb-Dependent Transcription through Activation of the NF-κB Pathway and Modulation of Coactivator Usage

机译：人类T细胞淋巴病毒1型税通过激活NF-κB途径和调节共激活剂的使用来抑制c-Myb依赖性转录

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The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-κB pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-κB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-κB activation by coexpression of IκBα restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1β), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-κB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-κB-mediated repression.
机译：原癌基因c- myb 对于控制细胞生长与分化之间的平衡至关重要。已经报道了许多人类癌症中异常的c-Myb活性，并且强制的c-Myb转录可以通过刺激细胞增殖和抑制细胞凋亡途径来转化淋巴样来源的细胞。在这里，我们证明了HTLV-1 Tax蛋白激活NF-κB通路会导致c-Myb的转录失活。不能刺激NF-κB途径的Tax突变体不能抑制c-Myb反式激活功能这一事实支持了这一结论。此外，通过共表达IκBα抑制Tax介导的NF-κB活化可恢复c-Myb转录，而Tax无法阻止NEMO基因敲除细胞系中的c-Myb转录。重要的是，诸如细胞细胞因子肿瘤坏死因子α，白介素1β（IL-1β）和脂多糖的信号传导等生理刺激也抑制了c-Myb的转录。这些结果揭示了细胞外信号传导与c-Myb依赖性转录之间的新联系。识别NF-κB介导的阻抑的潜在机制是RelA隔离共激活剂CBP / p300。有趣的是，缺少C / H1和KIX结构域且无法结合RelA的p300的氨基末端缺失形式保留了刺激c-Myb转录并阻止NF-κB介导的阻遏的能力。

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