Efficient DNA binding of NF-κB requires the chaperone-like function of NPM1.
Efficient DNA binding of NF-κB requires the chaperone-like function of NPM1.
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DOI：
10.1093/nar/gkw1285
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发表时间：
2017-04-20
影响因子：
14.9
通讯作者：
Okuwaki M
中科院分区：
文献类型：
--
作者：
Lin J;Kato M;Nagata K;Okuwaki M
NPM 1/nucleophosmin在各种肿瘤中经常过表达，尽管NPM 1的致癌作用仍不清楚。在这里，我们揭示了NPM 1和核因子-κB（NF-κB）之间的联系，NF-κB是炎症的主要调节因子。我们发现NPM 1敲低通过减少NF-κB B p65向基因启动子的募集而减少NF-κ B介导的选定靶基因的转录。NPM 1直接与p65的DNA结合结构域结合以增强其DNA结合活性，而不是DNA-NF-κB复合物的一部分。这一结果表明，NF-κB需要NPM 1的伴侣样功能来结合DNA。此外，我们证明NPM 1是由肿瘤坏死因子α（TNF-α）和脂多糖诱导的成纤维细胞和巨噬细胞中的有效炎症基因表达所必需的。NPM 1基因敲低可显著降低NF-κ B介导的乳腺癌细胞侵袭能力。我们的研究为NF-κ B介导的转录和NPM 1通过调节NF-κB在肿瘤细胞和肿瘤微环境中的致癌作用提供了新的机制。
NPM1/nucleophosmin is frequently overexpressed in various tumors, although the oncogenic role of NPM1 remains unclear. Here we revealed the link between NPM1 and nuclear factor-κB (NF-κB), a master regulator of inflammation. We found that NPM1 knockdown decreased NF-κB-mediated transcription of selected target genes by decreasing the recruitment of NF-κB p65 to the gene promoters. NPM1 is directly associated with the DNA binding domain of p65 to enhance its DNA binding activity without being a part of the DNA–NF-κB complex. This result suggests that NF-κB requires the chaperone-like function of NPM1 for DNA binding. Furthermore, we demonstrated that NPM1 was required for efficient inflammatory gene expression induced by tumor necrosis factor alpha (TNF-α) and lipopolysaccharide in fibroblasts and macrophages. The NF-κB-mediated invasion of breast cancer cells was significantly decreased by NPM1 knockdown. Our study suggests a novel mechanistic insight into the NF-κB-mediated transcription and an oncogenic role of NPM1 in both tumor cells and the tumor micro-environment through the regulation of NF-κB.