1] Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA [2] Oversea Laboratory, Center for Medical Research, Wuhan University, Wuhan, Hubei, China.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA.
Oncogene. 2014 Feb 20;33(8):996-1005. doi: 10.1038/onc.2013.8. Epub 2013 Feb 11.
The biological function of NF-κB1 (p50) in the regulation of protein expression is far from well understood owing to the lack of a transcriptional domain. Here, we report a novel function of p50 in its regulation of p53 protein translation under stress conditions. We found that the deletion of p50 (p50-/-) impaired arsenite-induced p53 protein expression, which could be restored after reconstitutive expression of HA-p50 in p50-/- cells, p50-/-(Ad-HA-p50). Further studies indicated that the amounts of p53 mRNA, p53 promoter-driven transcription activity and p53 protein degradation were comparable between wild-type and p50-/- cells. Moreover, we found that p50 was crucial for Akt/S6 ribosomal protein activation via inhibition of the translation of the PH domain and leucine-rich repeat protein phosphatases 1 (PHLPP1), a phosphatase of Akt. Further studies showed that p50-mediated upregulation of miR-190 was responsible for the inhibition of PHLPP1 translation by targeting the 3'-untranslated region of its mRNA. Collectively, we have identified a novel function of p50 in modulating p53 protein translation via regulation of the miR-190/PHLPP1/Akt-S6 ribosomal protein pathway.
由于缺乏转录结构域，NF-κB1（p50）在蛋白质表达调控中的生物学功能还远未被充分了解。在这里，我们报告了 p50 在应激条件下调节 p53 蛋白翻译中的一个新功能。我们发现，p50 的缺失（p50-/-）损害了亚砷酸盐诱导的 p53 蛋白表达，而在 p50-/-细胞中重建 HA-p50 的表达（p50-/-(Ad-HA-p50)）可以恢复这种表达。进一步的研究表明，野生型和 p50-/-细胞之间的 p53 mRNA 量、p53 启动子驱动的转录活性和 p53 蛋白降解没有差异。此外，我们发现 p50 通过抑制 Akt/S6 核糖体蛋白的 PH 结构域和富含亮氨酸重复的蛋白磷酸酶 1（PHLPP1）的翻译对于 Akt/S6 核糖体蛋白的激活至关重要，而 PHLPP1 是 Akt 的一种磷酸酶。进一步的研究表明，p50 介导的 miR-190 的上调通过靶向其 mRNA 的 3'-非翻译区来抑制 PHLPP1 的翻译。总之，我们已经确定了 p50 通过调节 miR-190/PHLPP1/Akt-S6 核糖体蛋白途径来调节 p53 蛋白翻译的新功能。
