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NF-κB1 p50 promotes p53 protein translation through miR-190 downregulation of PHLPP1

Oncogene volume 33, pages 996–1005 (2014)Cite this article

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Abstract

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.

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Acknowledgements

We thank Ms Nedda Tichi and Mr Andy Hu for their critical reading of this manuscript. We thank Dr Ping-Yee Law (Department of Pharmacology, University of Minnesota) for providing us with constructs of miR-190 and its control. We also thank Dr Fei Chen (Department of Pharmaceutical Sciences, Wayne State University) for providing us with the PHLPP1 3′-UTR luciferase reporter. This work was partially supported by grants from NSFC81229002, NIH/NCI CA112557, NBRPC2012CB525004 and NIH/NIEHS ES000260.

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Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA

    Y Yu, D Zhang, H Huang, J Li, M Zhang & C Huang

  2. Oversea Laboratory, Center for Medical Research, Wuhan University, Wuhan, Hubei, China

    Y Yu & Y Wan

  3. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China

    H Huang, M Zhang, J Gao & C Huang

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Correspondence to C Huang.

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Yu, Y., Zhang, D., Huang, H. et al. NF-κB1 p50 promotes p53 protein translation through miR-190 downregulation of PHLPP1. Oncogene 33, 996–1005 (2014). https://doi.org/10.1038/onc.2013.8

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