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  • Original Article
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Identification of ribosomal protein S25 (RPS25)–MDM2–p53 regulatory feedback loop

Oncogene volume 32, pages 2782–2791 (2013)Cite this article

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Abstract

There is an increasing interest in determining the role of ribosomal proteins (RPs) in the regulation of MDM2–p53 pathway in coordinating cellular response to stress. Herein, we report a novel regulatory role of ribosomal protein S25 (RPS25) in MDM2-mediated p53 degradation and a feedback regulation of S25 by p53. We demonstrated that S25 interacted with MDM2 and inhibited its E3 ligase activity, resulting in the reduction of MDM2-mediated p53 ubiquitination and the stabilization and activation of p53. S25, MDM2 and p53 formed a ternary complex following ribosomal stress. The nucleolar localization and MDM2-binding domains of S25 were critical for its role in MDM2-mediated p53 regulation. Knockdown of S25 by siRNA attenuated the induction and activation of p53 following ribosomal stress. S25 stabilized and cooperated with MDMX to regulate MDM2 E3 ligase activity. Furthermore, S25 was identified to be a transcriptional target of p53; p53 directly bound to S25 promoter and suppressed S25 expression. Our results suggest that there is a S25–MDM2–p53 regulatory feedback loop, which may have an important role in cancer development and progression.

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Acknowledgements

We thank Dr J Chen for the kind gift of the MDMX plasmid; Dr G Lozano for the mdmx−/−p53−/− and mdm2−/−p53−/− MEF cell lines; and Drs G Jin, D Chen, Z Zhang, L Ao, X Yang, J Qin and S Voruganti for helpful discussions and excellent technical support. This work was supported in part by NIH/NCI grants R01 CA112029, R01 CA121211 and a Susan G Komen Foundation grant BCTR0707731 (to RZ). MW was supported by NIH grant R01 CA91980. HW was supported by the One Hundred Talents Program, Chinese Academy of Sciences, grants from National Nature Science Foundation (30870513, 31070680, 91029715 and 81025017) and Ministry of Science and Technology of China (2007CB947100), the Science and Technology Commission of Shanghai Municipality (08391910800, 10391902100), National Science and Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ (2009ZX09102-114, 2009ZX09301-011).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX, USA

    X Zhang, W Wang & R Zhang

  2. Center for Clinical Laboratory of the Affiliated Hospital, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China

    X Zhang & W Xu

  3. Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA

    W Wang, M-H Wang & R Zhang

  4. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    H Wang

  5. Department of Biomedical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX, USA

    M-H Wang

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Zhang, X., Wang, W., Wang, H. et al. Identification of ribosomal protein S25 (RPS25)–MDM2–p53 regulatory feedback loop. Oncogene 32, 2782–2791 (2013). https://doi.org/10.1038/onc.2012.289

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