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hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14

Oncogene volume 33, pages 246–254 (2014)Cite this article

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Abstract

The tumor-suppressor p53 provides a critical brake on tumor development. HDM2 (human double-minute 2), a p53 E3 ubiquitin ligase, is the principal cellular antagonist of p53. Mounting evidence has suggested that ribosomal proteins (RPs) modulate HDM2-p53 as a novel pathway for regulating p53 signaling. However, the upstream regulators that mediate RP-HDM2-p53 circuits remain poorly understood. Here we identify human coilin-interacting nuclear ATPase protein (hCINAP) as an interacting partner of ribosomal protein S14 (RPS14). RPS14 stabilized and activated p53 by inhibiting HDM2-mediated p53 polyubiquitination and degradation. More importantly, RPS14 was specifically modified with NEDD8 and hCINAP inhibited RPS14 NEDDylation by recruiting NEDD8-specific protease 1. The decrease in RPS14 NEDDylation led to reduced stability and incorrect localization of RPS14, thereby attenuating the interaction between RPS14 and HDM2. Free HDM2 stimulated p53 polyubiquitination and degradation. In conclusion, we demonstrate that hCINAP acts as a novel regulator of RPS14-HDM2-p53 by regulating the interaction between RPS14 and HDM2 through the control of RPS14 NEDDylation. These findings suggest that hCINAP is an important regulator of RP-HDM2-p53 pathway and a potential anticancer drug target.

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Acknowledgements

We sincerely thank Dr Jian Wang from the State Key Laboratory of Proteomics, Beijing Proteome Research Center for providing plasmids for HDM2 and its truncation constructs. We thank Dr Jun Gu at Peking University for providing the HCT116 cells and reporter plasmids. This work was supported by Grants from the National Science Foundation of China (31170709, 30930020), the National High Technology and Development Program of China (973 Program, 2010CB911804) and the International Center for Genetic Engineering and Biotechnology (project no. CRP/CHN09-01). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. State Key Lab of Protein and Plant Gene Research, Beijing, China

    J Zhang, D Bai, J Guan & X Zheng

  2. Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China

    J Zhang, D Bai, X Ma, J Guan & X Zheng

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  1. J Zhang
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Correspondence to X Zheng.

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Zhang, J., Bai, D., Ma, X. et al. hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14. Oncogene 33, 246–254 (2014). https://doi.org/10.1038/onc.2012.560

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