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New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53

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Abstract

Most of the p53 target genes, all except MDM2, COP1 and PIRH2, perform functions in apoptosis, differentiation and cell cycle arrest. The aforementioned oncogenes downregulate p53 through a negative feedback mechanism, and thus contribute to tumor development. In this study, we report a new p53 target, PRL-1, which is believed to be a significant regulator in the development and metastasis of a variety of cancer types. Phosphatase of regenerating liver 1 (PRL-1) overexpression reduced the levels of endogenous and exogenous p53 proteins, and inhibited p53-mediated apoptosis. On the other hand, the ablation of PRL-1 by small interfering RNA (siRNA) increased p53 protein levels. The p53 downregulation was mediated by p53 ubiquitination and subsequent proteasomal degradation. Furthermore, p53 ubiquitination by PRL-1 was achieved through two independent pathways, by inducing PIRH2 transcription and by inducing MDM2 phosphorylation through Akt signaling. In addition, we showed that the PRL-1 gene harbors a p53 response element in the first intron, and its transcription is regulated by the p53 protein. These findings imply that the new oncogenic p53 target, PRL-1, may contribute to tumor development by the downregulation of p53 by a negative feedback mechanism.

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Acknowledgements

We thank Dr Sung Hyun Kang and Dr Kwang Hee Bae (KRIBB) for providing the FLAG-PRL-1. This work was supported by funding from the Ministry of Science and Technology of Korea (M1040101001-06N0101-00110).

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Author notes

  1. S-H Min and D M Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    S-H Min, Y-S Heo, Y-I Kim, H M Kim, J Kim, Y-M Han & O-J Yoo

  2. BK21 Higher Education Center for Bioregulator Research, Chonnam National University, Gwangju, Korea

    D M Kim

  3. Department of Biology, Chonnam National University, Buk-gu, Gwangju, Korea

    I-C Kim

  4. Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    O-J Yoo

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  1. S-H Min
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Correspondence to O-J Yoo.

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Min, SH., Kim, D., Heo, YS. et al. New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53. Oncogene 28, 545–554 (2009). https://doi.org/10.1038/onc.2008.409

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  • DOI: https://doi.org/10.1038/onc.2008.409

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