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

Oncogene volume 28, pages 545–554 (2009)Cite this article

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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