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The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response

Nature volume 419, pages 849–853 (2002)Cite this article

An Erratum to this article was published on 28 November 2002

Abstract

p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis1,2. It is well documented that DNA damage leads to phosphorylation and activation of p53 (refs 1–3), yet how p53 is activated is still not fully understood. Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase4,5,6,7,8,9. Furthermore, the interaction of Pin1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53. The Pin1-mediated p53 activation requires the WW domain, a phosphorylated Ser/Thr-Pro motif interaction module, and the isomerase activity of Pin1. Moreover, Pin1-deficient cells are defective in p53 activation and timely accumulation of p53 protein, and exhibit an impaired checkpoint control in response to DNA damage. Together, these data suggest a mechanism for p53 regulation in cellular response to genotoxic stress.

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Figure 1: DNA damage induces p53 phosphorylation on Ser-Pro motifs and p53–Pin1 interaction.
Figure 2: Pin1 enhances p53 transcription activity.
Figure 3: Pin1 activates p53 in response to DNA damage.
Figure 4: Cell cycle arrest induced by DNA damage is impaired in Pin1-/- MEF cells.

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Acknowledgements

We thank B. Vogelstein, K. Vousden and T. Jacks for plasmids; J. Chen for 2A-10 antibody; and G. Del Sal for discussion and sharing unpublished data. We also thank E. R. Flores for E1A-retrovirus and advice on ChIP analysis, and Y. Zhang for technical assistance on cell cycle analysis. This work was supported by the NIH (Z.-X.X) and Department of Defense (Z.-X.X).

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Authors and Affiliations

  1. Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, 02118, USA

    Hongwu Zheng, Han You, Stephen A. Murray, Ling Gu & Zhi-Xiong Jim Xiao

  2. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, 02118, USA

    Xiaoren Tang & Zhi-Xiong Jim Xiao

  3. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Xiao Zhen Zhou, Gerburg Wulf & Kun Ping Lu

  4. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    Takafumi Uchida

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  1. Hongwu Zheng
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Correspondence to Zhi-Xiong Jim Xiao.

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Zheng, H., You, H., Zhou, X. et al. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419, 849–853 (2002). https://doi.org/10.1038/nature01116

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