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

Author

Listed:
  • Hongwu Zheng

    (Boston University School of Medicine)

  • Han You

    (Boston University School of Medicine)

  • Xiao Zhen Zhou

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Stephen A. Murray

    (Boston University School of Medicine)

  • Takafumi Uchida

    (Institute of Development, Aging and Cancer, Tohoku University)

  • Gerburg Wulf

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Ling Gu

    (Boston University School of Medicine)

  • Xiaoren Tang

    (Boston University School of Medicine)

  • Kun Ping Lu

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Zhi-Xiong Jim Xiao

    (Boston University School of Medicine
    Boston University School of Medicine)

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.

Suggested Citation

  • Hongwu Zheng & Han You & Xiao Zhen Zhou & Stephen A. Murray & Takafumi Uchida & Gerburg Wulf & Ling Gu & Xiaoren Tang & Kun Ping Lu & Zhi-Xiong Jim Xiao, 2002. "The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response," Nature, Nature, vol. 419(6909), pages 849-853, October.
    • Handle: RePEc:nat:nature:v:419:y:2002:i:6909:d:10.1038_nature01116
    DOI: 10.1038/nature01116
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    Cited by:

    1. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Alexandra Born & Janne Soetbeer & Morkos A. Henen & Frauke Breitgoff & Yevhen Polyhach & Gunnar Jeschke & Beat Vögeli, 2022. "Ligand-specific conformational change drives interdomain allostery in Pin1," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Hui-Rong Xu & Zhong-Fa Xu & Yan-Lai Sun & Jian-Jun Han & Zeng-Jun Li, 2013. "The −842G/C Polymorphisms of PIN1 Contributes to Cancer Risk: A Meta-Analysis of 10 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-7, August.

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