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Nature 419, 849-853 (24 October 2002) | doi:10.1038/nature01116; Received 28 June 2002; Accepted 12 September 2002; Published online 2 October 2002

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

Hongwu Zheng1, Han You1, Xiao Zhen Zhou2, Stephen A. Murray1, Takafumi Uchida3, Gerburg Wulf2, Ling Gu1, Xiaoren Tang4, Kun Ping Lu2 & Zhi-Xiong Jim Xiao1,4

  1. Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
  2. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
  3. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

Correspondence to: Zhi-Xiong Jim Xiao1,4 Correspondence and requests for materials should be addressed to Z.-X.X. (e-mail: Email: jxiao@bu.edu).

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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.

  1. Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
  2. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
  3. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

Correspondence to: Zhi-Xiong Jim Xiao1,4 Correspondence and requests for materials should be addressed to Z.-X.X. (e-mail: Email: jxiao@bu.edu).