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The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults

Naturevolume 419, pages853–857 (2002)Cite this article

Abstract

The tumour suppressor p53 is important in the cell decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 post-translational modifications and association with other proteins have been implicated in the regulation of its stability and transcriptional activities1,2. Here we report that, on DNA damage, p53 interacts with Pin1, a peptidyl-prolyl isomerase3, which regulates the function of many proteins involved in cell cycle control and apoptosis4,5,6. The interaction is strictly dependent on p53 phosphorylation, and requires Ser 33, Thr 81 and Ser 315. On binding, Pin1 generates conformational changes in p53, enhancing its transactivation activity. Stabilization of p53 is impaired in UV-treatedPin1-/- cells owing to its inability to efficiently dissociate from Mdm2. As a consequence, a reduced p53-dependent response was detected inPin1-/- cells, and this correlates with a diminished transcriptional activation of some p53-regulated genes. Our results suggest that, following stress-induced phosphorylation, p53 needs to form a complex with Pin1 and to undergo a conformational change to fulfil its biological roles.

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Figure 1: Pin1 interacts with activated p53 in a phosphorylation-dependent manner.
Figure 2: Phosphorylated Ser 33, Thr 81 and Ser 315 are required for the interaction with Pin1, which drives conformational changes in p53.
Figure 3: p53 stabilization following DNA damage is reduced inPin1-/- MEFs.
Figure 4: p53 response following DNA damage is impaired inPin1-/- MEFs.

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Acknowledgements

We thank our colleagues at the LNCIB for advice, discussions and critical reading of the manuscript; S. Piazza, F. Agostini and E. Guida for experimental support; M. Oren for suggestions and for providing the luciferase constructs; M. Serrano, B. Amati, R. Maestro, X. Lu, T. Crook and S. Soddu for supplying other reagents; G. Zambetti for advice about the preparation of mouse thymocytes; R. Vidimari and A. Beorchia for helping in γ-irradiation experiments; M. Stebel for production of MEFs and technical assistance; and J. Xiao for discussions and for sharing unpublished data. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and MURST (PRIN Cofin 2000) (G.D.S.). M.G. is an FIRC (Fondazione Italiana per la Ricerca sul Cancro) Fellow.

Author information

Author notes

  1. Paola Zacchi, Monica Gostissa and Claudio Schneider: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, 34012, Trieste, Italy

    Paola Zacchi, Monica Gostissa, Clio Salvagno, Fabio Avolio, Claudio Schneider & Giannino Del Sal

  2. Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Università degli Studi di Trieste, via L. Giorgeri 1, 34100, Trieste, Italy

    Paola Zacchi, Clio Salvagno & Giannino Del Sal

  3. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, 980-8575, Sendai, Japan

    Takafumi Uchida

  4. Universita' di Ferrara, Sezione di Istologia ed Embriologia, Dipartimento di Morfologia ed Embriologia, via Fossato di Mortara 64/b, 44100, Ferrara, Italy

    Stefano Volinia

  5. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, 10029-6574, New York, USA

    Ze'ev Ronai

  6. Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, via Messi d'oro 156, 00158, Rome, Italy

    Giovanni Blandino

  7. Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, p. le Kolbe 1, 33100, Udine, Italy

    Claudio Schneider

Authors
  1. Paola Zacchi
  2. Monica Gostissa
  3. Takafumi Uchida
  4. Clio Salvagno
  5. Fabio Avolio
  6. Stefano Volinia
  7. Ze'ev Ronai
  8. Giovanni Blandino
  9. Claudio Schneider
  10. Giannino Del Sal

Corresponding author

Correspondence toGiannino Del Sal.

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The authors declare that they have no competing financial interests.

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Zacchi, P., Gostissa, M., Uchida, T.et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults.Nature419, 853–857 (2002). https://doi.org/10.1038/nature01120

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