The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults (original) (raw)

Nature volume 419, pages 853–857 (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-treated _Pin1_-/- cells owing to its inability to efficiently dissociate from Mdm2. As a consequence, a reduced p53-dependent response was detected in _Pin1_-/- 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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Sionov, R. & Haupt, Y. The cellular response to p53: the decision between life and death. Oncogene 18, 6145–6157 (1999)
    Article CAS Google Scholar
  2. Vousden, K. H. p53: death star. Cell 103, 691–694 (2000)
    Article CAS Google Scholar
  3. Lu, K. P., Hanes, S. D. & Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544–547 (1996)
    Article ADS CAS Google Scholar
  4. Sudol, M. & Hunter, T. NeW Wrinkles for an old domain. Cell 103, 1001–1004 (2000)
    Article CAS Google Scholar
  5. Pathan, N., Aime-Sempe, C., Kitada, S., Haldar, S. & Reed, J. C. Microtubule targeting drugs induce Bcl-2 phosphorylation and association with Pin1. Neoplasia 3, 70–79 (2001)
    Article CAS Google Scholar
  6. Shen, M., Stukenberg, P. T., Kirschner, M. W. & Lu, K. P. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 12, 706–720 (1998)
    Article CAS Google Scholar
  7. Winkler, K. E., Swenson, K. I., Kornbluth, S. & Means, A. R. Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287, 1644–1647 (2000)
    Article ADS CAS Google Scholar
  8. Lu, P. J., Zhou, X. Z., Shen, M. & Lu, K. P. Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283, 1325–1328 (1999)
    Article ADS CAS Google Scholar
  9. Verdecia, M. A., Bowman, M. E., Lu, K. P., Hunter, T. & Noel, J. P. Structural basis for phosphoserine-proline recognition by group IV WW domains. Nature Struct. Biol. 7, 639–643 (2000)
    Article CAS Google Scholar
  10. Bulavin, D. V. et al. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 18, 6845–6854 (1999)
    Article CAS Google Scholar
  11. Wang, Y. & Prives, C. Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases. Nature 376, 88–91 (1995)
    Article ADS CAS Google Scholar
  12. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)
    Article CAS Google Scholar
  13. de Stanchina, E. et al. E1A signaling to p53 involves the p19(ARF) tumour suppressor. Genes Dev. 12, 2434–2442 (1998)
    Article CAS Google Scholar
  14. Stukenberg, P. T. & Kirschner, M. W. Pin1 acts catalytically to promote a conformational change in Cdc25. Mol. Cell 7, 1071–1083 (2001)
    Article CAS Google Scholar
  15. Fujimori, F., Takahashi, K., Uchida, C. & Uchida, T. Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochem. Biophys. Res. Commun. 265, 658–663 (1999)
    Article CAS Google Scholar
  16. Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–967 (1993)
    Article CAS Google Scholar
  17. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000)
    Article ADS CAS Google Scholar
  18. Bates, S. & Vousden, K. Mechanisms of p53-mediated apoptosis. Cell Mol. Life Sci. 55, 28–37 (1999)
    Article CAS Google Scholar
  19. Wulf, G. M. et al. Pin1 is overexpressed in breast cancer and cooperates with Ras signalling in increasing the transcriptional activity of c-jun towards cyclin D1. EMBO J. 20, 3459–3472 (2001)
    Article CAS Google Scholar
  20. Ryo, A., Nakamura, M., Wulf, G., Liu, Y.-C. & Lu, K. P. Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nature Cell Biol. 3, 793–801 (2001)
    Article CAS Google Scholar
  21. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999)
    Article ADS CAS Google Scholar
  22. Damalas, A. et al. Excess β-catenin promotes accumulation of transcriptionally active p53. EMBO J. 18, 3054–3063 (1999)
    Article CAS Google Scholar
  23. Kwonseop, K., Pang, K. M., Evans, M. & Hay, E. D. Overexpression of β-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. Mol. Biol. Cell 11, 3509–3523 (2000)
    Article Google Scholar
  24. Park, D. S. et al. Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J. Cell Biol. 143, 457–467 (1998)
    Article CAS Google Scholar
  25. Buschmann, T. et al. Jun NH2-terminal Kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. Mol. Cell. Biol. 21, 2743–2754 (2001)
    Article CAS Google Scholar
  26. Gostissa, M. et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 18, 6462–6471 (1999)
    Article CAS Google Scholar
  27. Wu, Z. et al. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol. Cell. Biol. 22, 2441–2449 (2002)
    Article CAS Google Scholar
  28. Maestro, R. et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 13, 2207–2217 (1999)
    Article CAS Google Scholar

Download references

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
    You can also search for this author inPubMed Google Scholar
  2. Monica Gostissa
    You can also search for this author inPubMed Google Scholar
  3. Takafumi Uchida
    You can also search for this author inPubMed Google Scholar
  4. Clio Salvagno
    You can also search for this author inPubMed Google Scholar
  5. Fabio Avolio
    You can also search for this author inPubMed Google Scholar
  6. Stefano Volinia
    You can also search for this author inPubMed Google Scholar
  7. Ze'ev Ronai
    You can also search for this author inPubMed Google Scholar
  8. Giovanni Blandino
    You can also search for this author inPubMed Google Scholar
  9. Claudio Schneider
    You can also search for this author inPubMed Google Scholar
  10. Giannino Del Sal
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toGiannino Del Sal.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Zacchi, P., Gostissa, M., Uchida, T. et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults.Nature 419, 853–857 (2002). https://doi.org/10.1038/nature01120

Download citation

This article is cited by

Associated content