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

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.

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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 in Pin1-/- MEFs.
Figure 4: p53 response following DNA damage is impaired in Pin1-/- 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experiments; M. Stebel for production of MEFs and technical assistance; and J. Xiao for discussions and for sharing unpublished data.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.

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Correspondence to Giannino Del Sal.

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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. Nature 419, 853–857 (2002). https://doi.org/10.1038/nature01120

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