Abstract
The tumor-suppressor function of p53 relies on its transcriptional activity, which is modulated by post-translational modifications and interactions with regulatory proteins. The prolyl isomerase Pin1 has a central role in transducing phosphorylation of p53 into conformational changes that affect p53 stability and function. We found that Pin1 is required for efficient loading of p53 on target promoters upon stress. In addition, Pin1 is recruited to chromatin by p53 and stimulates binding of the p300 acetyltransferase and consequent p53 acetylation. Accordingly, tumor-associated mutations at Pin1-binding residues within the p53 proline-rich domain hamper acetylation of p53 by p300. After phosphorylation of p53 at Ser46 triggered by cytotoxic stimuli, Pin1 also mediates p53's dissociation from the apoptosis inhibitor iASPP, promoting cell death. In tumors bearing wild-type p53, expression of Pin1 and iASPP are inversely correlated, supporting the clinical relevance of these interactions.
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Acknowledgements
We thank C. Schneider, M. Monte and our colleagues at the Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie for advice and discussion; A. Grison, A. Bisso, M. Mioni and A. Soldano for technical assistance; B. Amati (European Institute of Oncology) for critical reading of the manuscript; M. Murphy (Fox Chase Cancer Center), Y. Haupt (Hadassah University Hospital), M. Oren (Weizmann Institute) and G. Blandino (Regina Elena Cancer Institute) for providing reagents; and M. Giacca, M. Lusic, M. Bestagno, N. Gammoh and L. Banks for access to International Centre for Genetic Engineering and Biotechnology facilities. pGFP-p300 was provided by B. Amati; pcDNA3-p53-Pro72, pcDNA3-p53-Arg72 and pcDNA3-p53-R175H were provided by L. Banks; GFP-specific polyclonal antiserum was provided by C. Brancolini (Udine University); polyclonal antibody to HMGA1b was provided by G. Manfioletti (Trieste University); purified recombinant p300 was provided by R. Mantovani (Milan University). J.G. is an International Centre for Genetic Engineering and Biotechnology Fellow. T.C. is a clinical research fellow of Cancer Research UK. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, Association for International Cancer Research UK and Ministero dell'Università e della Ricerca to G.D.S. and by European Community Sixth Framework Programme funding (contract 503576). This publication reflects the authors' views and not necessarily those of the European Community. The European Community is not liable for any use that may be made of the information contained herein.
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F.M., F.T. and J.G. performed biochemical and cell biology experiments, P.S. and M.G. analyzed tissue samples, X.L. produced constructs and reagents, and T.C. supervised P.S. and M.G. and produced reagents. G.D.S. was responsible for the overall project.
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Mantovani, F., Tocco, F., Girardini, J. et al. The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nat Struct Mol Biol 14, 912–920 (2007). https://doi.org/10.1038/nsmb1306
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DOI: https://doi.org/10.1038/nsmb1306
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