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.

1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, and Dipartimento di Biochimica Biofisica e Chimica delle Macromolecole, Università di Trieste, Trieste, 34100, Italy.
2. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
3. Department of Medical Oncology, S. Croce e Carle Hospital, 12100 Cuneo, Italy.
4. Ludwig Institute for Cancer Research, University College London, 91 Riding House Street, London W1W 7BS, UK.

Correspondence to: Giannino Del Sal¹ e-mail: delsal@lncib.trieste.it

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