1. Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, 34012 Trieste, Italy
2. Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Università degli Studi di Trieste, via L. Giorgeri 1, 34100, Trieste, Italy
3. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
4. Universita' di Ferrara, Sezione di Istologia ed Embriologia, Dipartimento di Morfologia ed Embriologia, via Fossato di Mortara 64/b, 44100, Ferrara, Italy
5. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York 10029-6574, USA
6. Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, via Messi d'oro 156, 00158 Rome, Italy
7. Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, p. le Kolbe 1, 33100 Udine, Italy
8. These authors contributed equally to this work

Correspondence to: Giannino Del Sal^1,2 Correspondence and requests for materials should be addressed to G.D.S. (e-mail: Email: delsal@sci.area.trieste.it).

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 activities^{1, 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 apoptosis^{4, 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.

1. Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, 34012 Trieste, Italy
2. Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Università degli Studi di Trieste, via L. Giorgeri 1, 34100, Trieste, Italy
3. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
4. Universita' di Ferrara, Sezione di Istologia ed Embriologia, Dipartimento di Morfologia ed Embriologia, via Fossato di Mortara 64/b, 44100, Ferrara, Italy
5. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York 10029-6574, USA
6. Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, via Messi d'oro 156, 00158 Rome, Italy
7. Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, p. le Kolbe 1, 33100 Udine, Italy
8. These authors contributed equally to this work

Correspondence to: Giannino Del Sal^1,2 Correspondence and requests for materials should be addressed to G.D.S. (e-mail: Email: delsal@sci.area.trieste.it).