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The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer

Nature Cell Biology volume 11, pages 133–142 (2009)Cite this article

Abstract

Signalling through Notch receptors requires ligand-induced cleavage to release the intracellular domain, which acts as a transcriptional activator in the nucleus. Deregulated Notch1 signalling has been implicated in mammary tumorigenesis; however the mechanisms underlying Notch activation in breast cancer remain unclear. Here, we demonstrate that the prolyl-isomerase Pin1 interacts with Notch1 and affects Notch1 activation. Pin1 potentiates Notch1 cleavage by γ-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing Notch1 transcriptional and tumorigenic activity. We found that Notch1 directly induces transcription of Pin1, thereby generating a positive loop. In human breast cancers, we observed a strong correlation between Pin1 overexpression and high levels of activated Notch1. Thus, the molecular circuitry established by Notch1 and Pin1 may have a key role in cancer.

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Figure 1: Pin1 binds to human Notch1.
Figure 2: Pin1 affects Notch1 activity.
Figure 3: Pin1 affects Notch1 processing by γ-secretase.
Figure 4: Pin1 improves cleavage of Notch1 by binding to the STR region.
Figure 5: Pin1 affects human Notch1 tumorigenic activity.
Figure 6: Pin1 is a transcriptional target of Notch1.
Figure 7: Expression of Pin1, Notch1 and HES-1 in breast cancer cell lines and in serial sections of breast carcinoma samples.
Figure 8: Inhibition of Pin1 sensitizes human breast cancer cell lines to GSI treatment.

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Acknowledgements

We thank LNCIB colleagues, F. Mantovani , L. Collavin and S. Piccolo for critical reading of the manuscript; R. Poddighe for technical support, and M. Stebel and C. Degrassi of the C.S.P.A., University of Trieste. We are grateful to M. Donzelli for generation of the pcDNA3N1ΔE–Flag construct, to T. Sudo for the anti-HES-1 antibody, A. Israel for pGL2-HES-1/LUC, T. Uchida for providing Pin1 knockout mice and to ICGEB for access to their facilities. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), from Italian University and Research Ministerium (Cofin MIUR), from Friuli-Venezia-Giulia (regional grant), from Association for International Cancer Research (AICR, UK) to G.D.S., and from R01 CA-83736-07 to A.C, AIRC and Fondazione Giancarla Vollaro to S.P. and to Fondazione Monzino and AIRC to P.P.D.F.; M.N. is a FIRC fellow (Fondazione Italiana per la Ricerca sul Cancro). This paper is dedicated to the memory of Stefano Ferrari.

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Author notes

  1. Alessandra Rustighi and Luca Tiberi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratorio Nazionale CIB (LNCIB), Area Science Park, Padriciano 99, 34012, Trieste, Italy

    Alessandra Rustighi, Luca Tiberi, Alessia Soldano, Marco Napoli & Giannino Del Sal

  2. and Dipartimento di Scienze della Vita, Università degli Studi di Trieste, via Giorgieri 1, 34128, Trieste, Italy

    Alessandra Rustighi, Luca Tiberi, Alessia Soldano, Marco Napoli & Giannino Del Sal

  3. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università di Milano, via di Rudinì 8, 20142, Milan, Italy

    Paolo Nuciforo, Salvatore Pece & Pier Paolo Di Fiore

  4. Dipartimento di Scienze Oncologiche e Chirurgiche dell'Università di Padova, via Gattamelata 64, 35128, Padova, Italy

    Antonio Rosato

  5. Istituto Oncologico Veneto, IOV, via Gattamelata 64, 35128, Padova, Italy

    Antonio Rosato

  6. The Wistar Institute, 3601 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Fred Kaplan & Anthony Capobianco

  7. Istituto Europeo di Oncologia, via Ripamonti 435, 20141, Milan, Italy

    Salvatore Pece & Pier Paolo Di Fiore

  8. IFOM, the FIRC Institute for Molecular Oncology Foundation, via Adamello 16, 20139, Milan, Italy

    Pier Paolo Di Fiore

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Contributions

A.R., L.T., A.S. and M.N. performed biochemical and cell biology experiments; P.N. performed analysis and evaluation of TMA under the supervision of S.P. and P.P.D.F; A.R. performed part of the in vivo experiments; F.K. and A.C. provided essential reagents and assisted with scientific support; G.D.S. was responsible for the overall project.

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Correspondence to Giannino Del Sal.

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Rustighi, A., Tiberi, L., Soldano, A. et al. The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol 11, 133–142 (2009). https://doi.org/10.1038/ncb1822

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