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

Alessandra Rustighi, Luca Tiberi, Alessia Soldano, Marco Napoli, Paolo Nuciforo, Antonio Rosato, Fred Kaplan, Anthony J Capobianco, Salvatore Pece, Pier Paolo Di Fiore, Giannino Del Sal

Research output: Contribution to journalArticle

114 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalNature Cell Biology
Volume11
Issue number2
DOIs
StatePublished - Jan 19 2009
Externally publishedYes

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Peptidylprolyl Isomerase
Notch Receptors
Breast Neoplasms
Amyloid Precursor Protein Secretases
Neoplasms
Carcinogenesis
Breast
Ligands

ASJC Scopus subject areas

  • Cell Biology

Cite this

Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., ... Del Sal, G. (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology, 11(2), 133-142. https://doi.org/10.1038/ncb1822

The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. / Rustighi, Alessandra; Tiberi, Luca; Soldano, Alessia; Napoli, Marco; Nuciforo, Paolo; Rosato, Antonio; Kaplan, Fred; Capobianco, Anthony J; Pece, Salvatore; Di Fiore, Pier Paolo; Del Sal, Giannino.

In: Nature Cell Biology, Vol. 11, No. 2, 19.01.2009, p. 133-142.

Research output: Contribution to journalArticle

Rustighi, A, Tiberi, L, Soldano, A, Napoli, M, Nuciforo, P, Rosato, A, Kaplan, F, Capobianco, AJ, Pece, S, Di Fiore, PP & Del Sal, G 2009, 'The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer', Nature Cell Biology, vol. 11, no. 2, pp. 133-142. https://doi.org/10.1038/ncb1822
Rustighi A, Tiberi L, Soldano A, Napoli M, Nuciforo P, Rosato A et al. The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology. 2009 Jan 19;11(2):133-142. https://doi.org/10.1038/ncb1822
Rustighi, Alessandra ; Tiberi, Luca ; Soldano, Alessia ; Napoli, Marco ; Nuciforo, Paolo ; Rosato, Antonio ; Kaplan, Fred ; Capobianco, Anthony J ; Pece, Salvatore ; Di Fiore, Pier Paolo ; Del Sal, Giannino. / The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. In: Nature Cell Biology. 2009 ; Vol. 11, No. 2. pp. 133-142.
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