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.

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; Pece, Salvatore; Di Fiore, Pier Paolo; Del Sal, Giannino. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 11:2(2009), pp. 133-142. [10.1038/ncb1822]

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

Soldano, Alessia;
2009-01-01

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.
2009
11
2
133
142
https://www.nature.com/articles/ncb1822
Rustighi, Alessandra; Tiberi, Luca; Soldano, Alessia; Napoli, Marco; Nuciforo, Paolo; Rosato, Antonio; Kaplan, Fred; Capobianco, Anthony; Pece, Salvat...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/133290
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