Journal
NATURE CELL BIOLOGY
Volume 11, Issue 2, Pages 133-U62Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1822
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Italian University and Research Ministerium (Cofin MIUR)
- Friuli-Venezia-Giulia
- Association for International Cancer Research (AICR, UK)
- Fondazione Giancarla Vollaro
- Fondazione Monzino
- FIRC fellow (Fondazione Italiana per la Ricerca sul Cancro)
- [R01 CA-83736-07]
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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 gamma-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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