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Nat Cell Biol. 2009 Feb;11(2):133-42. doi: 10.1038/ncb1822. Epub 2009 Jan 18.

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

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

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 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.

PMID:
19151708
[PubMed - indexed for MEDLINE]
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