title: The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.
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.
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park, Padriciano 99, 34012 Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rustighi
authors.forename: Luca
authors.initials: L
authors.lastname: Tiberi
authors.forename: Alessia
authors.initials: A
authors.lastname: Soldano
authors.forename: Marco
authors.initials: M
authors.lastname: Napoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Fred
authors.initials: F
authors.lastname: Kaplan
authors.forename: Anthony
authors.initials: A
authors.lastname: Capobianco
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pece
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase