The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer
Copyright policy )The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer
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.
- University of Milan Italy
- University of Padua Italy
- University of Trieste Italy
- University of Trento Italy
- KU Leuven Belgium
Transcriptional Activation, Protein Structure, 3101 Biochemistry and cell biology, Transcriptional Activation -- genetics, Neoplastic -- genetics -- metabolism, Peptidylprolyl Isomerase -- genetics -- metabolism, breast cancer; Notch1; NICD, Cell Transformation, Amyloid Precursor Protein Secretases -- metabolism, Cell Line, breast cancer, NICD, Cell Line, Tumor, Neoplasms, Humans, Enzyme Activation -- genetics, Tertiary -- genetics, Receptor, Notch1, Neoplasms -- enzymology -- genetics -- physiopathology, 11 Medical and Health Sciences, Neoplastic -- genetics, Neoplastic, Notch1, Tumor, Amyloid Precursor Protein Secretases; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Peptidylprolyl Isomerase; Protein Structure, Tertiary; Receptor, Notch1; Transcriptional Activation; Cell Biology, Notch1 -- genetics -- metabolism, Cell Biology, 06 Biological Sciences, Peptidylprolyl Isomerase, Protein Structure, Tertiary, Enzyme Activation, Gene Expression Regulation, Neoplastic, NIMA-Interacting Peptidylprolyl Isomerase, Cell Transformation, Neoplastic, Gene Expression Regulation, Biologie cellulaire, Amyloid Precursor Protein Secretases, Tertiary, Receptor, Developmental Biology
Transcriptional Activation, Protein Structure, 3101 Biochemistry and cell biology, Transcriptional Activation -- genetics, Neoplastic -- genetics -- metabolism, Peptidylprolyl Isomerase -- genetics -- metabolism, breast cancer; Notch1; NICD, Cell Transformation, Amyloid Precursor Protein Secretases -- metabolism, Cell Line, breast cancer, NICD, Cell Line, Tumor, Neoplasms, Humans, Enzyme Activation -- genetics, Tertiary -- genetics, Receptor, Notch1, Neoplasms -- enzymology -- genetics -- physiopathology, 11 Medical and Health Sciences, Neoplastic -- genetics, Neoplastic, Notch1, Tumor, Amyloid Precursor Protein Secretases; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Peptidylprolyl Isomerase; Protein Structure, Tertiary; Receptor, Notch1; Transcriptional Activation; Cell Biology, Notch1 -- genetics -- metabolism, Cell Biology, 06 Biological Sciences, Peptidylprolyl Isomerase, Protein Structure, Tertiary, Enzyme Activation, Gene Expression Regulation, Neoplastic, NIMA-Interacting Peptidylprolyl Isomerase, Cell Transformation, Neoplastic, Gene Expression Regulation, Biologie cellulaire, Amyloid Precursor Protein Secretases, Tertiary, Receptor, Developmental Biology
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