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

Alessandra Rustighi1, Luca Tiberi, Alessia Soldano

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

Nature Cell Biology
|January 20, 2009
PubMed

Insights

The prolyl-isomerase Pin1 enhances Notch1 activation in breast cancer by promoting its cleavage. This interaction creates a positive feedback loop, increasing Notch1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signalling

Background:

  • Notch1 signalling is crucial for normal development but its deregulation is linked to mammary tumorigenesis.
  • The precise mechanisms of Notch activation in breast cancer are not fully understood.

Purpose of the Study:

  • To investigate the role of prolyl-isomerase Pin1 in Notch1 activation and its implications in breast cancer.

Main Methods:

  • Co-immunoprecipitation assays to detect Pin1-Notch1 interaction.
  • Gamma-secretase cleavage assays to measure Notch1 activation.
  • Reporter assays to assess transcriptional activity.
  • Analysis of human breast cancer samples for Pin1 and activated Notch1 levels.

Main Results:

  • Pin1 directly interacts with Notch1.
  • Pin1 potentiates Notch1 cleavage by gamma-secretase, increasing the release of the active intracellular domain.
  • Notch1 induces Pin1 transcription, establishing a positive feedback loop.
  • Overexpression of Pin1 correlates with high levels of activated Notch1 in human breast cancers.

Conclusions:

  • The Pin1-Notch1 interaction enhances Notch1 transcriptional and tumorigenic activity.
  • The molecular circuitry involving Notch1 and Pin1 plays a significant role in breast cancer progression.

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