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EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and

Vihren Kolev1, Anna Mandinova, Juan Guinea-Viniegra

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.

Nature Cell Biology
|July 8, 2008
PubMed

Insights

Epidermal Growth Factor Receptor (EGFR) negatively regulates Notch1 gene expression, impacting cell fate and cancer. This discovery offers new therapeutic strategies for skin cancer by combining EGFR inhibitors with Notch pathway modulation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Dermatology

Background:

  • The Notch1 gene is crucial for mammalian cell-fate determination and tumorigenesis.
  • Mechanisms controlling Notch1 gene transcription remain largely unknown.
  • Epidermal Growth Factor Receptor (EGFR) signaling is implicated in various cancers, including skin.

Purpose of the Study:

  • To identify upstream regulators of Notch1 gene transcription.
  • To elucidate the role of EGFR in Notch1 regulation.
  • To explore the therapeutic implications of EGFR-Notch1 interactions in cancer.

Main Methods:

  • Chemical genetics screen for Notch signaling activators.
  • Analysis of Notch1 gene expression in human keratinocytes, epidermis, and squamous cell carcinomas (SCCs).
  • Investigation of EGFR-dependent skin carcinogenesis in a mouse model.

Main Results:

  • EGFR identified as a key negative regulator of Notch1 gene expression.
  • Mechanism involves EGFR-mediated transcriptional suppression of p53 by c-Jun.
  • Notch signaling suppression by EGFR counteracts EGFR inhibitor effects on differentiation but synergizes in apoptosis induction.

Conclusions:

  • EGFR signaling plays a critical role in the negative transcriptional regulation of Notch1.
  • Understanding this EGFR-Notch1 axis is relevant for developing combination cancer therapies.
  • Targeting EGFR and Notch signaling may offer synergistic benefits in cancer treatment, particularly for skin cancers.

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