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

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Serval ID
serval:BIB_1C2ED4311E24
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer.
Journal
Nature cell biology
Author(s)
Kolev V., Mandinova A., Guinea-Viniegra J., Hu B., Lefort K., Lambertini C., Neel V., Dummer R., Wagner E.F., Dotto G.P.
ISSN
1476-4679
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
10
Number
8
Pages
902-911
Language
english
Abstract
The Notch1 gene has an important role in mammalian cell-fate decision and tumorigenesis. Upstream control mechanisms for transcription of this gene are still poorly understood. In a chemical genetics screen for small molecule activators of Notch signalling, we identified epidermal growth factor receptor (EGFR) as a key negative regulator of Notch1 gene expression in primary human keratinocytes, intact epidermis and skin squamous cell carcinomas (SCCs). The underlying mechanism for negative control of the Notch1 gene in human cells, as well as in a mouse model of EGFR-dependent skin carcinogenesis, involves transcriptional suppression of p53 by the EGFR effector c-Jun. Suppression of Notch signalling in cancer cells counteracts the differentiation-inducing effects of EGFR inhibitors while, at the same time, synergizing with these compounds in induction of apoptosis. Thus, our data reveal a key role of EGFR signalling in the negative regulation of Notch1 gene transcription, of potential relevance for combinatory approaches for cancer therapy.
Keywords
Animals, Carcinoma, Squamous Cell, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Gene Expression Regulation, Humans, Keratinocytes, Mice, Receptor, Epidermal Growth Factor, Receptor, Notch1, Signal Transduction, Skin Neoplasms, Tumor Suppressor Protein p53
Pubmed
Create date
24/03/2009 15:00
Last modification date
20/08/2019 12:52
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