Article abstract
Nature Cell Biology 10, 902 - 911 (2008)
Published online: 6 July 2008 | doi:10.1038/ncb1750
EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer
Vihren Kolev1,6, Anna Mandinova1,6, Juan Guinea-Viniegra2, Bing Hu3, Karine Lefort3, Chiara Lambertini3, Victor Neel4, Reinhard Dummer5, Erwin F. Wagner2 & G. Paolo Dotto1,3,4
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.
- Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
- Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria.
- Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
- Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA.
- Department of Dermatology, University Hospital Zürich, Zürich CH-8091, Switzerland.
- These authors contributed equally to the work.
Correspondence to: G. Paolo Dotto1,3,4 e-mail: Gian-Paolo.Dotto@unil.ch
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive ratsKidney International Original Article
Prospective trials on anemia of chronic disease: The Trial to Reduce Cardiovascular Events with Aranesp ??? Therapy (TREAT)Kidney International Original Article
The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB responseThe EMBO Journal Article (23 Apr 2008)
See all 67 matches for Research
