EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer.
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.
Kolev
Vihren
V
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Mandinova
Anna
A
Guinea-Viniegra
Juan
J
Hu
Bing
B
Lefort
Karine
K
Lambertini
Chiara
C
Neel
Victor
V
Dummer
Reinhard
R
Wagner
Erwin F
EF
Dotto
G Paolo
GP
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors