EGFR signaling as a negative regulator of Notch1 gene expression : a differentiation/apoptosis control mechanism for proliferating keratinocytes and cancer cells

摘要

The Notch1 gene plays 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 signaling, 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 the 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 signaling 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 novel role of EGFR signaling in negative regulation of Notch1 gene transcription, of potential relevance for combinatory approaches of cancer therapy.