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

Kolev, V., Mandinova, A., Guinea-Viniegra, Juan., Hu, B., Lefort, K., Lambertini, C., Neel, V., Dummer, R., Wagner, E. F., and Dotto, G. P. 

Nature Cell Biol. 10(8): 902-911, 2008

Speaker: 曾鈺芬                           Time: 14:00-15:00, Nov. 5, 2008

Commentator: 蕭璦莉老師                  Place: Room 601

Abstract:

     The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. The epidermis is composed of approximately 90% of keratinocytes. However, if the epidermis overexpresses EGFR, it may cause epithelial tumors.¹ The Notchgene was first characterized in Drosophila melanogaster, and Notch signaling is a determinant of keratinocyte differentiation. Recent clinical studies show that Notch1 gene expression and activity are positively regulated by p53 and substantially down-modulated in tumors.² In this study, the authors compared the effects of EGFR inhibition and stimulation on endogenous Notch signaling in human primary keratinocytes (HKCs). Notch1 mRNA level was increased by inhibition of EGFR, but down-regulated by EGF treatment. Transcription factor c-jun is a positive regulator of cell proliferation. It represses p53 and p21 expression and accelerates cell proliferation.³ Suppression of EGFR signalling induces Notch1 expression through suppression of c-jun and activating of p53. In the transgenic mice harboring a GFP reporter gene driven by a Notch/CBF-1 promoter, suppression of EGFR activity was found to cause an increase in p53, Notch1 and differentiation marker genes expression. Consist with the results of HKCs, the authors showed that in cancer cells (SCCs), induction of Notch1 expression by suppressing EGFR is p53-dependent. Moreover, Notch-dependent differentiation of keratinocytes renders the cells more resistant to apoptosis, which was demonstrated by suppressing Notch signaling and EGFR pathway, and resulted in enhanced apoptosis of SCCs. In summary, this paper reveals EGFR as a negative regulator of Notch signallingwhich is p53-dependent.

References:

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2.         Yugawa, T. et al. Regulation of Notch1 gene expression by p53 in epithelial cells. Molecular and cellular biology 27, 3732-3742 (2007).

3.         Schreiber, M. et al. Control of cell cycle progression by c-Jun is p53 dependent. Genes & development 13, 607-619 (1999)