EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer (Nat Cell Biol, 2008, doi:10.1038/ncb1750)

報告日期: 2008/10/24
報告時間: 16:00/16:50
報告學生: 王冠傑
講評老師: 蔡少正
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971024-2.pdf

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

Vihren Kolev, Anna Mandinova, Juan Guinea-Viniegra, Bing Hu, Karine Lefort, Chiara Lambertini,Victor Neel, Reinhard Dummer, Erwin F. Wagner and G. Paolo Dotto

 

Nature Cell Biology,  June 2008

 

Speaker   : 王冠傑

Commentator : 蔡少正 老師

Date:  2008.10.24

Room: 602

 

Abstract:

Notch signalling provides an important form of intracellular communication        involved in cell fate determination, stem cell potential, differentiation and even tumor        formation. In human skin epithelial tissue, Notch1 gene acts as a positive regulator of keratinocyte differentiation. The upstream regulation of this gene is, however, yet to be elucidated. In this publication, the function of epidermal growth factor receptor (EGFR) in the negative control of Notch1 expression through p53-dependent mechanism was unveiled by chemical genetics and RNA interference. Increase in either p53 or Notch1 expression and induction of keratinocyte differentiation were found to linked to reduced EFGR signaling. These aforementioned phenomena were observed not only in primary human keratinocyte, but also in skin squamous cell carcinomas (SCCs). Furthermore, suppression of p53 activity by the c-Jun, an EGFR effector, is achieved by binding of c-Jun to the p53 promoter region. In the EGFR-dependent SOS-mouse skin tumor model, deletion of c-Jun resulted in significantly higher expression of p53 and Notch1 compared with the control group with intact c-Jun gene. Finally, suppression of EGFR and Notch1 signaling can synergistically enhance induction of apoptosis in SCCs. This work casts new light on  an effective combinatory therapeutic strategy for keratinocyte-derived cancer.

 

Reference  

1.    Lefort, K. & Dotto, G. P. Notch signaling in the integrated control of keratinocyte growth/ differentiation and tumor suppression. Semin. Cancer Biol. 14, 374–386 (2004).

2.    Lefort, K. et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKα kinases. Genes Dev. 21, 562–577 (2007).