Carcinogenesis Advance Access published online on March 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn079
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notch-1 Regulates Transcription of the Epidermal Growth Factor Receptor Through p53
1 Neuro-Oncology Division, Neurology Department, University of Virginia, Charlottesville, VA
2 Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
3 Robert Wood Johnson Medical School, New Brunswick, NJ
4 Howard Hughes Medical Institute/NIH Research Scholars Program
5 Cleveland Clinic Department of Radiation Oncology, Cleveland, OH
6 National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD
7 Contributed equally to this work
* Corresponding Author: Benjamin Purow, Contact telephone number: (434) 924-5545, Email: bwp5g{at}virginia.edu
The Notch pathway plays key roles in development and is increasingly recognized for its importance in cancer. We previously demonstrated over-expression of Notch-1 and its ligands in gliomas and showed their knockdown inhibits glioma cell proliferation and survival. To elucidate mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 siRNA. Notable among down-regulated transcripts was the epidermal growth factor receptor (EGFR), known to be over-expressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR mRNA and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 up-regulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development.
Key Words: Notch • EGFR • p53 • glioma
Received December 17, 2007; revised March 11, 2008; accepted March 14, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Li, F. Guessous, Y. Zhang, C. DiPierro, B. Kefas, E. Johnson, L. Marcinkiewicz, J. Jiang, Y. Yang, T. D. Schmittgen, et al. MicroRNA-34a Inhibits Glioblastoma Growth by Targeting Multiple Oncogenes Cancer Res., October 1, 2009; 69(19): 7569 - 7576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Meurette, S. Stylianou, R. Rock, G. M. Collu, A. P. Gilmore, and K. Brennan Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells Cancer Res., June 15, 2009; 69(12): 5015 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.J. Pierfelice, K.C. Schreck, C.G. Eberhart, and N. Gaiano Notch, Neural Stem Cells, and Brain Tumors Cold Spring Harb Symp Quant Biol, November 19, 2008; (2008) sqb.2008.73.013v2. [Abstract] [PDF]
|
|