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Carcinogenesis Advance Access published online on March 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn079
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Notch-1 Regulates Transcription of the Epidermal Growth Factor Receptor Through p53

Benjamin Purow1,7,*, Tilak K. Sundaresan3,4,7, Michael J. Burdick5, Benjamin Kefas1, Laurey Comeau1, Michael Hawkinson1, Qin Su6, Yuri Kotliarov2, Jeongwu Lee2, Wei Zhang2 and Howard A. Fine2

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.


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