Notch-1 regulates transcription of the epidermal growth factor receptor through p53

Benjamin W. Purow, Tilak K. Sundaresan, Michael J. Burdick, Benjamin A. Kefas, Laurey D. Comeau, Michael P. Hawkinson, Qin Su, Yuri Kotliarov, Jeongwu Lee, Wei Zhang, Howard A. Fine

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Abstract

The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (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 upregulates 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.

Original languageEnglish (US)
Pages (from-to)918-925
Number of pages8
JournalCarcinogenesis
Volume29
Issue number5
DOIs
StatePublished - May 1 2008

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Epidermal Growth Factor Receptor
Glioma
Cell Line
Null Lymphocytes
Neoplasms
Messenger RNA
Small Interfering RNA
Transfection
Cell Survival
Up-Regulation
Down-Regulation
Cell Proliferation
Ligands
Proteins

ASJC Scopus subject areas

  • Cancer Research

Cite this

Purow, B. W., Sundaresan, T. K., Burdick, M. J., Kefas, B. A., Comeau, L. D., Hawkinson, M. P., ... Fine, H. A. (2008). Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis, 29(5), 918-925. https://doi.org/10.1093/carcin/bgn079

Notch-1 regulates transcription of the epidermal growth factor receptor through p53. / Purow, Benjamin W.; Sundaresan, Tilak K.; Burdick, Michael J.; Kefas, Benjamin A.; Comeau, Laurey D.; Hawkinson, Michael P.; Su, Qin; Kotliarov, Yuri; Lee, Jeongwu; Zhang, Wei; Fine, Howard A.

In: Carcinogenesis, Vol. 29, No. 5, 01.05.2008, p. 918-925.

Research output: Contribution to journalArticle

Purow, BW, Sundaresan, TK, Burdick, MJ, Kefas, BA, Comeau, LD, Hawkinson, MP, Su, Q, Kotliarov, Y, Lee, J, Zhang, W & Fine, HA 2008, 'Notch-1 regulates transcription of the epidermal growth factor receptor through p53', Carcinogenesis, vol. 29, no. 5, pp. 918-925. https://doi.org/10.1093/carcin/bgn079
Purow BW, Sundaresan TK, Burdick MJ, Kefas BA, Comeau LD, Hawkinson MP et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis. 2008 May 1;29(5):918-925. https://doi.org/10.1093/carcin/bgn079
Purow, Benjamin W. ; Sundaresan, Tilak K. ; Burdick, Michael J. ; Kefas, Benjamin A. ; Comeau, Laurey D. ; Hawkinson, Michael P. ; Su, Qin ; Kotliarov, Yuri ; Lee, Jeongwu ; Zhang, Wei ; Fine, Howard A. / Notch-1 regulates transcription of the epidermal growth factor receptor through p53. In: Carcinogenesis. 2008 ; Vol. 29, No. 5. pp. 918-925.
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