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Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip

Shilpi Arora1, Yipeng Wang12, Zhenyu Jia1, Saynur Vardar-Sengul13, Ayla Munawar1, Kutbuddin S Doctor4, Michael Birrer5, Michael McClelland2, Eileen Adamson1 and Dan Mercola1*

Author Affiliations

1 Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA

2 Sidney Kimmel Cancer Center, San Diego, CA 92121, USA

3 Department of Periodontology, School of Dentistry, Ege University, Bornova 35100, Izmir, Turkey

4 Burnham Institute for Medical Research, La Jolla, CA 92037, USA

5 National Institutes of Health; Cell and Cancer Biology Branch, National Cancer Institute, Bethesda, MD 20892, USA

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Genome Biology 2008, 9:R166  doi:10.1186/gb-2008-9-11-r166

Published: 25 November 2008

Abstract

Background

UV irradiation activates the epidermal growth factor receptor, induces Egr1 expression and promotes apoptosis in a variety of cell types. We examined the hypothesis that Egr1 regulates genes that mediate this process by use of a chip-on-chip protocol in human tumorigenic prostate M12 cells.

Results

UV irradiation led to significant binding of 288 gene promoters by Egr1. A major functional subgroup consisted of apoptosis related genes. The largest subgroup of 24 genes belongs to the epidermal growth factor receptor-signal transduction pathway. Egr1 promoter binding had a significant impact on gene expression of target genes. Conventional chromatin immunoprecipitation and quantitative real time PCR were used to validate promoter binding and expression changes. Small interfering RNA experiments were used to demonstrate the specific role of Egr1 in gene regulation. UV stimulation promotes growth arrest and apoptosis of M12 cells and our data clearly show that a downstream target of the epidermal growth factor receptor, namely Egr1, mediates this apoptotic response. Our study also identified numerous previously unknown targets of Egr1. These include FasL, MAX and RRAS2, which may play a role in the apoptotic response/growth arrest.

Conclusions

Our results indicate that M12 cells undergo Egr1-dependent apoptotic response upon UV stimulation and led to the identification of downstream targets of Egr1, which mediate epidermal growth factor receptor function.