Article
- The EMBO Journal (2006) 25, 1093 - 1103
- doi:10.1038/sj.emboj.7600987
Published online: 2 February 2006
Subject Categories:
Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras
Soon Young Shin1, Young Yil Bahk2, Jesang Ko3, Il-Yup Chung1, Young Seek Lee1, Julian Downward4, Hermann Eibel5, Prem M Sharma6, Jerrold M Olefsky6, Young-Ho Kim7, Bonghee Lee8 and Young Han Lee1
- Division of Molecular & Life Science, College of Science & Technology, Hanyang University, Ansan, Korea
- Protein Network Research Center, Yonsei University, Seoul, Korea
- School of Life Sciences and Biotechnology, Korea University, Seoul, Korea
- Cancer Research UK London Research Institute, London, UK
- University Hospital Freiburg, Freiburg, Germany
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, CA, USA
- Department of Microbiology, Kyungpook National University, Daegu, Korea
- Department of Anatomy and Neurobiology, College of Medicine, Institute of Medical Science, Cheju National University, Jeju, Korea
Correspondence to:
Young Han Lee, Division of Molecular & Life Science, College of Science & Technology, Hanyang University, Ansan 426-791, Korea. Tel.: +82 31 400 5517; Fax: +82 31 416 9781; E-mail: younghan@hanyang.ac.kr
Received 4 April 2005; Accepted 16 January 2006
Abstract
The transcription factor Egr-1 functions as a key regulator in cellular growth, differentiation, and apoptosis. The loss of Egr-1 expression is closely associated with tumor development, although the molecular mechanism behind the suppression of Egr-1 is largely unknown. In this report, we show that growth factor-induced transcriptional activation of Egr-1 gene is downregulated by chronic expression of oncogenic H-Ras in NIH3T3 fibroblasts. Our results demonstrate that phosphoinositide 3-kinase (PI3K) signaling is necessary for oncogenic H-Ras-mediated reduction of Egr-1 gene expression. Aberrant activation of PI3K signaling by oncogenic Ras decreased the level of serum response factor (SRF) protein through the acceleration of proteolysis, which resulted in decreased SRF binding to the serum response element (SRE) sites within the Egr-1 promoter, leading to the suppression of Egr-1 transcription. Inhibition of PI3K signaling restored the downregulation of SRF and Egr-1 expression caused by oncogenic Ras. Our findings suggest a novel signaling mechanism by which prolonged activation of oncogenic H-Ras can trigger the loss of tumor suppressor Egr-1 through the PI3K pathway in NIH3T3 fibroblast model cell lines.
Keywords:
- Egr-1,
- oncogenic H-Ras,
- phosphoinositide 3-kinase,
- serum response element,
- serum response factor
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