Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras

Young Shin Soon, Yil Bahk Young, Jesang Ko, Il Yup Chung, Seek Lee Young, Julian Downward, Hermann Eibel, Prem M. Sharma, Jerrold M. Olefsky, Young Ho Kim, Bonghee Lee, Han Lee Young

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41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1093-1103
Number of pages11
JournalEMBO Journal
Volume25
Issue number5
DOIs
Publication statusPublished - 2006 Mar 8

Keywords

  • Egr-1
  • Oncogenic H-Ras
  • Phosphoinositide 3-kinase
  • Serum response element
  • Serum response factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Soon, Y. S., Young, Y. B., Ko, J., Chung, I. Y., Young, S. L., Downward, J., Eibel, H., Sharma, P. M., Olefsky, J. M., Kim, Y. H., Lee, B., & Young, H. L. (2006). Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras. EMBO Journal, 25(5), 1093-1103. https://doi.org/10.1038/sj.emboj.7600987