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c-Abl regulates Early Growth Response Protein (EGR1) in response to oxidative stress

Oncogene volume 24, pages 8085–8092 (2005)Cite this article

Abstract

c-Abl is a tyrosine kinase that can act as a regulator of cell growth and apoptosis in response to stress. Using cell lines expressing c-Abl in an inducible manner, we identified genes whose expression was regulated by c-Abl kinase activity. Microarray analysis indicated that Early Growth Response-1 (EGR1) gene expression is induced by c-Abl kinase activity, which was confirmed at the message and protein levels. Promoter mapping experiments revealed that c-Abl utilizes three distal serum response elements (SREs) in the EGR1 promoter, which are transactivated by mitogen/extracellular receptor kinase (MEK/ERK) signaling. PD 95089, a specific inhibitor of MEK/ERK signaling, attenuated c-Abl-mediated upregulation of EGR1 expression in a dose-dependent manner. Similar results were obtained by using a dominant-negative mutant of mitogen/extracellular kinase. Significantly, hydrogen peroxide-induced EGR1 expression appears to be mediated by c-Abl, as cells expressing dominant negative c-Abl, and c-Abl−/− murine embryonic fibroblasts, are completely defective in hydrogen peroxide-induced EGR1 expression. In addition, c-Abl-induced apoptosis is partially mitigated by EGR1 activity, as cells devoid of EGR1 expression undergo reduced rates of c-Abl-induced apoptosis. Together, these results indicate that c-Abl promotes the induction of EGR1 through the MEK/ERK pathway in regulating apoptotic response to oxidative stress.

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Acknowledgements

We thank Dr Dan Mercola (Sidney Kimmel Research Center, San Diego, CA, USA) for providing EGR1 null and WT MEFs, Dr Kathleen Sakamoto (Department of Pediatrics, Division of Hematology/Oncology, School of Medicine, Los Angeles, CA, USA) for providing the EGR1 promoter, and Dr Anthony Koleske (Dept. Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA) for providing Abl null MEFs. We also thank Claire Bailey (Center for Genomics Research, Harvard University, Cambridge, MA, USA) for microarray and Q-RT-PCR analysis, and Colleen Dionne for manuscript preparation and submission. This work was supported by NIH grant R29 CA85679.

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Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, 02115, MA, USA

    Jeremy R Stuart, Hidehiko Kawai, Kelvin K C Tsai & Zhi-Min Yuan

  2. Radiation Oncology Branch, National Cancer Institute, Bethesda, 20892, MD, USA

    Eric Y Chuang

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Correspondence to Zhi-Min Yuan.

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Stuart, J., Kawai, H., Tsai, K. et al. c-Abl regulates Early Growth Response Protein (EGR1) in response to oxidative stress. Oncogene 24, 8085–8092 (2005). https://doi.org/10.1038/sj.onc.1208953

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