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

Jeremy R. Stuart, Hidehiko Kawai, K. K C Tsai, Eric Y. Chuang, Zhi Min Yuan

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8085-8092
Number of pages8
JournalOncogene
Volume24
Issue number55
DOIs
Publication statusPublished - Dec 8 2005
Externally publishedYes

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Keywords

  • c-Abl
  • EGR1
  • Oxidative stress
  • Tyrosine kinase

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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