Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C δ

Baojie Li, Xueying Wang, Naslin Rasheed, Yuanyu Hu, Sharon Boast, Tetsuro Ishii, Keiko Nakayama, Keiichi I. Nakayama, Stephen P. Golf

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

c-Abl and Atm have been implicated in cell responses to DNA damage and oxidative stress. However, the molecular mechanisms by which they regulate oxidative stress response remain unclear. In this report, we show that deficiency of c-Abl and deficiency of ATM differentially altered cell responses to oxidative stress by induction of antioxidant protein peroxiredoxin I (Prx I) via Nrf2 and cell death, both of which required protein kinase C (PKC) δ activation and were mediated by reactive oxygen species. c-abl-/- osteoblasts displayed enhanced Prx I induction, elevated Nrf2 levels, and hypersusceptibility to arsenate, which were reinstated by reconstitution of c-Abl; Atm-/- osteoblasts showed the opposite. These phenotypes correlated with increased PKC δ expression in c-abl-/- osteoblasts and decreased PKC δ expression in Atm-/- cells, respectively. The enhanced responses of c-abl-/- osteoblasts could be mimicked by overexpression of PKC δ in normal cells and impeded by inhibition of PKC δ, and diminished responses of Atm-/- cells could be rescued by PKC δ overexpression, indicating that PKC δ mediated the effects of c-Abl and ATM in oxidative stress response. Hence, our results unveiled a previously unrecognized mechanism by which c-Abl and Atm participate in oxidative stress response.

Original languageEnglish
Pages (from-to)1824-1837
Number of pages14
JournalGenes and Development
Volume18
Issue number15
DOIs
Publication statusPublished - Aug 1 2004

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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    Li, B., Wang, X., Rasheed, N., Hu, Y., Boast, S., Ishii, T., Nakayama, K., Nakayama, K. I., & Golf, S. P. (2004). Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C δ. Genes and Development, 18(15), 1824-1837. https://doi.org/10.1101/gad.1223504