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

  1. Baojie Li1,6,
  2. Xueying Wang1,
  3. Naslin Rasheed1,
  4. Yuanyu Hu1,
  5. Sharon Boast2,5,
  6. Tetsuro Ishii3,
  7. Keiko Nakayama4,
  8. Keiichi I. Nakayama4, and
  9. Stephen P. Goff2
  10. 1Institute of Molecular and Cell Biology, Proteos Singapore 138673; 2Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA; 3Institute of Community medicine, University of Tsukuba, Ibaraki 305-8575, Japan; 4Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

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.

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