Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta.
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) delta 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 delta expression in c-abl-/- osteoblasts and decreased PKC delta expression in Atm-/- cells, respectively. The enhanced responses of c-abl-/- osteoblasts could be mimicked by overexpression of PKC delta in normal cells and impeded by inhibition of PKC delta, and diminished responses of Atm-/- cells could be rescued by PKC delta overexpression, indicating that PKC delta 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.
Institute of Molecular and Cell Biology, Proteos Singapore 138673. libj@imcb.nus.edu.sg
Baojie
B
Li
Xueying
X
Wang
Naslin
N
Rasheed
Yuanyu
Y
Hu
Sharon
S
Boast
Tetsuro
T
Ishii
Keiko
K
Nakayama
Keiichi I
KI
Nakayama
Stephen P
SP
Goff
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001149:Arsenates / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006540:Herbicides / Q000494:pharmacology; D006720:Homozygote; D016350:Leucine Zippers; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010544:Peroxidases / Q000378:metabolism; D054464:Peroxiredoxins; D010641:Phenotype; D010741:Phospholipases A / Q000378:metabolism; D011493:Protein Kinase C / Q000172:deficiency / Q000494:pharmacology*; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D000975:Antioxidants; D001149:Arsenates; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006540:Herbicides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010544:Peroxidases; D054464:Peroxiredoxins; C497259:Prkcd protein, mouse; D016315:Proto-Oncogene Proteins c-abl; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D010741:Phospholipases A; C025657:arsenic acid