Targeting of the c-Abl tyrosine kinase to mitochondria in the necrotic cell death response to oxidative stress.
The ubiquitously expressed c-Abl tyrosine kinase is activated in the response of cells to genotoxic and oxidative stress. The present study demonstrates that reactive oxygen species (ROS) induce targeting of c-Abl to mitochondria. We show that ROS-induced localization of c-Abl to mitochondria is dependent on activation of protein kinase C (PKC)delta and the c-Abl kinase function. Targeting of c-Abl to mitochondria is associated with ROS-induced loss of mitochondrial transmembrane potential. The results also demonstrate that c-Abl is necessary for ROS-induced depletion of ATP and the activation of a necrosis-like cell death. These findings indicate that the c-Abl kinase targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death.
Kumar
S
S
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bharti
A
A
Mishra
N C
NC
Raina
D
D
Kharbanda
S
S
Saxena
S
S
Kufe
D
D
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D016313:Genes, abl / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007425:Intracellular Membranes / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D007527:Isoenzymes; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D006861:Hydrogen Peroxide; C497259:Prkcd protein, mouse; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta