Caspase-2 activation in neural stem cells undergoing oxidative stress-induced apoptosis.
Oxidative stress occurs as a consequence of disturbance in the balance between the generation of reactive oxygen species (ROS) and the antioxidant defence mechanisms. The interaction of ROS with DNA can cause single-, or double-strand breaks that subsequently can lead to the activation of p53, which is central for the regulation of cellular response, e.g. apoptosis, to a range of environmental and intracellular stresses. Previous reports have suggested a regulatory role of p53 in the early activation of caspase-2, upstream of mitochondrial apoptotic signaling. Here we show that excessive ROS formation, induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) exposure, induces apoptosis in primary cultured neural stem cells (NSCs) from cortices of E15 rat embryos. Following DMNQ exposure cells exhibited apoptotic hallmarks such as Bax oligomerization and activation, cytochrome c release, caspase activation and chromatin condensation. Additionally, we could show early p53 accumulation and a subsequent activation of caspase-2. The attenuation of caspase-2 activity with selective inhibitors could antagonize the mitochondrial signaling pathway and cell death. Overall, our results strongly suggest that DMNQ-induced oxidative stress causes p53 accumulation and consequently caspase-2 activation, which in turn initiates apoptotic cell death via the mitochondria-mediated caspase-dependent pathway in NSCs.
Tamm
Christoffer
C
Division of Toxicology and Neurotoxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden. christoffer.tamm@ki.se
Zhivotovsky
Boris
B
Ceccatelli
Sandra
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D009285:Naphthoquinones / Q000633:toxicity; D009474:Neurons / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D009285:Naphthoquinones; D016159:Tumor Suppressor Protein p53; C063002:2,3-dimethoxy-1,4-naphthoquinone; C490359:Casp2 protein, rat; D003546:Cysteine Endopeptidases