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P53 - Dependent apoptosis induced by DNA damage and its relation to ERK signalling in sympathetic neurones

, : P53 - Dependent apoptosis induced by DNA damage and its relation to ERK signalling in sympathetic neurones. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 147 3

DNA damaging drugs induce a dominant p53-dependent apoptotic pathway in neurones of the superior cervival ganglion (SCG) in the presence of the nerve growth factor (NGF). The MEK/ERK1/2 signalling module induced by NGF protects against this apoptotic pathway. In contrast protection against trophic factor withdrawal (no NGF) is mediated by the PI3K/Akt signalling module. The regulation of the p53-dependent apoptotic pathway and its relation to ERK signalling is unknown. Therefore we characterized the regulation of p53 and its responsive genes in newly isolated SCG neurones. Cytosine arabinoside (AraC) and etoposide induced only a weak transcriptional induction of p53 followed by a upregulation of the p53-responsive genes mdm2, p21, Noxa and PUMA, but not Bax. AraC/etoposide mediated apoptosis was both p53 and Bax dependent. ERK1/2 inhibition lead to an increase in apoptosis in p53 and Bax containing neurones, but not in p53 and Bax knockout neurones. Because p53 and Bax have been implicated in oxidative stress occurring during apoptosis we investigated whether DNA damaging drugs induce oxidative stress in these neurones. Apoptosis induced by AraC/etoposide could be suppressed by antioxidant compounds and neurones exposed to AraC (1 millimolar) produced more reactive oxygen species (ROS) than control cells as measured with the oxidation sensitive dye CM-H2DCFDA. The increase in ROS (2-4 hours after AraC addition) occurred in parallel with an increase of p53 protein and p53 phosphorylation at Serine 15. Both increase of ROS and upregulation of p53 preceded signs of apoptosis (12-15 hours). The chemical ERK1/2 inhibitor U0126 (10 micromolar) did not modulate ROS production due to AraC and therefore the protective action of ERK1/2 is likely to occur downstream of ROS and p53 induction.


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