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Cross‐talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells
Author(s) -
Bianco Maria Rosaria,
Berbenni Miluscia,
Amara Flavio,
Viggiani Sandra,
Fragni Martina,
Galimberti Valentina,
Colombo Daniele,
Cirillo Giovanni,
Papa Michele,
Alberghina Lilia,
Colangelo Anna Maria
Publication year - 2011
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22665
Subject(s) - nerve growth factor , oxidative stress , programmed cell death , mitochondrion , endocrinology , biology , medicine , reactive oxygen species , cell cycle , microbiology and biotechnology , apoptosis , chemistry , biochemistry , receptor
Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)‐differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H 2 O 2 ‐induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (ΔΨm), increase in reactive oxygen species (ROS), and up‐regulation of cyclin D1 and phosphorylation (Ser‐780) of protein retinoblastoma (P‐pRb), without an increase of proliferation rates. Treatment with H 2 O 2 , but not NGF deprivation, also induced the phosporylation (Ser‐10) of p27 kip1 and the appearance of a cleaved P‐p27 kip1 fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H 2 O 2 ‐induced mitogenic responses appeared to be mediated by induction of P‐MAPK and P‐Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H 2 O 2 toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H 2 O 2 ‐induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF. © 2011 Wiley‐Liss, Inc.