title: Dissociation of JNK Activation from Elevated Levels of Reactive Oxygen Species, Cytochrome c Release, and Cell Death in NGF-Deprived Sympathetic Neurons.
abstract: Withdrawal of nerve growth factor (NGF) from sympathetic neurons causes their apoptotic death. Activation of c-Jun NH2-terminal kinase (JNK) may contribute to this death by the induction and phosphorylation of pro-apoptotic Bcl-2 proteins, such as Bax, that are involved in cytochrome c release from mitochondria and reactive oxygen species (ROS) production. Induction of either JNK or ROS may stimulate the other, and both may regulate release of apoptogenic factors from the mitochondria. In order to discern the relationship between JNK and ROS in apoptosis, we treated NGF-deprived, mouse sympathetic neurons with a JNK inhibitor and examined the effect on several important apoptotic events. Block of JNK activation prevented induction of c-Jun expression and resulted in a dose-dependent, yet surprisingly modest, increase in cell survival after 48 h of NGF deprivation. JNK suppression was also not sufficient to prevent the elevation in ROS or the release of cytochrome c from the mitochondria in NGF-deprived sympathetic neurons. Bax deletion prevents apoptotic death of NGF-deprived neurons by preventing release of cytochrome c from their mitochondria. It also prevents increased ROS on NGF deprivation. However, we found that induction of c-Jun in cells lacking Bax was equivalent to that in wild-type neurons. Our results suggest that while JNK activation plays an important role in many forms of apoptosis, it may not be a crucial regulator of Bax-dependent events involved in the apoptotic death of mouse sympathetic neurons deprived of NGF and that ROS is not involved in its activation in these cells.
authors.affiliation: Center of Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia's Colket Translational Research Building, 3501 Civic Center Blvd, Room 6100, Philadelphia, PA, 19104, USA.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McManus
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 357 Wilson Pharmacy, Athens, GA, 30602, USA. jfrankli@rx.uga.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Franklin
mesh_terms: D000320:Adrenergic Fibers / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000172:deficiency*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000378:metabolism* / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; Bax; Caspase; NGF; Reactive oxygen; Sympathetic neuron