title: CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults.
abstract: The c-Jun N-terminal kinase signaling cascade appears to play a role in some cases of cell death, including neuronal apoptosis. CEP-1347 (KT7515), an indolocarbazole of the K252a family, blocks this stress signaling cascade and promotes survival. Here, we used CEP-1347 to probe whether neuronal death pathways activated by distinct insults also possess elements in common. Cultured rat sympathetic neurons and neuronally differentiated PC12 cells were induced to die by withdrawal of nerve growth factor, exposure to ultraviolet irradiation, or subjection to oxidative stress. In each case, death was prevented by 100-200 nM CEP-1347. Moreover, in each of these death paradigms, c-Jun N-terminal kinase 1 activity in neuronally differentiated PC12 cells was elevated by two- or threefold, and this increase was totally blocked by CEP-1347 at concentrations that promoted survival. In contrast, 200 nM CEP-1347 did not block death due to serum withdrawal from undifferentiated PC12 cells or to activation of Fas in Jurkat T cell cultures, even though in each case c-Jun N-terminal kinase 1 activation occurred and was inhibited by CEP-1347. These observations suggest that some but not all death pathways triggered by different insults can include a common mechanistic component, a likely candidate for which is activation of the c-Jun N-terminal kinase signaling cascade.
authors.affiliation: Cephalon, West Chester, Pennsylvania 19380, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Maroney
authors.forename: J P
authors.initials: JP
authors.lastname: Finn
authors.forename: D
authors.initials: D
authors.lastname: Bozyczko-Coyne
authors.forename: T M
authors.initials: TM
authors.lastname: O'Kane
authors.forename: N T
authors.initials: NT
authors.lastname: Neff
authors.forename: A M
authors.initials: AM
authors.lastname: Tolkovsky
authors.forename: D S
authors.initials: DS
authors.lastname: Park
authors.forename: C Y
authors.initials: CY
authors.lastname: Yan
authors.forename: C M
authors.initials: CM
authors.lastname: Troy
authors.forename: L A
authors.initials: LA
authors.lastname: Greene
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005728:Ganglia, Sympathetic / Q000166:cytology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D019014:fas Receptor; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases