Fatal shift of signal transduction is an integral part of neuronal differentiation: JNKs realize TNFalpha-mediated apoptosis in neuronlike, but not naive, PC12 cells.
Tumor necrosis factor-alpha (TNFalpha, 10-100 ng/ml) provokes a dramatic cell death in differentiated PC12 cells (dPC12), but it does not affect the viability and the proliferation of naive PC12 cells (nPC12). We have analyzed the molecular alterations of the TNFalpha-signal cascade underlying this developmental switch toward propagation of apoptosis. The transcriptional inhibitor actinomycin D rendered nPC12 responsive for TNFalpha-induced death, but was hardly effective in dPC12, suggesting that TNFalpha evokes its harmful action in dPC12 predominantly by posttranslational modification of existing molecules. This suggestion was supported by the finding that differentiation of PC12 per se went along with the increased expression of the proapoptotic TNFalpha-receptor I (p55) and its adapter protein Traf-2, whereas expression and phosphorylation of the antiapoptotic Akt (PKB) declined. We could demonstrate that the c-Jun N-terminal kinases (JNKs) mediate this enhanced capacity of apoptotic signaling in dPC12. TNFalpha induced in dPC12, but not nPC12, a biphasic activation of JNKs with a rapid transient JNK1 activation and a second persistent activation of JNK1 and JNK2 paralleled by phosphorylation of c-Jun; in contrast, TNFalpha did not activate p38 kinase. Block of JNKs by CEP-11004, a MLK antagonist and subsequently indirect inhibitor of JNK activation, or L-JNK11, a direct peptidergic inhibitor of JNK activity, almost completely rescued dPC12. Summarizing, the NGF-triggered formation of neurites during differentiation of PC12 includes the reinforced propensity for apoptosis, with JNK2 as the effector in JNK3-negative PC12. These findings offer novel insights into the increased risk of neuronal death, which is linked to the potential to regenerate.
Mielke
Kirsten
K
Institute of Pharmacology, Christian-Albrechts-University of Kiel, Hospitalstrasse 4, Germany.
Herdegen
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases