Skip to main content
Article thumbnail
Location of Repository

C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

By S. Willaime-Morawek, K. Brami-Cherrier, J. Mariani, J. Caboche and B. Brugg


Understanding the regulation of the apoptotic program<br/>in neurons by intracellular pathways is currently a subject<br/>of great interest. Recent results suggest that c-Jun N-terminal<br/>kinases (JNK), mitogen-activated protein kinases<br/>and the transcription factor c-Jun are important regulators of<br/>this cell death program in post-mitotic neurons following<br/>survival-factor withdrawal. Our study demonstrates that ceramide levels increase upon survival-factor withdrawal in primary cultured cortical neurons. Furthermore, survival-factor<br/>withdrawal or addition of exogenous c2-ceramide induces<br/>JNK pathway activation in these cells. Western blot analyses<br/>of JNK and c-Jun using phospho-specific antibodies reveal<br/>that JNK and subsequent c-Jun phosphorylation occur hours<br/>before the initiation of apoptosis, reflected morphologically<br/>by neurite retraction and fragmentation, cell-body shrinkage<br/>and chromatin fragmentation. Immunocytochemistry using<br/>the same antibodies shows that phospho-JNK are localized<br/>in the neurites of control neurons and translocate to the<br/>nucleus where phospho-c-Jun concurrently appears upon<br/>ceramide-induced apoptosis. To determine if ceramide-induced<br/>c-Jun activation is responsible for the induction of the<br/>apoptotic program, we performed transient transfections of a<br/>dominant negative form of c-Jun, truncated in its transactivation<br/>region. Our results show that DNc-Jun partially protects<br/>cortical neurons from ceramide-induced apoptosis.<br/>Treatment of dominant negative c-Jun-expressing neurons<br/>with the pharmacological inhibitor of p38 kinase, SB203580,<br/>completely blocked neuronal death. Thus our data show that<br/>p38 and JNK/c-Jun pathways cooperate to induce neuronal<br/>apoptosis

Topics: R1, RC0321
Year: 2003
OAI identifier:
Provided by: e-Prints Soton

Suggested articles


  1. (1995). A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death.
  2. (1997). A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stressinduced activation of the p38 and JNK pathways.
  3. (1997). A novel mechanism of JNK1 activation: nuclear translocation and activation of JNK1 during ischemia and reperfusion.
  4. (1998). A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system.
  5. (1978). Acid and neutral sphingomyelinases of rat brain: activity in developing brain and regional distribution in adult brain.
  6. (1996). Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.
  7. (2001). Activation and redistribution of c-Jun N-terminal kinase/ stress activated protein kinase in degenerating neurons in Alzheimer’s disease.
  8. (2003). Activation of mitogen-activated protein kinase pathways during the death of PC12 cells is dependent on the state of differentiation.
  9. (1994). Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis.
  10. (1999). Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation.
  11. (2000). Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N- terminal protein kinase 3 and p38 mitogen-activated protein kinase.
  12. (1999). ASK1 mediates apoptotic cell death induced by genotoxic stress.
  13. (2001). Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.
  14. (1998). Bipotential roles of ceramide in the growth of hippocampal neurons: promotion of cell survival and dendritic outgrowth in dose- and developmental stagedependent manners.
  15. (2000). c-Jun and the transcriptional control of neuronal apoptosis.
  16. (2001). c-Jun mediates axotomy-induced dopamine neuron death in vivo.
  17. (2002). c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons.
  18. (2001). Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts.
  19. (2001). Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family.
  20. (1996). Ceramide induces apoptosis in cultured mesencephalic neurons.
  21. (1997). Ceramide induces apoptosis in PC12 cells.
  22. (1995). Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals.
  23. (2001). Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation.
  24. (1992). Changes in bioactive lipids, alkylacylglycerol and ceramide, occur in HIV-infected cells.
  25. (1986). Cryopreservation of primary neurons for tissue culture.
  26. (2001). Dominantnegative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release.
  27. (2000). Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons.
  28. (1997). Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153.
  29. (2001). Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis.
  30. (2000). JNK and p38 stress kinases: degenerative effectors of signal- transduction-cascades in the nervous system. Prog Neurobiol 61:45–60.
  31. (1998). Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N- terminal kinases after neuronal injury.
  32. (2000). Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus.
  33. (1999). MechaS. Willaime-Morawek et al.
  34. (1997). Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson’s disease.
  35. (1997). Nuclear translocation of NFkappaB is increased in dopaminergic neurons of patients with parkinson disease.
  36. (2000). p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.
  37. (2000). p38 Mitogen-activated protein kinase mediates Bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen, but not by hydrogen peroxide.
  38. (1998). Phosphorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons.
  39. (1998). Positive feedback control of neutral sphingomyelinase activity by ceramide.
  40. (1993). Programmed cell death induced by ceramide.
  41. (2000). Regulation of fas ligand expression during activation-induced cell death in T cells by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase.
  42. (1998). SB202190, a selective inhibitor of p38 mitogen-activated protein kinase, is a powerful regulator of LPS-induced mRNAs in monocytes.
  43. (1990). Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II.
  44. (1996). Selective interaction of JNK protein kinase isoforms with transcription factors.
  45. (1993). Selectivity of ceramide-mediated biology: lack of activity of erythrodihydroceramide.
  46. (2000). Signal transduction by the JNK group of MAP kinases.
  47. (1998). Signal transduction of stress via ceramide.
  48. (1963). Stra ¨uli U
  49. (1997). TAK1 mediates the ceramide signaling to stress activated potein kinase/c-Jun N-terminal kinase.
  50. (1976). Tetrazolium salts and formazans. Prog Histochem Cytochem 9:1–56.
  51. (1997). The c-Jun transcription factor: bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 20:227–231.
  52. (1988). The jun proto-oncogene is positively autoregulated by its product,
  53. (1997). The mode of ceramide action: the alkyl chain protrusion model. Cytokine Growth Factor Rev 8:103–107.
  54. (1999). Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.