Location of Repository

IGF-I protects cortical neurons against ceramide-induced apoptosis via activation of the PI-3K/Akt and ERK pathways; is this protection independent of CREB and Bcl-2?

By S. Willaime-Morawek, N. Arbez, J. Mariani and B. Brugg


Current understanding of IGF-I-mediated neuroprotection implies the activation of phosphatidylinositol-3-kinase (PI-3K), which leads to the activation of Akt/Protein Kinase B. In non-neuronal cells, Akt phosphorylates and activates the transcription factor CREB, implicated in the transcription of the anti-apoptotic bcl-2 gene. This paper further analyses the anti-apoptotic IGF-I action in neurons. We show that IGF-I protects cortical neurons against ceramide-induced apoptosis. Ceramide decreases Akt phosphorylation during apoptotic process whereas a simultaneous treatment with IGF-I increases Akt phosphorylation. Analysis of the signal transduction pathways revealed that IGF-I induces CREB phosphorylation via PI-3K and ERK, whereas simultaneous ceramide and IGF-I treatment decreases CREB phosphorylation. Although an overexpression of Bcl-2 protects cortical neurons against ceramide-induced apoptosis, our data indicate that the Bcl-2 protein level is not modulated during IGF-I, ceramide and/or LY294002 treatment. In consequence, we demonstrated that IGF protects neurons against ceramide-induced apoptosis and that IGF-I protection involves the PI-3K/Akt and ERK pathways; this protection may be independent of CREB and Bcl-2

Topics: R1, RC0321
Year: 2005
OAI identifier: oai:eprints.soton.ac.uk:66440
Provided by: e-Prints Soton

Suggested articles



  1. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1,
  2. (1997). Characterization of a 3-phosphoinositidedependent protein kinase which phosphorylates and activates protein kinase Balpha,
  3. (1976). Tetrazolium salts and formazans,
  4. (1993). Selectivity of ceramide-mediated biology.
  5. (2002). Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest,
  6. (2001). Ten years of protein kinase B signalling: a hard Akt to follow,
  7. (1996). Ceramide induces apoptosis in cultured mesencephalic neurons,
  8. (2001). Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway,
  9. (1998). Regulation of cell death protease caspase-9 by phosphorylation,
  10. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery,
  11. (1999). Cellular survival: a play in three Akts,
  12. (2000). Specificity and mechanism of action of some commonly used protein kinase inhibitors,
  13. (1994). The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction,
  14. (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt,
  15. (1997). Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity,
  16. (1994). Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death,
  17. (1997). Regulation of neuronal survival by the serine-threonine protein kinase Akt [see comments],
  18. (2001). Differentiationassociated apoptosis of neural stem cells is effected by Bcl-2 overexpression: impact on cell lineage determination,
  19. (1997). Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson’s disease,
  20. (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase,
  21. (1993). The effects of IGF-1 treatment after hypoxic–ischemic brain injury in adult rats,
  22. (1996). Functions of ceramide in coordinating cellular responses to stress,
  23. (1997). Ceramide induces apoptosis in PC12 cells,
  24. (1994). Phosphatidylinositol 3-kinase,
  25. (1986). Cryopreservation of primary neurons for tissue culture, Brain Res.
  26. (1997). The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis,
  27. (1990). Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic \broblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II,
  28. (1994). The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling,
  29. (2002). Control of ceramideinduced apoptosis by IGF-1: involvement of PI-3 kinase, caspase-3 and catalase,
  30. (2001). Distinct phosphorylation patterns underlie Akt activation by different survival factors in neurons,
  31. (1999). Mechanisms of apoptosis in PC12 cells irreversibly differentiated with nerve growth factor and cyclic AMP, Brain Res.
  32. (2004). Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons,
  33. (1993). Insulin-like growth factor-I: potential for treatment of motor neuronal disorders,
  34. (1994). Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse,
  35. (1999). The role of cell surface attachment and proteolysis in the insulin-like growth factor (IGF)-independent effects of IGF-binding protein-3 on apoptosis in breast epithelial cells,
  36. (2005). transgenic mice protects neurons from naturally occurring cell death and experimental ischemia,
  37. (1998). Signal transduction of stress via ceramide,
  38. (1997). Inhibition of phosphatidylinositol 3-kinase activity blocks depolarization- and insulin-like growth factor I-mediated survival of cerebellar granule cells,
  39. (1998). Bipotential roles of ceramide in the growth of hippocampal neurons: promotion of cell survival and dendritic outgrowth in dose- and developmental stagedependent manners,
  40. (2000). Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus,
  41. (1993). Insulin-like growth factors: putative muscle-derived trophic agents that promote motoneuron survival,
  42. (1993). The MAP kinase cascade is essential for diverse signal transduction pathways,
  43. (1998). Linking extracellular survival signals and the apoptotic machinery,
  44. (1993). Programmed cell death induced by ceramide,
  45. (1992). Mitogen-activated protein kinases: versatile transducers for cell signaling,
  46. (1999). Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells. Involvement of p38 mitogen-activated protein kinase-mediated pathway,
  47. (1999). Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response elementbinding protein,
  48. (2000). Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein,
  49. (1998). Insulinlike growth factor-I prevents apoptosis in neurons after nerve growth factor withdrawal,
  50. (2000). Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells,
  51. (2000). Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473,
  52. (1963). Stra ¨uli, Studies on succinate-tetrazolium reductase systems,
  53. (1978). Acid and neutral sphingomyelinases of rat brain. Activity in developing brain and regional distribution in adult brain,
  54. (2003). Ceramideinduced neuronal apoptosis is associated with dephosphorylation of Akt,
  55. (1997). Insulin-like growth factor-1 attenuates apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats,
  56. (1997). Insulin-like growth factors prevent apoptosis in cortical neurons isolated from stroke-prone spontaneously hypertensive rats,
  57. (1998). Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors,
  58. (1998). A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A,
  59. (2001). Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation,
  60. (2003). C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis,
  61. (1997). Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked,
  62. (2000). Akt regulates cell survival and apoptosis at a postmitochondrial level,

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