Neuroprotection by Brain-derived Neurotrophic Factor Is Mediated by Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase*

Apoptosis is a form of programmed cell death that plays a pivotal role during development and in the homeostasis of the adult nervous systems. However, mechanisms that regulate neuronal apoptosis are not well defined. Here, we report that brain-derived neurotrophic factor (BDNF) protects cortical neurons against apoptosis induced by camptothecin or serum deprivation and activates the extracellular-signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI 3-kinase) pathways. Using pharmacological agents and transient transfection with dominant interfering or constitutive active components of the ERK or the PI 3-kinase pathway, we demonstrate that the ERK pathway plays a major role in BDNF neuroprotection against camptothecin. Furthermore, ERK is activated in cortical neurons during camptothecin-induced apoptosis, and inhibition of ERK increases apoptosis. In contrast, the PI 3-kinase pathway is the dominant survival mechanism for serum-dependent survival under normal culture conditions and for BDNF protection against serum withdrawal. These results suggest that the ERK pathway is one of several neuroprotective mechanisms that are activated by stress to counteract death signals in central nervous system neurons. Furthermore, the relative contribution of the ERK and PI 3-kinase pathways to neuronal survival may depend on the type of cellular injury.

[1]  A. Tolkovsky,et al.  A Role for MAPK/ERK in Sympathetic Neuron Survival: Protection against a p53-Dependent, JNK-Independent Induction of Apoptosis by Cytosine Arabinoside , 1999, The Journal of Neuroscience.

[2]  David S. Park,et al.  Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents , 1998, The Journal of cell biology.

[3]  Scott T. Wong,et al.  Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation , 1998, Neuron.

[4]  M. Hanson,et al.  Depolarization and cAMP Elevation Rapidly Recruit TrkB to the Plasma Membrane of CNS Neurons , 1998, Neuron.

[5]  J C Reed,et al.  Mitochondria and apoptosis. , 1998, Science.

[6]  L. Greene,et al.  Prevention of PC12 Cell Death by N-Acetylcysteine Requires Activation of the Ras Pathway , 1998, The Journal of Neuroscience.

[7]  P. Fisher,et al.  Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells , 1998, Oncogene.

[8]  L. Facci,et al.  Neurotrophins Rescue Cerebellar Granule Neurons from Oxidative Stress‐Mediated Apoptotic Death: Selective Involvement of Phosphatidylinositol 3‐Kinase and the Mitogen‐Activated Protein Kinase Pathway , 1998, Journal of neurochemistry.

[9]  R. Crowder,et al.  Phosphatidylinositol 3-Kinase and Akt Protein Kinase Are Necessary and Sufficient for the Survival of Nerve Growth Factor-Dependent Sympathetic Neurons , 1998, The Journal of Neuroscience.

[10]  David S. Park,et al.  Multiple Pathways of Neuronal Death Induced by DNA-Damaging Agents, NGF Deprivation, and Oxidative Stress , 1998, The Journal of Neuroscience.

[11]  S. R. Datta,et al.  Molecular Mechanisms of Neuronal Survival and Apoptosis , 1998 .

[12]  S. Estus.  Gene Induction and Neuronal Apoptosis , 1998 .

[13]  M. Mattson.  Neuroprotective Signal Transduction , 1998, Nature Medicine.

[14]  T. Ikeuchi,et al.  Insulin Receptor Substrate (IRS)-1 and IRS-2 Are Tyrosine-phosphorylated and Associated with Phosphatidylinositol 3-Kinase in Response to Brain-derived Neurotrophic Factor in Cultured Cerebral Cortical Neurons* , 1997, The Journal of Biological Chemistry.

[15]  Yong Jiang,et al.  Characterization of the Structure and Function of the Fourth Member of p38 Group Mitogen-activated Protein Kinases, p38δ* , 1997, The Journal of Biological Chemistry.

[16]  M. Dragunow,et al.  Etoposide-induced PC12 cell death: apoptotic morphology without oligonucleosomal DNA fragmentation or dependency upon de novo protein synthesis. , 1997, Brain research. Molecular brain research.

[17]  R E Burke,et al.  Apoptosis in neurodegenerative disorders. , 1997, Current opinion in neurology.

[18]  M. Rothenberg.  Topoisomerase I inhibitors: review and update. , 1997, Annals of oncology : official journal of the European Society for Medical Oncology.

[19]  J. Tavaré,et al.  Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival. , 1997, The Biochemical journal.

[20]  M. Tansey,et al.  Inhibition of Phosphatidylinositol 3-Kinase Activity Blocks Depolarization- and Insulin-like Growth Factor I-mediated Survival of Cerebellar Granule Cells* , 1997, The Journal of Biological Chemistry.

[21]  A. Kay,et al.  Trophic Support of Cultured Spiral Ganglion Neurons by Depolarization Exceeds and Is Additive with that by Neurotrophins or cAMP and Requires Elevation of [Ca2+]i within a Set Range , 1997, The Journal of Neuroscience.

[22]  L. Greene,et al.  Nedd2 Is Required for Apoptosis after Trophic Factor Withdrawal, But Not Superoxide Dismutase (SOD1) Downregulation, in Sympathetic Neurons and PC12 Cells , 1997, The Journal of Neuroscience.

[23]  S. D’Mello,et al.  Insulin-Like Growth Factor and Potassium Depolarization Maintain Neuronal Survival by Distinct Pathways: Possible Involvement of PI 3-Kinase in IGF-1 Signaling , 1997, The Journal of Neuroscience.

[24]  Lewis C Cantley,et al.  PI3K: Downstream AKTion Blocks Apoptosis , 1997, Cell.

[25]  David S. Park,et al.  G1/S Cell Cycle Blockers and Inhibitors of Cyclin-Dependent Kinases Suppress Camptothecin-Induced Neuronal Apoptosis , 1997, The Journal of Neuroscience.

[26]  G. Evan,et al.  Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB , 1997, Nature.

[27]  David R. Kaplan,et al.  Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt , 1997, Science.

[28]  D. Leroith,et al.  Insulin-like Growth Factor 1 Inhibits Apoptosis Using the Phosphatidylinositol 3′-Kinase and Mitogen-activated Protein Kinase Pathways* , 1997, The Journal of Biological Chemistry.

[29]  J. Bockaert,et al.  Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38) Protects Cerebellar Granule Neurons from Apoptosis by Activating the Mitogen-Activated Protein Kinase (MAP Kinase) Pathway , 1997, The Journal of Neuroscience.

[30]  M. Chao,et al.  Trans-signaling by cytokine and growth factor receptors. , 1996, Cytokine & growth factor reviews.

[31]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[32]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[33]  A. Tolkovsky,et al.  Inhibition of p42 and p44 Mitogen‐Activated Protein Kinase Activity by PD98059 Does Not Suppress Nerve Growth Factor‐Induced Survival of Sympathetic Neurones , 1996, Journal of neurochemistry.

[34]  M. Greenberg,et al.  Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK-Dependent Mechanism , 1996, The Journal of Neuroscience.

[35]  J. Lawrence,et al.  Mitogen-activated Protein Kinase-independent Pathways Mediate the Effects of Nerve Growth Factor and cAMP on Neuronal Survival* , 1996, The Journal of Biological Chemistry.

[36]  F. Mcmorris,et al.  Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. , 1996, Development.

[37]  H. M. Geller,et al.  Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity , 1996, The Journal of cell biology.

[38]  G. Johnson,et al.  Fibroblast Growth Factor-2 Suppression of Tumor Necrosis Factor α-Mediated Apoptosis Requires Ras and the Activation of Mitogen-activated Protein Kinase* , 1996, Journal of Biological Chemistry.

[39]  A. Prochiantz,et al.  The contrasting roles of ICE family proteases and interleukin-1beta in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Qingbo Xu,et al.  Activation of Mitogen-activated Protein Kinase by HO , 1996, The Journal of Biological Chemistry.

[41]  M. Greenberg,et al.  Intracellular signaling pathways activated by neurotrophic factors. , 1996, Annual review of neuroscience.

[42]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[43]  D. Choi,et al.  Staurosporine-Induced Neuronal Apoptosis , 1995, Experimental Neurology.

[44]  H. Manev,et al.  Opposite Effect of Protein Synthesis Inhibitors on Potassium Deficiency‐Induced Apoptotic Cell Death in Immature and Mature Neuronal Cultures , 1995, Journal of neurochemistry.

[45]  A. Bridges,et al.  A synthetic inhibitor of the mitogen-activated protein kinase cascade. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Choi,et al.  Potentiated necrosis of cultured cortical neurons by neurotrophins. , 1995, Science.

[47]  W. Fantl,et al.  Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. , 1995, Science.

[48]  G. Cooper,et al.  Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. , 1995, Science.

[49]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[50]  L. Lindenboim,et al.  Inhibition of Drug‐Induced Apoptosis by Survival Factors in PC12 Cells , 1995, Journal of neurochemistry.

[51]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[52]  G L Johnson,et al.  Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. , 1994, Science.

[53]  N. Ahn,et al.  Transformation of mammalian cells by constitutively active MAP kinase kinase. , 1994, Science.

[54]  M E Greenberg,et al.  Requirement for BDNF in activity-dependent survival of cortical neurons. , 1994, Science.

[55]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[56]  M. Kasuga,et al.  PI 3‐kinase: structural and functional analysis of intersubunit interactions. , 1994, The EMBO journal.

[57]  S. D’Mello,et al.  Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[58]  B. Barres,et al.  Programmed cell death and the control of cell survival: lessons from the nervous system. , 1993, Science.

[59]  S. Green,et al.  PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity , 1992, Neuron.

[60]  R. Oppenheim.  Cell death during development of the nervous system. , 1991, Annual review of neuroscience.

[61]  R. Schreiber,et al.  Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death , 1990, Nature.

[62]  D. Martin,et al.  Cytosine arabinoside kills postmitotic neurons in a fashion resembling trophic factor deprivation: evidence that a deoxycytidine-dependent process may be required for nerve growth factor signal transduction , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[63]  Yves-Alain Barde,et al.  Trophic factors and neuronal survival , 1989, Neuron.

[64]  M. Hansen,et al.  Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. , 1989, Journal of immunological methods.

[65]  J. Cherrington,et al.  Human cytomegalovirus ie1 transactivates the alpha promoter-enhancer via an 18-base-pair repeat element , 1989, Journal of virology.

[66]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[67]  LA Greene,et al.  Nerve growth factor prevents the death and stimulates the neuronal differentiation of clonal PC12 pheochromocytoma cells in serum-free medium , 1978, The Journal of cell biology.

[68]  R. Levi‐montalcini,et al.  Destruction of the sympathetic ganglia in mammals by an antiserum to a nerve-growth protein* , 1960, Proceedings of the National Academy of Sciences.