Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.

[1]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[2]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[3]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[4]  R. Davis,et al.  MAPKs: new JNK expands the group. , 1994, Trends in biochemical sciences.

[5]  A. Sharrocks,et al.  Integration of MAP kinase signal transduction pathways at the serum response element. , 1995, Science.

[6]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[7]  Natalie G. Ahn,et al.  The MAP kinase cascade. Discovery of a new signal transduction pathway. , 1993 .

[8]  A. Ashworth,et al.  An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1 , 1995, Science.

[9]  R. Rose,et al.  Glucocorticoid receptor binding in three different cell types in major depressive disorder: Lack of evidence op receptor binding defect , 1992, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[10]  I. Herr,et al.  ATF‐2 is preferentially activated by stress‐activated protein kinases to mediate c‐jun induction in response to genotoxic agents. , 1995, The EMBO journal.

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

[12]  Masahiko Hibi,et al.  JNK is involved in signal integration during costimulation of T lymphocytes , 1994, Cell.

[13]  M. Raff,et al.  Programmed cell death and Bcl‐2 protection in the absence of a nucleus. , 1994, The EMBO journal.

[14]  J. Tavaré,et al.  Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen‐activated protein kinase , 1994, FEBS letters.

[15]  Y. Hannun,et al.  Programmed cell death induced by ceramide. , 1993, Science.

[16]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[17]  L. Rubin,et al.  A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death , 1995, Neuron.

[18]  L. Greene,et al.  The role of transcription-dependent priming in nerve growth factor promoted neurite outgrowth. , 1982, Developmental biology.

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

[20]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[21]  C. Dinarello,et al.  The biological properties of interleukin-1. , 1994, European cytokine network.

[22]  L. Butcher,et al.  Induction of apoptosis by the low-affinity NGF receptor. , 1993, Science.

[23]  R. Kolesnick,et al.  The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling , 1994, Cell.

[24]  J. John,et al.  ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons , 1989, Neuron.

[25]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[26]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

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

[28]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[29]  S. Ho,et al.  Site-directed mutagenesis by overlap extension using the polymerase chain reaction. , 1989, Gene.

[30]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[31]  M. Karin,et al.  Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. , 1993, Genes & development.

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

[33]  M. Greenberg,et al.  Nerve growth factor and epidermal growth factor induce rapid transient changes in proto-oncogene transcription in PC12 cells. , 1985, The Journal of biological chemistry.

[34]  E. Van Obberghen,et al.  Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells. , 1994, The Journal of biological chemistry.

[35]  C. Lange-Carter,et al.  A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf , 1993, Science.

[36]  L. Greene,et al.  Internucleosomal DNA cleavage and neuronal cell survival/death , 1993, The Journal of cell biology.

[37]  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.

[38]  J C Mills,et al.  A system for characterizing cellular and molecular events in programmed neuronal cell death , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  L. Greene,et al.  Aurintricarboxylic acid rescues PC12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity , 1991, The Journal of cell biology.

[40]  E. Krebs,et al.  The MAP kinase cascade. , 1995, Recent progress in hormone research.

[41]  A. Tolkovsky,et al.  Expression of the Cyclic AMP‐dependent Protein Kinase (PKA) Catalytic Subunit from a Herpes Simplex Virus Vector Extends the Survival of Rat Sympathetic Neurons in the Absence of NGF , 1994, The European journal of neuroscience.

[42]  Peter Angel,et al.  The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1 , 1988, Cell.

[43]  H. K. Sluss,et al.  Signal transduction by tumor necrosis factor mediated by JNK protein kinases , 1994, Molecular and cellular biology.

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

[45]  S. Grant,et al.  Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

[47]  L. Zon,et al.  Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 , 1994, Nature.

[48]  J. Boonstra,et al.  Ionic responses and growth stimulation induced by nerve growth factor and epidermal growth factor in rat pheochromocytoma (PC12) cells , 1983, The Journal of cell biology.

[49]  T. Hunter,et al.  Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling , 1995, Cell.

[50]  J. Blenis,et al.  Signal transduction via the MAP kinases: proceed at your own RSK. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[51]  M. Greenberg,et al.  Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras , 1994, Neuron.

[52]  R. Davis,et al.  The mitogen-activated protein kinase signal transduction pathway. , 1993, The Journal of biological chemistry.

[53]  T. Sturgill,et al.  Rapid stimulation by insulin of a serine/threonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Estus,et al.  Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis , 1994, The Journal of cell biology.

[55]  L. Greene,et al.  Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[56]  I. Tsigelny,et al.  JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. , 1994, Genes & development.

[57]  D. Burstein,et al.  Activated N‐ras gene induces neuronal differentiation of PC12 rat pheochromocytoma cells , 1986, Journal of cellular physiology.

[58]  A. Saltiel,et al.  Nerve growth factor stimulates a protein kinase in PC-12 cells that phosphorylates microtubule-associated protein-2. , 1990, The Journal of biological chemistry.

[59]  L. Greene,et al.  Multiple agents rescue PC12 cells from serum-free cell death by translation- and transcription-independent mechanisms , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[60]  J. Fawcett,et al.  Regressive events in neurogenesis. , 1984, Science.

[61]  M. Birrer,et al.  Transformation by Raf and other oncogenes renders cells differentially sensitive to growth inhibition by a dominant negative c-jun mutant. , 1994, Oncogene.

[62]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[63]  H. Steller.  Mechanisms and genes of cellular suicide , 1995, Science.

[64]  G. Ferrari,et al.  Gangliosides rescue neuronal cells from death after trophic factor deprivation , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[65]  John Calvin Reed,et al.  Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA , 1993, Nature.

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

[67]  M. Cobb,et al.  ERKs, extracellular signal-regulated MAP-2 kinases. , 1991, Current opinion in cell biology.

[68]  N. Jones,et al.  ATF‐2 contains a phosphorylation‐dependent transcriptional activation domain. , 1995, The EMBO journal.

[69]  R. Dobrowsky,et al.  Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. , 1994, Science.

[70]  P. W. Mesner,et al.  Nerve growth factor withdrawal-induced cell death in neuronal PC12 cells resembles that in sympathetic neurons , 1992, The Journal of cell biology.

[71]  E. Nishida,et al.  Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. , 1990, European journal of biochemistry.

[72]  C. Marshall,et al.  Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells , 1994, Cell.

[73]  T. Sturgill,et al.  Recent progress in characterization of protein kinase cascades for phosphorylation of ribosomal protein S6. , 1991, Biochimica et biophysica acta.

[74]  A. Wittinghofer,et al.  Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons , 1993, The Journal of cell biology.

[75]  G. Barrett,et al.  The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[76]  G. Dickens,et al.  The neurite-promoting effect of fibroblast growth factor on PC12 cells. , 1983, Biochemical and biophysical research communications.

[77]  K. Teng,et al.  Depolarization maintains neurites and priming of PC12 cells after nerve growth factor withdrawal , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[78]  R. Davis,et al.  An osmosensing signal transduction pathway in mammalian cells. , 1994, Science.

[79]  S. Green,et al.  NGF and EGF rapidly activate p21 ras in PC12 cells by distinct, convergent pathways involving tyrosine phosphorylation , 1991, Neuron.