Abstract
To determine which intracellular pathways mediate the survival effects of ciliary neurotrophic factor and cardiotrophin-1 cytokines on motoneurons, we studied the activation of the Jak/STAT, the PI 3-kinase/Akt, and the ERK pathways. At shorter time points, cytokines induced the activation of STAT3 and ERK, but not PI 3-kinase. Jak3 inhibitor suppressed cytokine- and muscle extract-induced survival. In contrast, PD 98059, a MEK inhibitor, was not able to prevent cytokine-induced survival, demonstrating that ERK is not involved. Surprisingly, the PI 3-kinase inhibitor LY 294002 prevented the survival-promoting effects of cytokines. When assays of PI 3-kinase activity were performed at later stages following cytokine treatment a significant increase was observed compared to control cultures. This delayed increase of activity could be completely prevented by treatment with protein synthesis or Jak3 inhibitors. Collectively, these results demonstrate that cytokines induce motoneuron survival through a PI 3-kinase activation requiring de novo protein synthesis dependent on Jak pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Brain-Derived Neurotrophic Factor / metabolism
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Brain-Derived Neurotrophic Factor / pharmacology
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Cell Survival / drug effects
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Cell Survival / physiology*
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Cells, Cultured
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Chick Embryo
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Ciliary Neurotrophic Factor / metabolism
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Ciliary Neurotrophic Factor / pharmacology
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Cytokines / metabolism*
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Cytokines / pharmacology
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Glial Cell Line-Derived Neurotrophic Factor
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Hepatocyte Growth Factor / metabolism
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Hepatocyte Growth Factor / pharmacology
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Immunohistochemistry
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Janus Kinase 1
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Janus Kinase 3
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Motor Neurons / cytology
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Motor Neurons / drug effects
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Motor Neurons / metabolism*
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Muscle, Skeletal / metabolism
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Nerve Growth Factors*
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / pharmacology
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Spinal Cord / cytology
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Spinal Cord / embryology*
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Spinal Cord / growth & development
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Trans-Activators / drug effects
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Trans-Activators / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Ciliary Neurotrophic Factor
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Cytokines
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DNA-Binding Proteins
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Enzyme Inhibitors
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Glial Cell Line-Derived Neurotrophic Factor
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Nerve Growth Factors
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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Trans-Activators
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Hepatocyte Growth Factor
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cardiotrophin 1
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Protein-Tyrosine Kinases
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Janus Kinase 1
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Janus Kinase 3
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases