Abstract
The extracellular signal-regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase that phosphorylates and regulates various transcription factors in response to growth factors and extracellular stresses. To address its biological function during the development of the peripheral nervous system (PNS), we have engineered a novel model of sympathetic neurons in which the erk5 gene can be deleted in vitro. Our data provide for the first time genetic evidence that ERK5 is required to mediate the survival response of neurons to nerve growth factor. Increased cell death associated with the loss of ERK5 is caused by elevated expression of the BH3-only members of the Bcl-2 family, Bad and Bim. Further investigation indicated that ERK5 suppresses the transcription of the bad and the bim genes by Ca(2+)/cAMP response element-binding protein and Forkhead box O3a, respectively. Consistently, we found that the phosphorylation of both p90 ribosomal S6 kinase and protein kinase B is impaired in neurons lacking ERK5. Together these findings reveal a novel signaling mechanism that promotes neuronal survival during the development of the PNS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenovirus E1A Proteins / metabolism
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Animals
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Animals, Newborn
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Survival
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Cell Transformation, Viral
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Cyclic AMP Response Element-Binding Protein / metabolism
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Developmental
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Membrane Proteins / metabolism
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Mice
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Mitogen-Activated Protein Kinase 7 / deficiency
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Mitogen-Activated Protein Kinase 7 / metabolism*
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Neurons / enzymology*
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Neurons / metabolism
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Peripheral Nervous System / enzymology
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Peripheral Nervous System / metabolism*
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Phosphorylation
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Signal Transduction
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bcl-Associated Death Protein / metabolism
Substances
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Adenovirus E1A Proteins
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Membrane Proteins
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Proto-Oncogene Proteins
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bcl-Associated Death Protein
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 90-kDa
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Mitogen-Activated Protein Kinase 7