Abstract
The elevation of intracellular cAMP synergistically enhances the neuregulin-dependent proliferation of cultured Schwann cells (SCs); however, the mechanism by which this occurs has not been completely defined. To better understand this mechanism, we investigated the effect of cAMP on the activation of the extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)-Akt (PKB) pathways by heregulin, a member of the neuregulin family. Using primary cultures of adult SCs, we demonstrated that the adenylyl cyclase activator, forskolin, enhanced heregulin-dependent SC proliferation by reducing the time required for S-phase entry. When cAMP levels were increased, using either forskolin or a cell permeable analogue of cAMP, the heregulin-induced phosphorylation of ERK was converted from transient to sustained and the heregulin-induced phosphorylation of Akt was synergistically increased. Consistent with these observations, studies in which inhibitors of MEK, the upstream stimulating ERK kinase, and PI3-K were administered at different times following the onset of stimulation indicated that sustained high levels of both MEK/ERK and PI3-K/Akt activity before S-phase initiation were essential for S-phase entry. Overall, these novel results indicate that in neuregulin-stimulated SCs the activation of cAMP-mediated pathways accelerates G1-S progression by prolonging ERK activation and concurrently enhancing Akt activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / drug effects
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Adenylyl Cyclases / metabolism
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Animals
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Cell Cycle / drug effects
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Cell Cycle / physiology*
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Cell Proliferation / drug effects
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP / metabolism*
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Cyclic AMP / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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G1 Phase / drug effects
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G1 Phase / physiology
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Genes, cdc / drug effects
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Genes, cdc / physiology
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Humans
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Intracellular Fluid / drug effects
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Intracellular Fluid / enzymology
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / metabolism
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / metabolism*
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Neuregulin-1
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Oncogene Protein v-akt / drug effects
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Oncogene Protein v-akt / metabolism*
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Rats
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S Phase / drug effects
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S Phase / physiology
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Schwann Cells / drug effects
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Schwann Cells / enzymology*
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Enzyme Inhibitors
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NRG1 protein, human
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Nerve Tissue Proteins
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Neuregulin-1
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Colforsin
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Cyclic AMP
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Phosphatidylinositol 3-Kinases
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Oncogene Protein v-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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Adenylyl Cyclases