Abstract
Cell response to a wide variety of extracellular signals is mediated by either mitogenic activation of the Raf/MEK/ERK kinase cascade or stress-induced activation of the mitogen-activated protein kinase (MAPK) family members c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) or p38. We have examined communications between these stress- and mitogen-induced signaling pathways. We show here that the stress cascade activator arsenite activates extracellular signal-regulated kinase (ERK) in addition to p38 albeit with different kinetics. Whereas p38 is an early response kinase, ERK activation occurs with delayed time kinetics at 2-4 h. We observed activation of ERK upon arsenite treatment in many different cell lines. ERK activation is strongly enhanced by overexpression of p38 and mitogen-activated protein kinase kinase 6 (MKK6) but is blocked by dominant negative kinase versions of p38 and MKK6 or the specific p38 inhibitor SB203580. Arsenite-induced ERK activation is mediated by Ras, Raf, and MEK but appears to be independent of de novo protein synthesis. These data provide the first evidence for a p38 dependent activation of the mitogenic kinase cascade in stress-stimulated cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arsenites / pharmacology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / enzymology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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HL-60 Cells
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Humans
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Imidazoles / pharmacology
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase 6
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Protein Kinases*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-raf / metabolism
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Pyridines / pharmacology
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Up-Regulation / drug effects
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ras Proteins / metabolism
Substances
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Arsenites
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Enzyme Inhibitors
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Imidazoles
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Intracellular Signaling Peptides and Proteins
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Pyridines
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Protein Kinases
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MAP-kinase-activated kinase 2
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 6
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MAP2K6 protein, human
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ras Proteins
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arsenite
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SB 203580