Abstract
Epidermal growth factor induction of c-jun expression requires ATF1 and MEF2 sites in the c-jun promoter. We find that activation of the c-jun promoter through the ATF1 site requires phosphorylation of ATF1 at serine 63. A serine 63 to alanine mutation of ATF1 acts to block epidermal growth factor (EGF) induction of a transfected c-jun gene. ATF1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (MSK1), which is activated by EGF and ERK1/2. Kinase-dead MSK1 mutants blocked EGF induction of a transfected c-jun gene suggesting that MSK1 or a similar family member is required for induced c-jun expression. Use of the MEK1 inhibitor U0126 and dominant negative MEK1 further showed that MSK1 activation and c-jun induction require the ERK pathway. In contrast, a JNK inhibitor blocked EGF induction of c-jun expression but not ATF1 phosphorylation. These results show that the two MAPK pathways, ERK and JNK, are required for EGF-induced c-jun expression and that the ERK pathway acts through downstream phosphorylation of ATF1.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factor 1
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Animals
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DNA-Binding Proteins*
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor / pharmacology*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Genes, jun / drug effects
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Genes, jun / physiology*
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HeLa Cells
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mice
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Mitogen-Activated Protein Kinases / metabolism*
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Phosphorylation
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Promoter Regions, Genetic / drug effects
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Recombinant Proteins / pharmacology
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Transfection
Substances
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Activating Transcription Factor 1
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Atf1 protein, mouse
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DNA-Binding Proteins
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Enzyme Inhibitors
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Recombinant Proteins
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Transcription Factors
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Epidermal Growth Factor
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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Mitogen-Activated Protein Kinases