Abstract
The transcription factor GATA-4 plays a central role in the regulation of cardiac-muscle gene transcription. The present study demonstrates that endothelin-1 (ET-1) induces GATA-4 activation and phosphorylation. The treatment of HL-1 adult mouse atrial-muscle cells with ET-1 (30 nM) caused a rapid increase in the DNA binding activity of GATA-4 within 3 min. The activation was associated with an upward mobility shift of the GATA-4 band on native PAGE in an electrophoretic- mobility-shift assay. The upward shift of the GATA-4 band also occurred on SDS/PAGE as monitored by immunoblotting. The in vitro treatment of nuclear extracts with lambda-protein phosphatase abolished the upward shift, indicating that GATA-4 was phosphorylated. ET-1 activated the p44/42 mitogen-activated protein kinase (MAPK) and the MAPK kinase (MEK) within 3 min, and PD98059 (a specific inhibitor of MEK) abolished the ET-1-induced GATA-4 phosphorylation. PMA also caused the rapid activation of MAPK and the phosphorylation of GATA-4. In contrast, the activation of MAPK by phenylephrine or H(2)O(2) was weak and did not lead to GATA-4 phosphorylation. Thus ET-1 induces a GATA-4 phosphorylation by activating a MEK-MAPK pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endothelin-1 / physiology*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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GATA4 Transcription Factor
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Hydrogen Peroxide / pharmacology
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Mice
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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 Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Myocardium / metabolism
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Phosphorylation
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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Endothelin-1
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Enzyme Inhibitors
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Flavonoids
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GATA4 Transcription Factor
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Transcription Factors
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Hydrogen Peroxide
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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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Mitogen-Activated Protein Kinase Kinases
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Tetradecanoylphorbol Acetate
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one