Hepatocyte Growth Factor Induces GATA-4 Phosphorylation and Cell Survival in Cardiac Muscle Cells

Hepatocyte growth factor (HGF) is released in response to myocardial infarction and may play a role in regulating cardiac remodeling. Recently, HGF was found to inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell survival, the effects of HGF on GATA-4 activity were investig...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-02, Vol.278 (7), p.4705-4712
Main Authors: Kitta, Kazumi, Day, Regina M, Kim, Yuri, Torregroza, Ingrid, Evans, Todd, Suzuki, Yuichiro J
Format: Article
Language:English
Subjects:
Animals
Cell Survival - drug effects
Cells, Cultured
DNA-Binding Proteins - metabolism
GATA4 Transcription Factor
Hepatocyte Growth Factor - metabolism
Hepatocyte Growth Factor - pharmacology
Male
MAP Kinase Signaling System
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Phosphorylation
Rats
Rats, Inbred Lew
Signal Transduction
Transcription Factors - metabolism
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Summary:Hepatocyte growth factor (HGF) is released in response to myocardial infarction and may play a role in regulating cardiac remodeling. Recently, HGF was found to inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell survival, the effects of HGF on GATA-4 activity were investigated. Treatment of HL-1 cells or primary adult rat cardiac myocytes with HGF, at concentrations that can be detected in the human serum after myocardial infarction, rapidly enhances GATA-4 DNA-binding activity. The enhanced DNA-binding activity is associated with the phosphorylation of GATA-4. HGF-induced phosphorylation and activation of GATA-4 is abolished by MEK inhibitors or the mutation of the ERK phosphorylation site (S105A), suggesting that HGF activates GATA-4 via MEK-ERK pathway-dependent phosphorylation. HGF enhances the expression of anti-apoptotic Bcl-x L , and this is blocked by dominant negative mutants of MEK or GATA-4. Forced expression of wild-type GATA-4, but not the GATA-4 mutant (S105A) increases the expression of Bcl-x L . Furthermore, expression of the GATA-4 mutant (S105A) suppresses HGF-mediated protection of cells against daunorubicin-induced apoptosis. These results demonstrate that HGF protects cardiac muscle cells against apoptosis via a signaling pathway involving MEK/ERK-dependent phosphorylation of GATA-4.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M211616200