Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Endothelin-1 induces phosphorylation of GATA-4 transcription factor in the HL-1 atrial-muscle cell line. 1158 84

Our previous study demonstrated that endothelin-1 induced a phosphorylation of GATA-4 transcription factor, which plays important roles in cardiac hypertrophy and failure. The goal of the present study was to determine whether protein kinase C (PKC) is involved in the signaling pathway, and, if so, whether alpha-tocopherol inhibits the GATA-4 phosphorylation. Treatment of HL-1 adult mouse cardiac muscle cells with PMA, a known activator of PKC, induced a transient phosphorylation of GATA-4. PMA also phosphorylated MEK and ERK, and PMA-induced GATA-4 phosphorylation was blocked by an MEK inhibitor, PD98059, suggesting that PMA phosphorylates GATA-4 via the MEK-ERK pathway. Treatment of HL-1 cells with 1 microM PMA for 24 h resulted in a downregulation of PKC. In PKC-downregulated cells, PMA- or ET-1-induced GATA-4 phosphorylation was suppressed, suggesting the role of PKC in GATA-4 phosphorylation. However, alpha-tocopherol (5--100 microM) did not inhibit the phosphorylation of GATA-4 or ERK in HL-1 cells. In contrast, alpha-tocopherol potently inhibited the PMA-induced ERK activation in smooth muscle cells. Our studies in HL-1 cells showed that PKC inhibitors, such as calphostin C and chelerythrin, failed to inhibit the PMA signaling. Furthermore, HL-1 cells appear to possess a unique PKC-signaling mechanism as PKC is constitutively phosphorylated and PMA did not cause further phosphorylation. Thus, in HL-1 cardiac muscle cells, PMA activates the MEK-ERK-GATA-4 pathway, apparently via a PKC-independent mechanism.
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PMID:Roles of protein kinase C and alpha-tocopherol in regulation of signal transduction for GATA-4 phosphorylation in HL-1 cardiac muscle cells. 1184 24