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)

GATA-4 regulates gene transcription in the heart. This study examined whether GATA-4 is influenced by stress-induced signaling events. Treatment of HL-1 cardiac muscle cells with mercury results in the induction of apoptosis that is blocked by overexpression of catalase. Similar to daunorubicin (DNR), mercury causes downregulation of GATA-4 mRNA expression. However, mercury is less effective in inducing apoptosis compared to DNR. Analyses of GATA-4 protein expression and activity reveal that mercury initially enhances the GATA-4 DNA-binding activity, before subsequent downregulation of GATA-4 expression. The mercury-induced GATA-4 activation is associated with a phosphorylation of GATA-4, which appears to occur via the MEK/ERK pathway. The level of phosphorylated GATA-4 is more slowly decreased by mercury or actinomycin D, compared to unphosphorylated GATA-4, suggesting that phosphorylated GATA-4 is more resistant to cellular degradation. Consistent with a previous finding that GATA-4 phosphorylation induces cell survival, mercury decreases cell death induced by DNR. These results suggest that cardiac muscle cells respond to mercury stress by eliciting MEK/ERK signaling to form phosphorylated GATA-4 that is more resistant to cellular degradation and induce cell survival.
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PMID:Stress-induced activation of GATA-4 in cardiac muscle cells. 1278 78

GATA-4, a zinc finger transcription factor, plays a critical role in heart development. Previous studies have shown that p300-targeted GATA-4 acetylation increases GATA-4 stability and transcriptional activity, which then stimulates hypertrophy of cardiomyocyte. Erythropoietin (EPO), an essential hypoxia-induced hormone for normal erythropoiesis, is known to exert cardioprotective effects against heart disease of either ischemic or non-ischemic origins. Although, various action mechanisms of EPO have been proposed in the diseased heart, its action mechanism in normal condition has not been investigated. In this study, we aimed to investigate the influence of EPO-induced ERK signaling on the regulation of GATA-4 protein action. EPO treatment increased the protein level of endogenous GATA-4 via ERK signaling pathway. Inhibition of ERK activity by U0126, suppressed EPO-induced expression of GATA-4 protein in rat cardiac myocytes. In addition, ERK activation by over-expression of constitutively active MEK1 strongly increased GATA-4 phosphorylation and subsequently enhanced its acetylation in P19 cells. EPO-induced ERK activation further increased the association of GATA-4 with p300. On the other hand, knock-down of p300 using siRNA diminished ERK-induced GATA-4 acetylation. As EPO-induced GATA-4 phosphorylation via ERK signaling pathway directly correlated with GATA-4 acetylation, we investigated to identify the ERK-dependent phosphorylation sites in GATA-4. Site-directed mutagenesis implicated that Ser-261 in GATA-4 played an important role for ERK-mediated GATA-4 acetylation. Taken together, these results indicated that EPO-induced ERK signaling activation increased GATA-4 phosphorylation and acetylation, partly via increase in the association between GATA-4 and p300, and these processes required the phosphorylation of GATA-4 at Ser-261 residue.
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PMID:Erythropoietin-activated ERK/MAP kinase enhances GATA-4 acetylation via phosphorylation of serine 261 of GATA-4. 2267 27