Crosstalk between ERK_(1/2) and STAT_3 in the modulation of cardiomyocyte hypertrophy induced by cardiotrophin-1  

作　　者：李拥军 崔炜 田泽君 郝玉明 都军 刘凡 张辉 祖秀光 刘素云 谢瑞琴 杨晓红 武宇洲 陈莉 安威 

机构地区：[1]Hebei Institute of Cardiovascular & Cerebrovascular Diseases Shijiazhuang050000,China [2]Department of Cell Biology Capital University of Medical Sciences,Beijing100054,China

出　　处：《Chinese Medical Journal》2004年第8期1135-1142,共8页中华医学杂志（英文版）

基　　金：ThisworkwassupportedbytheHebeiProvincialDoctoralResearchFoundation (NoB2001104)andtheBeijingSpecialGrantforMunicipalKeyLaboratories

摘　　要：Background The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the extracellular signal-regulated kinases 1/2 (ERK 1/2 ) pathway are the two major independent signal transduction pathways However, it has recently been found that STAT 3 may be negatively regulated by ERK 1/2 in gp130-dependent signaling Cardiotrophin-1 (CT-1), a potent novel hypertrophic cytokine, depends on gp130 to induce signaling and depends on STAT 3 to exert hypertrophic effect In this study, we examined whether STAT 3 activity was negatively regulated by ERK 1/2 during CT-1-induced signaling in rat cardiomyocytes and, if so, whether such crosstalk interfered with the hypertrophic effect of CT-1 and, furthermore, whether the mechanism underlying the crosstalk involved phosphorylation of serine 727 (S727) in STAT 3 Methods The activities of ERK 1/2 and STAT 3 were assessed by in-gel kinase assay and Western blot analysis, respectively The role of S727 phosphorylation in the crosstalk between ERK 1/2 and STAT 3 was determined by a transient transfection study using a STAT 3S727A mutant Cardiomyocyte hypertrophy was evaluated by the cellular protein-to-DNA ratio and [ 3H]-leucine incorporation Results CT-1 simultaneously activated both ERK 1/2 and STAT 3 in rat cardiomyocytes Inhibition of ERK 1/2 by U0126 resulted in an increase of CT-1-induced tyrosine phosphorylation of STAT 3 and, consequently, the protein-to-DNA ratio and [ 3H]-leucine incorporation Transient transfection of the cells with STAT 3S727A had no significant effect on CT-1-induced tyrosine phosphorylation of STAT 3 Conclusions STAT 3 is activated by CT-1 in rat cardiomyocytes, but full activation is mitigated by the simultaneous activation of ERK 1/2 The inhibition of ERK 1/2 increases the activity of STAT 3, which, in turn, enhances the hypertrophic effect of CT-1 The crosstalk between ERK 1/2 and STAT 3 is independent of the phosphorylation of the S7Background The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the extracellular signal-regulated kinases 1/2 (ERK 1/2 ) pathway are the two major independent signal transduction pathways However, it has recently been found that STAT 3 may be negatively regulated by ERK 1/2 in gp130-dependent signaling Cardiotrophin-1 (CT-1), a potent novel hypertrophic cytokine, depends on gp130 to induce signaling and depends on STAT 3 to exert hypertrophic effect In this study, we examined whether STAT 3 activity was negatively regulated by ERK 1/2 during CT-1-induced signaling in rat cardiomyocytes and, if so, whether such crosstalk interfered with the hypertrophic effect of CT-1 and, furthermore, whether the mechanism underlying the crosstalk involved phosphorylation of serine 727 (S727) in STAT 3 Methods The activities of ERK 1/2 and STAT 3 were assessed by in-gel kinase assay and Western blot analysis, respectively The role of S727 phosphorylation in the crosstalk between ERK 1/2 and STAT 3 was determined by a transient transfection study using a STAT 3S727A mutant Cardiomyocyte hypertrophy was evaluated by the cellular protein-to-DNA ratio and [ 3H]-leucine incorporation Results CT-1 simultaneously activated both ERK 1/2 and STAT 3 in rat cardiomyocytes Inhibition of ERK 1/2 by U0126 resulted in an increase of CT-1-induced tyrosine phosphorylation of STAT 3 and, consequently, the protein-to-DNA ratio and [ 3H]-leucine incorporation Transient transfection of the cells with STAT 3S727A had no significant effect on CT-1-induced tyrosine phosphorylation of STAT 3 Conclusions STAT 3 is activated by CT-1 in rat cardiomyocytes, but full activation is mitigated by the simultaneous activation of ERK 1/2 The inhibition of ERK 1/2 increases the activity of STAT 3, which, in turn, enhances the hypertrophic effect of CT-1 The crosstalk between ERK 1/2 and STAT 3 is independent of the phosphorylation of the S7

关 键 词：cardiac hypertrophy CYTOKINES signal transduction 

分 类 号：R542.2[医药卫生—心血管疾病]