Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy.
Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5-ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant specifically blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIF-induced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-specific expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly.
Nicol
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RL
Department of Molecular Biology, University of Texas, Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Frey
N
N
Pearson
G
G
Cobb
M
M
Richardson
J
J
Olson
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EN
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D019556:COS Cells; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006131:Growth Inhibitors / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D048671:MAP Kinase Kinase 5; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012518:Sarcomeres / Q000502:physiology*; D017384:Sequence Deletion; D014162:Transfection
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D011994:Recombinant Proteins; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; C482565:Map2k5 protein, rat; D020929:Mitogen-Activated Protein Kinase Kinases