MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes.
A combination of in vitro embryonic stem (ES) cell differentiation and targeted gene disruption has defined complex regulatory events underlying oxidative stress-induced cardiac apoptosis, a model of postischemic reperfusion injury of myocardium. ES cell-derived cardiac myocytes (ESCM) having targeted disruption of the MEKK1 gene were extremely sensitive, relative to wild-type ESCM, to hydrogen peroxide-induced apoptosis. In response to oxidative stress, MEKK1-/- ESCM failed to activate c-Jun kinase (JNK) but did activate p38 kinase similar to that observed in wild-type ESCM. The increased apoptosis was mediated through enhanced tumor necrosis factor alpha production, a response that was positively and negatively regulated by p38 and the MEKK1-JNK pathway, respectively. Thus, MEKK1 functions in the survival of cardiac myocytes by inhibiting the production of a proapoptotic cytokine. MEKK1 regulation of the JNK pathway is a critical response for the protection against oxidative stress-induced apoptosis in cardiac myocytes.
Minamino
T
T
Program in Molecular Signal Transduction, Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Yujiri
T
T
Papst
P J
PJ
Chan
E D
ED
Johnson
G L
GL
Terada
N
N
D000693:Anaerobiosis; D017209:Apoptosis; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology; D004625:Embryo, Nonmammalian; D018390:Gene Targeting; D006321:Heart / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology*; D018384:Oxidative Stress / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D015427:Reperfusion Injury; D013234:Stem Cells / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases