MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner
In cardiac myocytes the stimulation of p38 mitogen-activated protein kinase activates a hypertrophic growth program and the induction of the cardiac-specific genes associated with this program. This study focused on determining whether these novel growth-promoting effects are accompanied by the p38-...
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Published in | The Journal of biological chemistry Vol. 273; no. 14; p. 8232 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
03.04.1998
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Abstract | In cardiac myocytes the stimulation of p38 mitogen-activated protein kinase activates a hypertrophic growth program and the
induction of the cardiac-specific genes associated with this program. This study focused on determining whether these novel
growth-promoting effects are accompanied by the p38-mediated inhibition of apoptosis, and if so, what signaling pathways might
be responsible. Primary neonatal rat ventricular myocytes were driven into apoptosis by treatments known to induce apoptosis
in other cell types, e.g. incubation with anisomycin or overexpression constitutively active MEKK-1 (MEKK-1 COOH ), a protein that strongly activates extracellular signal-regulated kinase and N-terminal c-Jun kinase, but not p38. Overexpression
of constitutively active MKK6, MKK6 (Glu), which selectively activates p38 in cardiac myocytes, protected cells from either
anisomycin- or MEKK-1 COOH -induced apoptosis. This protection was blocked by SB 203580, a selective p38 inhibitor. MKK6 (Glu) also activated transcription
mediated by NF-κB, a factor which protects other cell types from apoptosis. The activation of NF-κB and the protection from
apoptosis mediated by MKK6 (Glu) were both blocked by SB 203580. Interestingly, overexpression of a mutant form of I-κBα,
which inhibits nuclear translocation of NF-κB, completely blocked MKK6 (Glu)-activated NF-κB but had little effect on MKK6s
anti-apoptotic effects. These findings suggest that, in part, the overexpression of MKK6 (Glu) may foster growth and survival
of cardiac myocytes by protecting them from apoptosis in a p38-dependent manner. Additionally, while NF-κB is activated in
myocardial cells by p38, this does not appear to be the major mechanism by which MKK6 (Glu) exerts its anti-apoptotic effects
in this cell type, suggesting a novel pathway for p38-mediated protection from apoptosis. |
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AbstractList | In cardiac myocytes the stimulation of p38 mitogen-activated protein kinase activates a hypertrophic growth program and the
induction of the cardiac-specific genes associated with this program. This study focused on determining whether these novel
growth-promoting effects are accompanied by the p38-mediated inhibition of apoptosis, and if so, what signaling pathways might
be responsible. Primary neonatal rat ventricular myocytes were driven into apoptosis by treatments known to induce apoptosis
in other cell types, e.g. incubation with anisomycin or overexpression constitutively active MEKK-1 (MEKK-1 COOH ), a protein that strongly activates extracellular signal-regulated kinase and N-terminal c-Jun kinase, but not p38. Overexpression
of constitutively active MKK6, MKK6 (Glu), which selectively activates p38 in cardiac myocytes, protected cells from either
anisomycin- or MEKK-1 COOH -induced apoptosis. This protection was blocked by SB 203580, a selective p38 inhibitor. MKK6 (Glu) also activated transcription
mediated by NF-κB, a factor which protects other cell types from apoptosis. The activation of NF-κB and the protection from
apoptosis mediated by MKK6 (Glu) were both blocked by SB 203580. Interestingly, overexpression of a mutant form of I-κBα,
which inhibits nuclear translocation of NF-κB, completely blocked MKK6 (Glu)-activated NF-κB but had little effect on MKK6s
anti-apoptotic effects. These findings suggest that, in part, the overexpression of MKK6 (Glu) may foster growth and survival
of cardiac myocytes by protecting them from apoptosis in a p38-dependent manner. Additionally, while NF-κB is activated in
myocardial cells by p38, this does not appear to be the major mechanism by which MKK6 (Glu) exerts its anti-apoptotic effects
in this cell type, suggesting a novel pathway for p38-mediated protection from apoptosis. |
Author | Rian Craig Dietmar Zechner Christopher C. Glembotski Patrick M. McDonough Roger A. Sabbadini Deanna S. Hanford |
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Snippet | In cardiac myocytes the stimulation of p38 mitogen-activated protein kinase activates a hypertrophic growth program and the
induction of the cardiac-specific... |
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Title | MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner |
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