MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner

Abstract

In cardiac myocytes the stimulation of p38 mitogenactivated 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-B, a factor which protects other cell types from apoptosis. The activation of NF-B and the protection from apoptosis mediated by MKK6 (Glu) were both blocked by SB 203580. Interestingly, overexpression of a mutant form of I-B␣, which inhibits nuclear translocation of NF-B, completely blocked MKK6 (Glu)-activated NF-B 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-B 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.

Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

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Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

“…There is conflicting evidence for the role of p38/MAPK in influencing cell survival of cisplatin-treated cells. For example, studies have suggested that over expressing an active form of the p38/MAPK activator MKK6 protects cardiac myocytes from treatment with anisomyc [42]. Similarly, early activation of p38/MAPK is necessary and sufficient to protect Kym cells from tumour necrosis factor-α-mediated apoptosis [43], and expression of the p38/MAPK attenuates cell death induced by Fas ligand and UV light [44].…”

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