Abstract
Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute a family of 11 dual-specificity phosphatases that inactivate the MAPKs by dephosphorylation. Although the contribution of MAPKs to cell growth and cell death has been examined extensively, it remains unclear whether MKPs play an essential role in the regulation of these processes. To clarify the role of MKP-1, we determined the effects on the MAPKs and cell growth and death in primary fibroblasts derived from mice lacking MKP-1. Here we have shown that MKP-1 is critical for the inactivation of p38 MAPK and JNK following stimulation with serum, anisomycin, and osmotic stress. In addition, MKP-1 was identified as a critical negative regulator of the cAMP-mediated p38 MAPK pathway. MKP-1-deficient mouse embryonic fibroblasts (MEFs) displayed enhanced p38 MAPK activity and cAMP-response element-dependent transcriptional activation in response to forskolin. Surprisingly, MKP-1-deficient fibroblasts exhibited reduced cell growth compared with wild type MEFs as a result of enhanced cell death. The enhanced level of cell death in MKP-1-deficient MEFs was rescued by SB203580, an inhibitor of p38 MAPK. MKP-1-deficient MEFs were also sensitive to anisomycin-induced apoptosis. Collectively, these data demonstrate that MKP-1 promotes cell survival by attenuating stress-responsive MAPK-mediated apoptosis.
Highlights
Ment for the family of enzymes known as Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) that inactivate mitogen-activated protein kinases (MAPKs) in these cellular processes
MAPK phosphatases (MKPs)-1 Is a Critical Regulator of p38 MAPK and Jun NH2-terminal kinase (JNK) in Primary mouse embryonic fibroblasts (MEFs)—Primary MEFs were derived from wild type (MKP-1ϩ/ϩ) embryos and embryos in which MKP-1 expression was disrupted through insertion of a neomycin cassette into exon 2 of the MKP-1 gene [17]
These results demonstrate that MKP-1 is a critical negative regulator of p38 MAPK and JNK, but not extracellular-regulated kinases 1/2 (Erk), activation in fibroblasts stimulated with serum
Summary
Ment for the family of enzymes known as MAPK phosphatases (MKPs) that inactivate MAPKs in these cellular processes. It has been reported that MKP-1 plays a redundant role in MAPK-mediated signaling because fibroblasts derived from mice lacking MKP-1 were reported to have unaltered Erk activation, cell growth, and c-fos expression in response to serum [17]. These observations have led to the perception that the function of MKP-1 can be subserved by other MKPs and/or other phosphatases. MKP-1-deficient MEFs exhibited reduced cell growth as a result of enhanced sensitivity to cell death and stress-induced apoptosis These data demonstrate that MKP-1 plays a critical role in the negative regulation of p38 MAPK and JNK in response to stress to promote cell survival
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