MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells.
Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcepsilonRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-alpha. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcepsilonRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.
D000818:Animals; D005786:Gene Expression Regulation; D016758:Genes, jun; D048671:MAP Kinase Kinase 5; D048688:MAP Kinase Kinase 7; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D064326:MEF2 Transcription Factors; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000502:physiology*; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D014409:Tumor Necrosis Factor-alpha; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482619:Map3k2 protein, mouse; D048671:MAP Kinase Kinase 5; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases