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- Title
MEF2C regulates c-Jun but not TNF-α gene expression in stimulated mast cells.
- Authors
Wei, Xudong; Sun, Weiyong; Fan, Ruihua; Hahn, Joanne; Joetham, Anthony; Li, Guiming; Webb, Saiphone; Garrington, Timothy; Dakhama, Azzeddine; Lucas, Joseph; Johnson, Gary L.; Gelfand, Erwin W.
- Abstract
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 (FcϵRI). 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-α. 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 FcϵRI 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 FcϵRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.
- Publication
European Journal of Immunology, 2003, Vol 33, Issue 10, p2903
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.200324127