Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating κB enhancer activation

Christian F. Meyer, Xiaoping Wang, Carol Chang, Dennis Templeton, Tse Hua Tan

Research output: Contribution to journalArticlepeer-review

157 Scopus citations


The Rel family of transcription factors are important mediators of various cytokine stimuli such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, and CD28 co-stimulation in T cell effector responses. These stimuli induce Rel family DNA-binding activity to the κB enhancer and CD28 response elements of many cytokine gone promoters leading to cytokine production. Consistent with the importance of Rel family induction during immune responses, c-Rel knockout mice exhibit profound defects in T cell functions including IL-2 secretion and T cell proliferative responses to CD28 plus T cell receptor costimulation. The novel protein kinases, c-Jun NH2-terminal kinases (JNKs)/stress-activated protein kinases, are also activated by TNF- α, IL-1, and CD28 costimulation. Because of the common regulation of c-Rel and JNK1 by these agents in T cells, we investigated the role of JNK1 in c- Rel activation. We found that MAP kinase kinase kinase (MEKK) 1, a JNK1 activator, induced transcription from the human immunodeficiency virus-1 long terminal repeat and IL-2Rα promoters in a κB-dependent manner. Coexpression of IκBα, a c-Rel inhibitor, inhibited the MEKK1-induced transcriptional activity. JNK1 synergized with MEKK1 in activating transcription from a κB- driven heterologous promoter. Furthermore, JNK1 associated with c-Rel in vivo in Jurkat T cells by coimmunoprecipitation assays and bound directly to c- Rel in a yeast two-hybrid assay. c-Rel also competed with c-Jun in in vitro kinase assays. However, JNK1 did not phosphorylate c-Rel, NF-κB, and IκBα in vitro, indicating that c-Rel may serve as a docking molecule to allow JNK1 phosphorylation of certain Rel-associated proteins. Transactivation of the IL-2Rα and HIV-κB-driven promoters by c-Rel was augmented by coexpression of MEKK1. These results demonstrate the first significant role for the MEKK1 kinase cascade module in c-Rel-mediated transcription.

Original languageEnglish (US)
Pages (from-to)8971-8976
Number of pages6
JournalJournal of Biological Chemistry
Issue number15
StatePublished - Apr 12 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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