Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation.
The Rel family of transcription factors are important mediators of various cytokine stimuli such as interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and CD28 costimulation in T cell effector responses. These stimuli induce Rel family DNA-binding activity to the kappaB enhancer and CD28 response elements of many cytokine gene 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-alpha, 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-2R alpha promoters in a kappaB-dependent manner. Coexpression of IkappaBalpha, a c-Rel inhibitor, inhibited the MEKK1-induced transcriptional activity. JNK1 synergized with MEKK1 in activating transcription from a kappaB-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-kappaB, and IkappaB alpha 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-2Ralpha and HIV-kappaB-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.
Meyer
C F
CF
Department of Microbiology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Wang
X
X
Chang
C
C
Templeton
D
D
Tan
T H
TH
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D016325:HIV Long Terminal Repeat; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D015375:Receptors, Interleukin-2 / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases