Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation. 862 42

Costimulation of TCR/CD3 and CD28 receptors leads to activation of the Jun kinase (JNK) cascade, which plays a key role in T cell activation, including activation of the IL-2 promoter. We demonstrate that the JNK cascade plays a central role in the activation of the CD28 response element (CD28RE) in the IL-2 promoter. This response element is linked to an activating protein-1 (AP-1) site, which functions synergistically with the CD28RE. The role of the JNK cascade in the activation of this composite element is twofold: 1) activation of the AP-1 site through transcriptional activation of c-Jun, and 2) activation of the CD28RE through selective cross-talk with I kappa B kinase-beta (IKK beta). Dominant-negative versions of JNK kinase, c-Jun, and IKK beta interfered In CD3- plus CD28-induced CD28RE/AP-1 luciferase activity in Jurkat cells. In contrast, the dominant-active JNK kinase kinase, MEKK1, induced CD28RE/AP-1 luciferase activity, in parallel with induction of c-Jun and c-Rel binding to this combined promoter site. Dominant-active MEKK1 also induced transfected IKK beta, but not IKK alpha, activity. In contrast to the JNK cascade, the extracellular signal-regulated kinase (ERK) cascade did not exert an affect on the CD28RE/AP-1 site, but did contribute to activation of the distal NF-AT/AP-1 site.
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PMID:The Jun kinase cascade is responsible for activating the CD28 response element of the IL-2 promoter: proof of cross-talk with the I kappa B kinase cascade. 1009 68

Cot/Tpl-2 kinase, homologous to members of mitogen-activated protein kinase kinase kinase, was initially discovered by its capacity to promote cell transformation. Cot/Tpl-2 mRNA levels are increased during G(0) to G(1) phase progression in T lymphocytes, suggesting a role for this kinase later on in the cell cycle. The IL-2-dependent CTLL-2 cells were used to investigate the role of Cot kinase in G(1) to S phase transition. Transient expression of Cot kinase in CTLL-2 cells increases DNA synthesis triggered by IL-2 and the transient expression of a dominant negative form of Cot kinase in CTLL-2 markedly reduces the DNA synthesis triggered by this cytokine. Cell cycle analysis of synchronized CTLL-2 stabling overexpressing Cot kinase indicates that this kinase contributes to the passage to S and G(2)-M phases of the cell cycle. Cot kinase reduces the levels of the cyclin kinase inhibitor p27(kip), whereas bcl-x(L) expression is unaffected. Cot kinase also increases E2F transcriptional activity in a phosphatidylinositol 3 kinase-independent way and acts in synergy with this kinase. These data give evidence, for the first time, of the regulation of different G(1) progression events by Cot kinase.
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PMID:p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. 1134 26