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    Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity

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    Authors
    Yang, Di
    Tournier, Cathy
    Wysk, Mark Allen
    Lu, Hong-Tao
    Xu, Jie
    Davis, Roger J.
    Flavell, Richard A.
    UMass Chan Affiliations
    Program in Molecular Medicine
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    1997-04-01
    Keywords
    Animals; Calcium-Calmodulin-Dependent Protein Kinases; inhibitors; Embryonic and Fetal Development; Enzyme Activation; *Genes, Lethal; Heterozygote; Homozygote; JNK Mitogen-Activated Protein Kinases; *MAP Kinase Kinase 4; Mice; Mice, Knockout; *Mitogen-Activated Protein Kinase Kinases; *Mitogen-Activated Protein Kinases; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Transcription Factor AP-1
    Life Sciences
    Medicine and Health Sciences
    
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20312/
    Abstract
    MKK4 is a member of the mitogen-activated protein kinase kinase group of dual specificity protein kinases that functions as an activator of the c-Jun NH2-terminal kinase (JNK) in vitro. To examine the function of MKK4 in vivo, we investigated the effect of targeted disruption of the MKK4 gene. Crosses of heterozygous MKK4 (+/-) mice demonstrated that homozygous knockout (-/-) animals die before embryonic day 14, indicating that the MKK4 gene is required for viability. The role of MKK4 in JNK activation was examined by investigation of cultured MKK4 (+/+) and MKK4 (-/-) cells. Disruption of the MKK4 gene blocked JNK activation caused by: (i) the mitogen-activated protein kinase kinase kinase MEKK1, and (ii) treatment with anisomycin or heat shock. In contrast, JNK activation caused by other forms of environmental stress (UV-C radiation and osmotic shock) was partially inhibited in MKK4 (-/-) cells. Regulated AP-1 transcriptional activity, a target of the JNK signal transduction pathway, was also selectively blocked in MKK4 (-/-) cells. Complementation studies demonstrated that the defective AP-1 transcriptional activity was restored by transfection of MKK4 (-/-) cells with an MKK4 expression vector. These data establish that MKK4 is a JNK activator in vivo and demonstrate that MKK4 is an essential component of the JNK signal transduction pathway.
    Source

    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.

    DOI
    10.1073/pnas.94.7.3004
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34085
    PubMed ID
    9096336
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.94.7.3004
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      A mammalian scaffold complex that selectively mediates MAP kinase activation

      Whitmarsh, Alan J.; Cavanagh, Julie; Tournier, Cathy; Yasuda, Jun; Davis, Roger J. (1998-09-11)
      The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by the exposure of cells to multiple forms of stress. A putative scaffold protein was identified that interacts with multiple components of the JNK signaling pathway, including the mixed-lineage group of MAP kinase kinase kinases (MLK), the MAP kinase kinase MKK7, and the MAP kinase JNK. This scaffold protein selectively enhanced JNK activation by the MLK signaling pathway. These data establish that a mammalian scaffold protein can mediate activation of a MAP kinase signaling pathway.
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      Molecular determinants that mediate selective activation of p38 MAP kinase isoforms

      Enslen, Herve; Brancho, Deborah Marie; Davis, Roger J. (2000-03-16)
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      Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6

      Enslen, Herve; Raingeaud, Joel; Davis, Roger J. (1998-01-27)
      The cellular response to treatment with proinflammatory cytokines or exposure to environmental stress is mediated, in part, by the p38 group of mitogen-activated protein (MAP) kinases. We report the molecular cloning of a novel isoform of p38 MAP kinase, p38 beta 2. This p38 MAP kinase, like p38 alpha, is inhibited by the pyridinyl imidazole drug SB203580. The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms, while MKK3 activates only p38 alpha and p38 gamma MAP kinase isoforms. The MKK3 and MKK6 signal transduction pathways are therefore coupled to distinct, but overlapping, groups of p38 MAP kinases.
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