Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity
Wysk, Mark Allen
Davis, Roger J.
Flavell, Richard A.
Document TypeJournal Article
KeywordsAnimals; 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
Medicine and Health Sciences
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AbstractMKK4 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.
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/34085
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A mammalian scaffold complex that selectively mediates MAP kinase activationWhitmarsh, 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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