Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity
Graduate School of Biomedical Sciences; Program in Molecular Medicine
Medical Subject Headings
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
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.
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Citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.
Proceedings of the National Academy of Sciences of the United States of America
Yang, Di; Tournier, Cathy; Wysk, Mark Allen; Lu, Hong-Tao; Xu, Jie; Davis, Roger J.; and Flavell, Richard A., "Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity" (1997). GSBS Student Publications. 749.