Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH 2 -terminal kinase activation, and defects in AP-1 transcriptional activity

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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 NH 2 -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.