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

Di Yang, Cathy Tournier, Mark Wysk, Hong Tao Lu, Jie Xu, Roger J. Davis, Richard A. Flavell

Research output: Contribution to journalArticlepeer-review

259 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3004-3009
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number7
DOIs
StatePublished - Apr 1 1997

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity'. Together they form a unique fingerprint.

Cite this