Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity
dc.contributor.author | Yang, Di | |
dc.contributor.author | Tournier, Cathy | |
dc.contributor.author | Wysk, Mark Allen | |
dc.contributor.author | Lu, Hong-Tao | |
dc.contributor.author | Xu, Jie | |
dc.contributor.author | Davis, Roger J. | |
dc.contributor.author | Flavell, Richard A. | |
dc.date | 2022-08-11T08:09:00.000 | |
dc.date.accessioned | 2022-08-23T16:15:26Z | |
dc.date.available | 2022-08-23T16:15:26Z | |
dc.date.issued | 1997-04-01 | |
dc.date.submitted | 2008-11-04 | |
dc.identifier.citation | <p>Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.</p> | |
dc.identifier.issn | 0027-8424 (Print) | |
dc.identifier.doi | 10.1073/pnas.94.7.3004 | |
dc.identifier.pmid | 9096336 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/34085 | |
dc.description.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. | |
dc.language.iso | en_US | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=9096336&dopt=Abstract">Link to Article in PubMed</a></p> | |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20312/ | |
dc.title | Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity | |
dc.type | Journal Article | |
dc.source.journaltitle | Proceedings of the National Academy of Sciences of the United States of America | |
dc.source.volume | 94 | |
dc.source.issue | 7 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/gsbs_sp/749 | |
dc.identifier.contextkey | 660868 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | gsbs_sp/749 | |
dc.contributor.department | Program in Molecular Medicine | |
dc.contributor.department | Morningside Graduate School of Biomedical Sciences | |
dc.source.pages | 3004-9 |