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dc.contributor.authorYang, Di
dc.contributor.authorTournier, Cathy
dc.contributor.authorWysk, Mark Allen
dc.contributor.authorLu, Hong-Tao
dc.contributor.authorXu, Jie
dc.contributor.authorDavis, Roger J.
dc.contributor.authorFlavell, Richard A.
dc.date2022-08-11T08:09:00.000
dc.date.accessioned2022-08-23T16:15:26Z
dc.date.available2022-08-23T16:15:26Z
dc.date.issued1997-04-01
dc.date.submitted2008-11-04
dc.identifier.citation<p>Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.</p>
dc.identifier.issn0027-8424 (Print)
dc.identifier.doi10.1073/pnas.94.7.3004
dc.identifier.pmid9096336
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34085
dc.description.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.
dc.language.isoen_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.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC20312/
dc.subjectAnimals; 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
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleTargeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume94
dc.source.issue7
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/749
dc.identifier.contextkey660868
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.submissionpathgsbs_sp/749
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages3004-9


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