The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
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
Open accessAbstract
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.
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Cites
Independent Human MAP-Kinase Signal Transduction Pathways Defined by MEK and MKK Isoforms
Dérijard, B., Raingeaud, J., Barrett, T., Wu, I.-H., Han, J., Ulevitch, R. J., & Davis, R. J. (1995) · Science · doi:10.1126/science.7839144 · Cited by 1,555
Self-citationWhitmarsh, A. J., & Davis, R. J. (1996) · Journal of Molecular Medicine · doi:10.1007/s001090050063 · Cited by 1,543
Self-citationThe jun proto-oncogene is positively autoregulated by its product, Jun/AP-1
Angel, P., Hattori, K., Smeal, T., & Karin, M. (1988) · Cell · doi:10.1016/0092-8674(88)90143-2 · Cited by 1,239
Smeal, T., Binetruy, B., Mercola, D. A., Birrer, M., & Karin, M. (1991) · Nature · doi:10.1038/354494a0 · Cited by 789
Cited by
Signal transduction by the JNK group of MAP kinases
Davis, R. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00116-1 · Cited by 4,237
Self-citationDiverse functions of JNK signaling and c-Jun in stress response and apoptosis
Leppä, S., & Bohmann, D. (1999) · Oncogene · doi:10.1038/sj.onc.1203173 · Cited by 522
Mielke, K., & Herdegen, T. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00042-8 · Cited by 490
The JIP Group of Mitogen-Activated Protein Kinase Scaffold Proteins
Yasuda, J., Whitmarsh, A. J., Cavanagh, J., Sharma, M., & Davis, R. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.10.7245 · Cited by 458
Self-citationThe Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease
Zhu, X., Lee, H.-G., Raina, A. K., Perry, G., & Smith, M. A. (2002) · Neurosignals · doi:10.1159/000067426 · Cited by 391
Metadata
- Authors
- Yang, D., Tournier, C., Wysk, M., Lu, H.-T., Xu, J., Davis, R. J., & Flavell, R. A.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1997-04
- Volume
- 94
- Issue
- 7
- Pages
- 3004-3009
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2078065785
- Cited by
- 270
- References
- 4
- FWCI
- 10.80
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: 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. https://app.cochat.ai/papers/10.1073/pnas.94.7.3004
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- Yang, D., Tournier, C., Wysk, M., Lu, H.-T., Xu, J., Davis, R. J., & Flavell, R. A. (1997). 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. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.94.7.3004
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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