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A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Open accessAbstract
Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.
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Citations
Cited by
Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T., & Saltiel, A. R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.46.27489 · Cited by 3,393
Self-citationActivation and function of the MAPKs and their substrates, the MAPK-activated protein kinases
Cargnello, M., & Roux, P. P. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00031-10 · Cited by 3,274
MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts
Thum, T., Gross, C., Fiedler, J., Fischer, T., Kissler, S., Bussen, M., Galuppo, P., Just, S., Rottbauer, W., Frantz, S., et al. (2008) · Nature · doi:10.1038/nature07511 · Cited by 2,349
MAPK cascade signalling and synaptic plasticity
Thomas, G. M., & Huganir, R. L. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1346 · Cited by 1,454
The specificities of protein kinase inhibitors: an update
BAIN, J., McLAUCHLAN, H., ELLIOTT, M., & COHEN, P. (2003) · Biochemical Journal · doi:10.1042/bj20021535 · Cited by 1,369
Metadata
- Authors
- Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., & Saltiel, A. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1995-08-15
- Volume
- 92
- Issue
- 17
- Pages
- 7686-7689
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1971915141
- Cited by
- 2,679
- References
- 0
- FWCI
- 52.70
- Type
- journal article
- Language
- en
- Open access
- green
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- Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., & Saltiel, A. R. (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.92.17.7686
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