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- Title
Activation of ERK1/2 by ?Raf-1?:?ER* represses Bim expression independently of the JNK or PI3K pathways.
- Authors
Weston, Claire R; Balmanno, Kathryn; Chalmers, Claire; Hadfield, Kathryn; Molton, Sarah A; Ley, Rebecca; Wagner, Erwin F; Cook, Simon J
- Abstract
CC139 fibroblasts are one of several model systems in which the Raf?MEK?ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of BimEL, a proapoptotic 'BH3-only' member of the Bcl-2 protein family. BimEL expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK?c-Jun pathway was neither necessary nor sufficient to induce BimEL expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of BimEL. Furthermore, selective activation of the ERK1/2 pathway by ?Raf-1:ER* substantially reduced BimEL expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of ?Raf-1:ER* to repress BimEL expression required the ERK pathway but was independent of the PI3K?PDK?PKB pathway. Thus, serum withdrawal-induced expression of BimEL occurs independently of the JNK?c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.Oncogene (2003) 22, 1281-1293. doi:10.1038/sj.onc.1206261
- Subjects
APOPTOSIS; GENE expression; FIBROBLASTS
- Publication
Oncogene, 2003, Vol 22, Issue 9, p1281
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1206261