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Role of Bim in the survival pathway induced by Raf in epithelial cells

2003; Springer Nature; Volume: 23; Issue: 14 Linguagem: Inglês

10.1038/sj.onc.1207364

1476-5594

Michela Marani, David C. Hancock, Rita Lopes, Tencho Tenev, Julian Downward, Nicholas R. Lemoine,

Melanoma and MAPK Pathways

Selective and sustained activation of the Raf/MAP kinase pathway in MCF-10A ΔRaf-ER cells, a spontaneously immortalized human mammary epithelial cell line, was previously shown to protect these cells from suspension-induced cell death, a critical feature of the Ras-transformed phenotype. Although autocrine signalling through the EGF receptor is crucial for the protection induced by Raf in these cells, we report here the existence of an additional, more direct survival mechanism, linking Raf activation to the inhibition of a proapoptotic member of the Bcl-2 family, Bim. While detachment from the matrix results in transcriptional induction of two variants of this BH3-only protein, BimEL and BimL, activation of the Raf/ERK signalling both prevents Bim upregulation specifically and leads to phosphorylation and degradation of the BimEL isoform. This represents an important route to protect epithelial cells from the proapoptotic effect of Bim.