Oncogenic B-RafV600E inhibits apoptosis and promotes ERK-dependent inactivation of Bad and Bim.

摘要: Recent studies have revealed that B-Raf mutations are very common in malignant melanoma and required for tumor growth maintenance. The majority of melanoma-associated involve a single point mutation, V600E, which results greatly elevated kinase activity constitutive activation MAPK/ERK downstream. Here we show B-RafV600E increases resistance to apoptosis induced by chemotherapeutic drugs promotes ERK-dependent phosphorylation the BH3-only proteins Bim Bad involved setting thresholds apoptosis. resulted degradation this protein, whereas has previously been shown result its sequestration 14-3-3 proteins. Consistent with this, inhibition ERK panel cell lines stabilization dephosphorylation Bad. Furthermore, through overexpression or was efficiently blocked coexpression mutant B-RafV600E. However, small interfering RNA-mediated silencing expression conferred only modest protection against cytotoxic drugs, oncogenic strongly protected same stimuli. These observations suggest B-Raf-initiated inactivation partly contributes anti-apoptotic activities oncogene other points within death machinery also targeted deregulated signaling.