Upregulation of two BH3-only proteins, Bmf and Bim, during TGFβ-induced apoptosis

Transforming growth factor-beta (TGF beta)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGF beta-induced apoptosis remain controversial; although changes in gene expression are thought to be pivotal to the process, several different candidate apoptotic initiators and mediators have been proposed. Smad4, a critical component of the TGF beta-induced transcriptional machinery, is shown here to be essential for induction of apoptosis. Gene expression analysis identified the proapoptotic Bcl-2 family members, Bmf and Bim, as induced by TGFb, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGF beta-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGF beta-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGF beta-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.