1. ¹Signal Transduction, Cancer Research UK London Research Institute, London, UK
2. ²Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK
3. ³Fluorescence Activated Cell Sorting Laboratories, Cancer Research UK London Research Institute, London, UK

Correspondence: Professor J Downward, Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. E-mail: downward@cancer.org.uk

Received 2 February 2006; Revised 27 June 2006; Accepted 28 June 2006; Published online 14 August 2006.

Abstract

Transforming growth factor- (TGF)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGF-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-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 TGF, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGF-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGF-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGF-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.