Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis.
Transforming growth factor-beta (TGFbeta)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGFbeta-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 TGFbeta-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 TGFbeta, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGFbeta-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGFbeta-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGFbeta-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.
Ramjaun
A R
AR
1Signal Transduction, Cancer Research UK London Research Institute, London, UK.
Tomlinson
S
S
Eddaoudi
A
A
Downward
J
J
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D045744:Cell Line, Tumor; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; C435486:Bmf protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta