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

Oncogene volume 26, pages 970–981 (2007)Cite this article

Abstract

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

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Acknowledgements

We would like to thank Yvonne Hey at the Paterson Institute for performing the Affymetrix Microarray analysis. We would also like to thank David Huang, Lorraine O'Reilly and Andreas Strasser for Bmf antibody, as well as members of the Downward laboratory for helpful discussions and advice. This work was funded by Cancer Research UK.

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Authors and Affiliations

  1. Signal Transduction, Cancer Research UK London Research Institute, London, UK

    A R Ramjaun & J Downward

  2. Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK

    S Tomlinson

  3. Fluorescence Activated Cell Sorting Laboratories, Cancer Research UK London Research Institute, London, UK

    A Eddaoudi

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  1. A R Ramjaun
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Correspondence to J Downward.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ramjaun, A., Tomlinson, S., Eddaoudi, A. et al. Upregulation of two BH3-only proteins, Bmf and Bim, during TGFβ-induced apoptosis. Oncogene 26, 970–981 (2007). https://doi.org/10.1038/sj.onc.1209852

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