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Role of Bim in the survival pathway induced by Raf in epithelial cells

Oncogene volume 23, pages 2431–2441 (2004)Cite this article

Abstract

Selective and sustained activation of the Raf/MAP kinase pathway in MCF-10A ΔRaf-ER cells, a spontaneously immortalized human mammary epithelial cell line, was previously shown to protect these cells from suspension-induced cell death, a critical feature of the Ras-transformed phenotype. Although autocrine signalling through the EGF receptor is crucial for the protection induced by Raf in these cells, we report here the existence of an additional, more direct survival mechanism, linking Raf activation to the inhibition of a proapoptotic member of the Bcl-2 family, Bim. While detachment from the matrix results in transcriptional induction of two variants of this BH3-only protein, BimEL and BimL, activation of the Raf/ERK signalling both prevents Bim upregulation specifically and leads to phosphorylation and degradation of the BimEL isoform. This represents an important route to protect epithelial cells from the proapoptotic effect of Bim.

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Acknowledgements

This work was supported by programme grants from Cancer Research UK. Michela Marani and Nick Lemoine thank the Mike Stone Cancer Research Fund and the Special Trustees of Hammersmith Hospitals Trust for support; Rita Lopes is supported by the Fundaçâo para Ciência e Tecnologia of Portugal.

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Authors and Affiliations

  1. Cancer Research UK Molecular Oncology Unit, Imperial College London, Hammersmith Hospital, DuCane Road, London, W12 0NN, UK

    Michela Marani, Rita Lopes, Tencho Tenev & Nicholas R Lemoine

  2. Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    David Hancock & Julian Downward

  3. The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London, SW3 6JB, UK

    Tencho Tenev

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  1. Michela Marani
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Correspondence to Nicholas R Lemoine.

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Marani, M., Hancock, D., Lopes, R. et al. Role of Bim in the survival pathway induced by Raf in epithelial cells. Oncogene 23, 2431–2441 (2004). https://doi.org/10.1038/sj.onc.1207364

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