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    The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity

    Access Status
    Open access via publisher
    Authors
    Velaithan, R.
    Kang, J.
    Hirpara, J.
    Loh, T.
    Goh, B.
    Le Bras, M.
    Brenner, C.
    Clement, M.
    Pervaiz, Shazib
    Date
    2011
    Type
    Journal Article
    
    Metadata
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    Citation
    Velaithan, R. and Kang, J. and Hirpara, J. and Loh, T. and Goh, B. and Le Bras, M. and Brenner, C. et al. 2011. The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity. Blood. 117 (23): pp. 6214-6226.
    Source Title
    Blood
    DOI
    10.1182/blood-2010-08-301283
    ISSN
    0006-4971
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/51018
    Collection
    • Curtin Research Publications
    Abstract

    The small GTPase Rac1 is involved in the activation of the reduced NAD phosphate oxidase complex resulting in superoxide production.We recently showed that Bcl-2 overexpression inhibited apoptosis in leukemia cells by creating a pro-oxidant intracellular milieu, and that inhibiting intracellular superoxide production sensitized Bcl-2-overexpressing cells to apoptotic stimuli. We report here that silencing and functional inhibition of Rac1 block Bcl-2- mediated increase in intracellular superoxide levels in tumor cells. Using confocal, electron microscopy and coimmunoprecipitation, as well as glutathione S-transferase- fusion proteins, we provide evidence for a colocalization and physical interaction between the 2 proteins. This interaction is blocked in vitro and in vivo by the BH3 mimetics as well as by synthetic Bcl-2 BH3 domain peptides. That this interaction is functionally relevant is supported by the ability of the Bcl-2BH3peptide as well as the silencing and functional inhibition of Rac1 to inhibit intracellular superoxide production as well as overcome Bcl-2-mediated drug resistance in human leukemia cells and cervical cancer cells. Notably, the interaction was observed in primary cells derived from patients with B-cell lymphoma overexpressing Bcl-2 but not in noncancerous tissue. These data provide a novel facet in the biology of Bcl-2 with potential implications for targeted anticancer drug design. © 2011 by The American Society of Hematology.

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