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Title: The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity
Authors: Velaithan, R. 
Kang, J.
Hirpara, J.L. 
Loh, T.
Goh, B.C.
Le Bras, M.
Brenner, C.
Clement, M.-V. 
Pervaiz, S.
Issue Date: 9-Jun-2011
Citation: Velaithan, R., Kang, J., Hirpara, J.L., Loh, T., Goh, B.C., Le Bras, M., Brenner, C., Clement, M.-V., Pervaiz, S. (2011-06-09). The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity. Blood 117 (23) : 6214-6226. ScholarBank@NUS Repository.
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.
Source Title: Blood
ISSN: 00064971
DOI: 10.1182/blood-2010-08-301283
Appears in Collections:Staff Publications

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