The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity
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 sup...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
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American Society of Hematology
2011
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| Online Access: | http://hdl.handle.net/20.500.11937/51018 |
| _version_ | 1848758593727234048 |
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| author | Velaithan, R. Kang, J. Hirpara, J. Loh, T. Goh, B. Le Bras, M. Brenner, C. Clement, M. Pervaiz, Shazib |
| author_facet | Velaithan, R. Kang, J. Hirpara, J. Loh, T. Goh, B. Le Bras, M. Brenner, C. Clement, M. Pervaiz, Shazib |
| author_sort | Velaithan, R. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T09:46:28Z |
| format | Journal Article |
| id | curtin-20.500.11937-51018 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:46:28Z |
| publishDate | 2011 |
| publisher | American Society of Hematology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-510182017-09-13T15:34:51Z The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity Velaithan, R. Kang, J. Hirpara, J. Loh, T. Goh, B. Le Bras, M. Brenner, C. Clement, M. Pervaiz, Shazib 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. 2011 Journal Article http://hdl.handle.net/20.500.11937/51018 10.1182/blood-2010-08-301283 American Society of Hematology unknown |
| spellingShingle | Velaithan, R. Kang, J. Hirpara, J. Loh, T. Goh, B. Le Bras, M. Brenner, C. Clement, M. Pervaiz, Shazib The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title | The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title_full | The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title_fullStr | The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title_full_unstemmed | The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title_short | The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity |
| title_sort | small gtpase rac1 is a novel binding partner of bcl-2 and stabilizes its antiapoptotic activity |
| url | http://hdl.handle.net/20.500.11937/51018 |