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Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-12-3718. This Article Full Text (PDF) All Versions of this Article: 2002-12-3718v1 102/1/269    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nimmanapalli, R. Articles by Bhalla, K. N Search for Related Content PubMed PubMed Citation Articles by Nimmanapalli, R. Articles by Bhalla, K. N Social Bookmarking                   What's this? Submitted December 16, 2002 Accepted February 23, 2003 Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-xL, and Bax downstream of 17-AAG-mediated downregulation of Akt, Raf-1 and Src kinases Ramadevi Nimmanapalli, Erica O'Bryan, Deborah Kuhn, Hirohito Yamaguchi, Hong-Gang Wang, and Kapil N Bhalla* Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA * Corresponding author; email: bhallakn{at}moffitt.usf.edu. 17-allylamino-demethoxy geldanamycin (17-AAG) is a less toxic analogue of the ansamycin antiobiotic geldanamycin. By inhibiting the chaperone function of heat shock protein-90 (Hsp-90), 17-AAG promotes the proteasomal degradation of the misfolded client proteins of Hsp-90. Here, we demonstrate that treatment of the human AML HL-60 cells with 17-AAG attenuates the intracellular levels of a number of Hsp-90-client proteins, including Akt, c-Raf-1, and c-Src protein kinases, which are known to mediate growth, proliferation and survival signaling in AML cells. 17-AAG also induced the mitochondrial release and cytosolic accumulation of cytochrome (cyt) c and Smac/DIABLO, resulting in the activation of caspase-9 and -3 and apoptosis. Treatment with 17-AAG triggered the Bax conformational change associated with apoptosis, while Bax deficient cells were resistant to 17-AAG induced apoptosis. In addition, in HL-60/Bcl-2 and HL-60/ Bcl-xL cells, which contain an ectopic overexpression of Bcl-2 and Bcl-xL, respectively, 17-AAG-induced Bax conformational change, cytosolic accumulation of cyt c and Smac/DIABLO and apoptosis were markedly inhibited. Although the state of 17-AAG mediated decline in Akt, c-Raf-1 and c-Src protein levels was blunted, the totalt decline was not compromised in HL-60/Bcl-2 and HL-60/ Bcl-xL cells. Co-treatment with HA14-1, a non-peptidic small molecule ligand that can bind to the surface pocket of Bcl-2 and inhibits its antiapoptotic activity, significantly overcame the resistance to 17-AAG-induced apoptosis in HL-60/Bcl-2 cells. Taken together, these findings indicate that although treatment with 17-AAG causes a decline in the levels of a number of survival signaling protein kinases, the downstream engagement of the mitochondrial pathway of apoptosis is regulated by the activity of the Bcl-2 family of proteins. The findings also highlight that neutralizing the antiapoptotic effect of Bcl-2 would further enhance the antileukemia activity of 17-AAG. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Hermanson, S. N. 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