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Sci. STKE, 22 August 2000
Vol. 2000, Issue 46, p. tw6
[DOI: 10.1126/stke.2000.46.tw6]

EDITORS' CHOICE

Apoptosis HSP90 Inhibits Intrinsic Apoptosis

The extrinsic apoptosis pathway depends on the activation of death receptors and caspase-8 leading to the cleavage of Bid and the release of cytochrome c (cyt c). The intrinsic apoptosis pathway, however, is receptor-independent and requires cyt c to form a complex with Apaf-1, leading to the oligomerization of Apaf-1 and the activation of caspase-9 and, subsequently, caspase-3. Cellular stress often leads to increased levels of heat shock proteins (HSPs); these proteins have various roles in regulating proper protein folding and preventing protein aggregation. Additionally, levels of HSPs increase after apoptotic stimulation. Pandey et al. examined the role of HSP90 in intrinsic apoptosis and observed that HSP90 can block caspase-3 activation and apoptosis. HSP90β coprecipitated with cyt c; however, this association was indirect and, subsequently, the authors showed that Apaf-1 directly associates with HSP90β. Immunodepletion of HSP90β from cell lysates also depleted Apaf-1, preventing the cyt c-dependent proteolytic cleavage (activation) of caspase-3. Neither caspase-9 nor caspase-3 coprecipitated with HSP90β. The authors observed that HSP90β blocked the ability of Apaf-1 to oligomerize in vitro and in vivo, which suggests a braking mechanism preventing inexorable apoptosis, whereby the prevention of Apaf-1 oligomerization by HSP90β blocks the ability of caspase-9 to bind to the Apaf-1 complex and to be activated by it.

Pandey, P., Saleh, A., Nakazawa, A., Kumar, S., Srinivasula, S.M., Kumar, V., Weichselbaum, R., Nalin, C., Alnemri, E.S., Kufe, D., and Kharbanda, S.S. (2000) Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 19: 4310-4322. [Abstract] [Full Text]

Citation: HSP90 Inhibits Intrinsic Apoptosis. Sci. STKE 2000, tw6 (2000).


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