Journal of Oral Biosciences
Online ISSN : 1880-3865
Print ISSN : 1349-0079
ISSN-L : 1349-0079
Involvement of HSP90 in Anti-Fas-induced Apoptosis Signaling in the Human Salivary Gland Adenocarcinoma Cell Line HSG
Noriko KitoSeiko KyakumotoNaoyuki Chosa
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2004 Volume 46 Issue 3 Pages 229-242


It has been reported that heat shock protein (HSP) 90 is involved in the regulation of signaling cascades including those resulting in cell proliferation and apoptosis. However, little is known about how HSP90 affects apoptosis signaling.
In this study, using a specific inhibitor of HSP90, geldanamycin (GDM), we investigated the relationship between HSP90 and anti-Fas antibody-induced apoptosis in HSG cells and concomitantly examined the apoptosis-inducing ability of GDM. We also sought to identify the target proteins of HSP90. When HSG cells were treated with GDM, a time-dependent increase in cell death was found. From the morphological features, the positive TdT-mediated dUTP nick end labeling (TUNEL) staining, and the cleavage of poly (ADP-ribose) polymerase (PARP), we concluded that the induced cell death was apoptotic. The pretreatment with GDM prior to that with anti-Fas antibody (CH-11) significantly increased the cell death as compared with that obtained with GDM or CH-11 alone. Further, prolonged incubation with GDM prominently enhanced the cell death. The induced cell death was also apoptotic. The transfection of HSG cells with recombinant HSP90α significantly inhibited the CH-11- and GDM-induced apoptosis. From the inhibition and overexpression experiments on HSP90 using GDM treatment and transfection with HSP90, respectively, we showed that HSP90 has an anti-apoptotic activity toward HSG cells. Immunoprecipitation with antihuman HSP90 antibody and subsequent Western blotting analysis of the precipitates detected bands for Caspase-8 and FADD-like ICE inhibitory protein (FLIP), which is known to regulate Fas cascade. Therefore, Caspase-8 and FLIP were shown to be target proteins of HSP90. These results suggest that HSP90 inhibits apoptosis by associating with Caspase-8 and FLIP and negatively regulating their functions.

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© 2004 by Japanese Association for Oral Biology
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