|
Title
|
|
|
|
Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Triggering tumor necrosis factor receptor-1 (TNFR1) induces apoptosis in various cell lines. In contrast, stimulation of TNFR1 in L929sA leads to necrosis. Inhibition of HSP90, a chaperone for many kinases, by geldanamycin or radicicol shifted the response of L929sA cells to TNF from necrosis to apoptosis. This shift was blocked by CrmA but not by BCL-2 overexpression, suggesting that it occurred through activation of procaspase-8. Geldanamycin pretreatment led to a proteasome-dependent decrease in the levels of several TNFR1-interacting proteins including the kinases receptor-interacting protein, inhibitor of kappaB kinase-alpha, inhibitor of kappaB kinase-beta, and to a lesser extent the adaptors NF-kappaB essential modulator and tumor necrosis factor receptor-associated factor 2. As a consequence, NF-kappaB, p38MAPK, and JNK activation were abolished. No significant decrease in the levels of mitogen-activated protein kinases, adaptor proteins TNFR-associated death domain and Fas-associated death domain, or caspase-3, -8, and -9 could be detected. These results suggest that HSP90 client proteins play a crucial role in necrotic signaling. We conclude that inhibition of HSP90 may alter the composition of the TNFR1 complex, favoring the caspase-8-dependent apoptotic pathway. In the absence of geldanamycin, certain HSP90 client proteins may be preferentially recruited to the TNFR1 complex, promoting necrosis. Thus, the availability of proteins such as receptor-interacting protein, Fas-associated death domain, and caspase-8 can determine whether TNFR1 activation will lead to apoptosis or to necrosis. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Journal of biological chemistry. - Baltimore, Md
| |
|
Publication
|
|
|
|
Baltimore, Md
:
2003
| |
|
ISSN
|
|
|
|
0021-9258
[print]
1083-351X
[online]
| |
|
DOI
|
|
|
|
10.1074/JBC.M208925200
| |
|
Volume/pages
|
|
|
|
278
:8
(2003)
, p. 5622-5629
| |
|
ISI
|
|
|
|
000181129400019
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|