Journal
CELLULAR SIGNALLING
Volume 22, Issue 3, Pages 467-475Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.10.018
Keywords
Apoptosis; Burkitt's lymphoma; Shiga toxin family; Gb3/CD77; Bcl-2 family
Categories
Funding
- Association pour la Recherche Sur le Cancer [ARC 3454]
- ARC
- Societe Francaise d'Hematologie
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Verotoxin (VT-1) is a cytotoxin, produced by Shigella dysenteriae type I or by Shiga toxin-producing Escherichia coli, which binds specifically to globotriaosylceramide (Gb3). This glycosphingolipid is a B cell differentiation antigen (Gb3/CD77) strongly expressed on Burkitt's lymphoma cells. We have previously shown that, in these cells, VT-1 induces apoptosis via a caspase- and mitochondria-dependent pathway. In this report, we provide new insights into this signal transduction pathway. First, we demonstrate that VT-1-induced apoptosis requires degradation of the caspase-8 inhibitory molecule c-FLIP,, and that this degradation occurs through the ubiquitin-proteasome pathway. Furthermore, we show that mitochondrial activation is mainly due to i) cleavage and activation of the pro-apoptotic Bcl-2 family member Bid by caspase-8 and ii) Bax relocalization to mitochondrial membranes which lead to cytochrome c release. However, tBid is not involved in Bax relocalization, and relocalization is most likely controlled by the extent of Bax phosphorylation: in non-treated BL cells, p38 MAPK participates in the retention of Bax in the cytoplasm in an inactive form whereas in VT-1 treated cells, protein phosphatase 2A is activated and induces Bax relocalization to mitochondria. (C) 2009 Elsevier Inc. All rights reserved.
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