Shiga toxin induces decreased expression of the anti-apoptotic protein Mcl-1 concomitant with the onset of endothelial apoptosis.
Shiga toxin (Stx) has been implicated in the pathogenesis of several human and animal disease states. A key host target of Stx is the endothelial cell. Stx induces endothelial cell apoptosis through a mechanism that remains unknown. In the present report, we demonstrate that Stx-1 and Stx-2 inhibit endothelial cell expression of the anti-apoptotic Bcl-2 family member, Mcl-1. Decreased expression of Mcl-1 preceded the onset of Stx-induced apoptosis. Further, Stx-1-induced decrements in Mcl-1 expression correlated in a dose-dependent manner with sensitization to Stx-1-induced apoptosis. Finally, inhibition of Mcl-1 degradation with the proteasome inhibitor, lactacystin, protected against Stx-1-induced apoptosis. These combined data suggest a role for Mcl-1 in protecting endothelial cells against Stx-1-induced apoptosis.
Erwert
Ryan D
RD
Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
Eiting
Kristine T
KT
Tupper
Joan C
JC
Winn
Robert K
RK
Harlan
John M
JM
Bannerman
Douglas D
DD
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D022622:Shiga Toxin 1 / Q000633:toxicity*; D022641:Shiga Toxin 2 / Q000633:toxicity*
D006657:Histones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases