Tributyltin (TBT) induces ultra-rapid caspase activation independent of apoptosome formation in human platelets.
Activation of caspases has been demonstrated to be involved in thrombocytopenia and prolonged storage of platelet concentrates. Platelets represent enucleate cells that comprise all elements of the mitochondrial apoptosis pathway. However, no apoptotic stimuli capable of activating the endogenous caspase cascade have been identified so far. Using tributyltin (TBT) we could identify a compound that is capable of activating caspase-9 and -3 in platelets. Recent studies implicate that TBT induces apoptosis via the mitochondrial signaling pathway that is characterized by the formation of a high-molecular-weight complex (apoptosome) containing the adapter protein Apaf-1 and active caspase-9. Interestingly, addition of TBT induced the activation of caspase-9 in an ultra-rapid kinetic within the first 2 min. In addition, size exclusion chromatography revealed that TBT-mediated processing of caspase-9 occurs in the absence of the apoptosome. Thus, these data implicate that TBT induces the activation of caspase-9 by a mechanism not involving the formation of the apoptosome.
Berg
Christoph P
CP
Department of Internal Medicine I, University of Tübingen, Germany.
Rothbart
Andreas
A
Lauber
Kirsten
K
Stein
Gerburg M
GM
Engels
Ingo H
IH
Belka
Claus
C
Jänicke
Reiner U
RU
Schulze-Osthoff
Klaus
K
Wesselborg
Sebastian
S
D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D013997:Time Factors; D014220:Trialkyltin Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*
D014220:Trialkyltin Compounds; C011559:tributyltin; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases