Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function
Details
Publication Year 2012-05-03, Volume 119, Issue #18, Page 4283-4290
Journal Title
BLOOD
Publication Type
Journal Article
Abstract
Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737-induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9(-/-) platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function. (Blood. 2012;119(18):4283-4290)
Publisher
AMER SOC HEMATOLOGY
Keywords
PROGRAMMED CELL-DEATH; CYTOCHROME-C; PHOSPHATIDYLSERINE EXPOSURE; DIFFERENTIAL REQUIREMENT; ACTIVATION; BAX; INHIBITION; PATHWAY; BIM; MITOCHONDRIA
WEHI Research Division(s)
Cancer And Haematology; Molecular Genetics Of Cancer; Molecular Medicine; Chemical Biology
Rights Notice
© 2012 by The American Society of Hematology


Creation Date: 2012-05-03 12:00:00
Last Modified: 0001-01-01 12:00:00
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