title: Promotion of Caspase Activation by Caspase-9-mediated Feedback Amplification of Mitochondrial Damage.
abstract: Mitochondrial disruption during apoptosis results in the activation of caspase-9 and a downstream caspase cascade. Triggering this caspase cascade leads to the cleavage of anti-apoptotic Bcl-2 family proteins, resulting in feedback amplification of mitochondrial disruption. However, whether such a feedback loop plays an important role in the promotion of caspase activation and execution of apoptosis has not been well established. We observed that mutated Bcl-2 or Bcl-xL that are resistant to cleavage by caspases inhibited caspase-9-induced caspase activation in human H9 T cells. The release of Smac after the activation of caspase-9 was also inhibited by cleavage-resistant Bcl-2 or Bcl-xL. Consistently, caspase-9-deficient cells were defective in the release of Smac after induction of apoptosis. Moreover, addition of a Smac mimetic overcame the inhibitory effects of cleavage-resistant Bcl-2/Bcl-xL, and restored caspase-9-mediated cell death. Our data suggest that caspase-9-induced feedback disruption of mitochondria plays an important role in promoting the activation of caspases, while a defect in this process can be overcome by promoting Smac functions.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Guerrero
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
keywords: bcl-2; bcl-xL; caspase-9; mitochondrial feedback
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