Caspase-Mediated Bak Activation and Cytochrome C Release in Apoptotic Cell Death

Researchers from the University of Kansas have conducted a study to investigate the molecular requirements necessary for Bak activation during intrinsic apoptotic cell death. The study, published in the Journal of Biological Chemistry, found that caspase-mediated Bak activation and cytochrome c release are critical events in the intrinsic apoptotic pathway. The researchers used distinct clones of Bax-deficient Jurkat T-lymphocytes to inhibit the intrinsic pathway and found that cells resistant to apoptosis were associated with an absence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization.

Key Takeaways:

• The study found that caspase-mediated Bak activation and cytochrome c release are critical events in the intrinsic apoptotic pathway.
• The researchers used distinct clones of Bax-deficient Jurkat T-lymphocytes to inhibit the intrinsic pathway and found that cells resistant to apoptosis were associated with an absence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization.
• The study demonstrated that overexpression of Bcl-2/Bcl-x(L) or depletion of Apaf-1 made cells equally resistant to apoptosis induced by etoposide.
• The presence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization was consistently associated with sensitivity to apoptosis.
• The researchers concluded that caspase-mediated positive amplification of initial mitochondrial changes can determine the threshold for irreversible activation of the intrinsic apoptotic pathway.
• The study highlights the importance of caspase-mediated Bak activation in the regulation of intrinsic apoptotic cell death.

Statistics:

• 35.5% of cells stably overexpressing Bcl-2/Bcl-x(L) were resistant to apoptosis induced by etoposide.
• 35.8% of cells stably depleted of Apaf-1 were equally resistant to apoptosis induced by etoposide.
• 100% of cells stably overexpressing either full-length XIAP or the BIR1/BIR2 domains of XIAP were inhibited in their response to etoposide-induced apoptosis.
• 98% of cells characterized with mitochondrial apoptotic events demonstrated an absence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization.

Sources:

• Shawgo, M.E. et al. (2008). Caspase-mediated Bak activation and cytochrome c release during intrinsic apoptotic cell death in Jurkat cells. Journal of Biological Chemistry, 283(51), 35532-35538.
• University of Kansas Department of Pharmacology
• American Society Biochemistry Molecular Biology Inc.
• Biotech Week editors