Executioner Caspase-3, -6, and -7 Perform Distinct, Non-redundant Roles during the Demolition Phase of Apoptosis*

By E. Slee, C. Adrain, Seamus J. Martin. Journal of Biological Chemistry, 2001

1,162 citations recorded by the source corpus.

Apoptosis is orchestrated by a family of cysteine proteases known as the caspases. Fourteen mammalian caspases have been identified, three of which (caspase-3, -6, and -7) are thought to coordinate the execution phase of apoptosis by cleaving multiple structural and repair proteins. However, the relative contributions that the “executioner” caspases make to the demolition of the cell remains speculative. Here we have used cell-free extracts immuno-depleted of either caspase-3, -6, or -7 to examine the caspase requirements for apoptosis-associated proteolysis of 14 caspase substrates as well as nuclear condensation, chromatin margination, and DNA fragmentation. We show that caspase-3 is the primary executioner caspase in this system, necessary for cytochromec/dATP-inducible cleavage of fodrin, gelsolin, U1 small nuclear ribonucleoprotein, DNA fragmentation factor 45 (DFF45)/inhibitor of caspase-activated DNase (ICAD), receptor-interacting protein (RIP), X-linked inhibitor of apoptosis protein (X-IAP), signal transducer and activator of transcription-1 (STAT1), topoisomerase I, vimentin, Rb, and lamin B but not for cleavage of poly(ADP-ribose) polymerase (PARP) or lamin A. In addition, caspase-3 was also essential for apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse in this system. Surprisingly, although caspase-6 and -7 are considered to be important downstream effector caspases, depletion of either caspase had minimal impact on any of the parameters investigated, calling into question their precise role during the execution phase of apoptosis.

Subfields: Immunology, Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/3fd600496d8999f9af9a1aabe8c48d250f3287ae

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In Immunology

1. Junying Yuan
2. Susan A. Elmore
3. D. Ofengeim
4. Simone Fulda
5. M. Circu
6. T. Aw

In Molecular Biology

1. Junying Yuan
2. M. Boyce
3. Alexei Degterev
4. Susan A. Elmore
5. D. Ofengeim
6. Simone Fulda
7. M. Circu
8. T. Aw

Citations in the corpus

• A decade of caspases (2003, background): “Similarly, depletion of caspase-3 in a cell-free apoptotic system inhibited most of the downstream events, including various substrate cleavages, DNA fragmentation, chromatin marginalization, etc., whereas elimination of either caspase-6 or -7 had no effect (Slee et al., 2001).”
• Nuclear lamins: building blocks of nuclear architecture. (2002, background): “In the case of human lamins A and B1, the aspartic acid that is cleaved is conserved, but the remainder of the caspase recognition sequence differs, suggesting that different caspases may be involved in the cleavage of different lamin isotypes (Takahashi et al. 1996, 1997; Slee et al. 2001).”
• Apoptosis: A Review of Programmed Cell Death (2007, background): “…as effector or “executioner” caspases, cleaving various substrates including cytokeratins, PARP, the plasma membrane cytoskeletal protein alpha fodrin, the nuclear protein NuMA and others, that ultimately cause the morphological and biochemical changes seen in apoptotic cells (Slee et al., 2001).”