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The caspase family of cysteine proteases
1Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey, 07065, USA.
Abstract:
The discovery that CED-3, the product of a gene necessary for programmed cell death in the nematode Caenorhabditis elegans, is related to the mammalian cysteine protease interleukin-1 beta converting enzyme (ICE/caspase-1) has led to intense interest in the role of proteases in apoptosis. It is now clear that at least some members of the caspase (ICE/CED-3) family, which at present includes ten homologues of human origin, are essential components of an evolutionarily conserved pathway of apoptosis. These enzymes appear to be involved in both the initial signaling events and the downstream proteolytic cleavages that result in the apoptotic phenotype. Selective macromolecular and peptide-based inhibitors attenuate apoptosis in whole cells, suggesting that one or more of these enzymes will be suitable targets for therapeutic intervention in diseases resulting from inappropriate cell death.
Insights
The discovery of CED-3
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Programmed cell death (apoptosis) is crucial in multicellular organisms.
- The nematode CED-3 gene product is essential for apoptosis.
- CED-3 shows homology to mammalian cysteine proteases like ICE/caspase-1.
Purpose of the Study:
- To investigate the role of proteases, specifically caspases, in apoptosis.
- To understand the evolutionary conservation of apoptotic pathways.
- To identify potential therapeutic targets for diseases involving abnormal cell death.
Main Methods:
- Comparative gene analysis between nematodes and mammals.
- Identification and characterization of caspase family members.
- Inhibition studies using selective macromolecular and peptide-based inhibitors.
Main Results:
- CED-3 is evolutionarily related to mammalian caspases.
- The caspase (ICE/CED-3) family includes at least ten human homologues.
- Caspases are integral to a conserved apoptotic pathway.
- These enzymes mediate both early signaling and downstream proteolytic events in apoptosis.
Conclusions:
- Caspases are essential components of the apoptotic pathway.
- Inhibiting caspases can attenuate apoptosis in cellular models.
- Caspase family members represent promising therapeutic targets for diseases characterized by inappropriate cell death.