Trends in Cell Biology
Volume 9, Issue 12, 1 December 1999, Pages M49-M52
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Review
Death by design: mechanism and control of apoptosis

https://doi.org/10.1016/S0962-8924(99)01670-0Get rights and content

Abstract

Active cellular suicide by apoptosis plays important roles in animal development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke and many neurodegenerative disorders. A central step in the execution of apoptosis is the activation of an unusual class of cysteine proteases, termed caspases, that are widely expressed as inactive zymogens. Originally, the mechanisms for regulating the caspase-based cell death programme seemed to be different in Caenorhabditis elegans, mammals and insects. However, recent results suggest that these apparent differences in the control of cell death reflect our incomplete knowledge, rather than genuine mechanistic differences between different organisms.

Section snippets

Caspases: the loaded gun

Caspases are a family of cysteine proteases that function in apoptosis or cytokine processing, or both. They are synthesized as pro-enzymes (or zymogens) and remain inactive in most healthy cells. Upon activation by different death signals, the single-chain pro-caspases are cleaved at specific aspartic acid residues to remove an inhibitory N-terminal pro-domain and to generate two distinct subunits. These subunits assemble into a heterotetramer to form the active protease9. Once activated,

Death receptors, the direct physical activators of caspases

Possibly the best-understood pathway for activating caspases through induced proximity is the CD-95/Fas/Apo-1 system11, 12. CD-95 belongs to the tumour-necrosis factor receptor (TNFR) family and functions in the removal of activated T cells at the end of the immune response. Binding of extracellular ligands, such as the Fas ligand, to these receptors induces trimerization of the receptor. This trimerization, in turn, recruits the adaptor molecule FADD and pro-caspase-8 into a multimeric complex

Caspase activation by CED-4/Apaf-1 and cytochrome c, the unexpected internal death signal

Another important class of caspase-activating molecules is represented by C. elegans CED-4 and mammalian Apaf-1. The ced-4 gene acts genetically upstream of ced-3 in C. elegans, and CED-4 can physically interact with pro-CED-3 and certain mammalian pro-caspases15, 16, 17. Apaf-1, which shares significant amino acid homology with CED-4, can bind to the pro-domain of pro- caspase-9 and activate it in the presence of cytochrome c and dATP in a cell-free system18. These observations suggest that

Double-edged swords in the regulation of caspase activation: the Bcl-2 protein family

In C. elegans, the activity of CED-9 is required to prevent inappropriate cell deaths, and ced-9 acts genetically upstream of ced-4 and ced-3 (Ref. 21). Significantly, ced-9 encodes a protein homologous to mammalian Bcl-2-like molecules that regulates apoptosis in mammals22, 23. The human BCL-2 gene was identified initially at a translocation breakpoint that is common in many B-cell lymphomas. As a result of this translocation, BCL-2 comes under the control of the immunoglobulin heavy chain

The other brake on death: inhibitor of apoptosis proteins (IAPs)

Inhibitor of apoptosis proteins (IAPs) were first discovered in baculovirus through their ability to inhibit apoptosis of insect cells upon viral infections32, 33. The characteristic structural motif of all IAP family members is the baculovirus IAP-repeat (BIR) of ∼70 amino acids. Different IAPs can have between one and three BIRs. Besides the BIR domain, some IAP members also contain additional structural motifs that have been described in other molecules, such as a RING and a CARD domain. To

Harbingers of death from Drosophila: REAPER, HID and GRIM

The induction of apoptosis in Drosophila requires the activities of three closely linked genes, reaper (rpr), grim and head involution defective (hid), whose gene products kill by activating a caspase pathway36. reaper, hid and grim are all transcriptionally regulated by a variety of death-inducing stimuli, and the hid gene is repressed by active Ras signalling37, 38. Therefore, it appears that these genes act as integrators for relaying different death-inducing signals to the core death

Have insects evolved a distinct mechanism for the control of apoptosis?

The apparent absence of Bcl-2- and CED-4/Apaf-1-family proteins in Drosophila, and the lack of mammalian homologues for RPR, HID and GRIM, led to the impression that the regulation of programmed cell death in Drosophila might be distinct from that in C. elegans and vertebrates43, 44. However, the recent discovery of Drosophila homologues of ced-4/Apaf-1 and Bcl-2- like sequences indicates that these apparent differences might be of historical, but not of functional, significance45, 46. Rather,

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