Trends in Immunology
OpinionCaspases: more than just killers?
Section snippets
Apoptosis and cell proliferation
Although the processes of cell proliferation and cell death appear to be opposing and mutually contradictory, some evidence suggests that the two events are linked. The maintenance of genomic stability is essential for the survival of organisms. To ensure this stability, checkpoints exist to interrupt cell-cycle progression when damage to the genome is detected. In multicellular organisms, a further checkpoint is the induction of apoptosis to eliminate cells with irreparable DNA damage that
The role of caspases
Why should caspases be required for cell-cycle progression? One attractive hypothesis is that caspases could confer additional checkpoints, assuring that only healthy cells will complete the cell cycle. During apoptosis, FADD together with caspase-8 forms the death-inducing signaling complex (DISC). During mitosis, FADD could also associate with caspase-8 or with another hypothetical ‘mitotic DISC-forming protein’ (MDP), an event that might be facilitated by the phosphorylation of FADD at the
Apoptosis inhibitors and cell-cycle regulation
To protect cell-cycle-regulatory and other vital structures, the activity of caspases must be tightly regulated. This could be achieved by various apoptosis inhibitors. It has been observed that Bcl-2 (which, like FADD, is phosphorylated at the G2/M transition) delays the re-entry of resting NIH-3T3 cells into the cell cycle 15. Moreover, Bcl-2-transgenic mice have delayed T-cell proliferation, whereas transgenic overexpression of Bax accelerates cell-cycle progression and apoptosis 15., 16..
Concluding remarks
Clearly, much remains to be learned about a potential dual role of caspases in apoptosis and cell proliferation. Although the model presented in Fig. 1 is hypothetical, it may provide an explanation for the proliferative abnormalities and developmental defects that are observed in caspase-8- and FADD-deficient mice, as well as in animals overexpressing an inactive FADD mutant. Likewise, it could explain why caspases are generally not deleted or silenced in most tumors. In contrast to earlier
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