Genetics of Apoptosis

two proteins Bcl-2 and Apaf-1 do not directly interact in vivo (Conus et al., 2000).
In addition, the order of protein function is supported by the fact that overexpression
of both CED-3 and CED-4 can trigger programmed cell death in C. elegans, as well
as upon transfection into mammalian cells (Shaham and Horvitz, 1996; Chinnaiyan
et al., 1997a,b; Wu, D. et al., 1997). Upon liberation from CED-9, CED-4
translocates to the nuclear membrane in vivo (Chen et al., 2000b). This translocation
can be induced by egl-1 overexpression, and it precedes the activation of programmed
cell death; therefore, it might be an integral part of cell-death activation (Chen et al.,
2000b). Consequently, CED-4 is thought to confer CED-3 activation by its
association with a homopolymeric complex that is needed to bring inactive CED-3
molecules into close proximity (via CED-4 binding), thereby leading to the activation
of programmed cell death via CED-3 caspase activation (Yang, X. et al., 1998).

9.

Modulators and downstream components of the cell-death

pathway

Very little is known about components that modulate the cell-death pathway or about
targets of the cell-death pathway. ced-8 causes an overall slowing down of the cell-
death process (Ellis et al., 1991; Stanfield and Horvitz, 2000). As compared to the
wild-type animals, an equal number of programmed cell deaths occur, and these
deaths are initiated at the same time as in wild-type animals. When ced-8 is combined
with very weak alleles of ced-3 or ced-4, the weak cell-death defect of these two
mutations is enhanced. ced-8 encodes a protein similar to the human XK

Figure 4. A molecular model for the activation of the core cell-death program.

The corresponding model is described in the text.

170 GENETICS OF APOPTOSIS