Programmed Cell Death and Its Regulation in C. e/egans
45
As expected from results obtained with the mammalian BH3-only
containing proteins, the EGL-l protein interacts with the Bcl-2-like
cell-death inhibitor CED-9 in a BH3-dependent manner in vitro and in a
yeast two-hybrid system (Conradt and Horvitz 1998). This finding suggests a molecular mechanism for the initiation of the programmed
cell-death process in C. elegans (Fig. 2B). egl-l initiates programmed
cell death in C. elegans in a ced-4- and ced-3-dependent manner. Furthermore, egl-l acts through ced-9. It is therefore likely that the EGL-l
protein induces programmed cell death by binding to the CED-9 protein, thereby negatively regulating the ability of CED-9 to inhibit CED4. How the binding of EGL-l to CED-9 might negatively regulate
CED-9 is not known. However, it has been suggested that the binding of
EGL-l to CED-9 results in the release of CED-4 from the membranebound complex (del Peso et al. 1998) (Fig. 2B). CED-4 could, for
example, be displaced if EGL-l and CED-4 competed for the same
binding site or if the binding of EGL-l to CED-9 resulted in a conformational change in the CED-9 protein which disrupts the interaction between CED-9 and CED-4.
3.7 Cell-Death Initiation Might Be Regulated
by Cell-Type Specific Factors
The EGL-l protein can be regarded as the initiator of programmed cell
death in the C. elegans soma. But how is EGL-l itself regulated? The
mammalian BH3-only containing proteins appear to be regulated by
diverse mechanisms. The removal of nerve growth factor from cultures
of sympathetic neurons, for instance, results in the transcriptional
upregulation of the BH3-only containing protein DPS (lmaizumi et al.
1997). The availability of growth factors also regulates the activity of
the BH3-only containing protein Bad. The ability of Bad to bind to
Bcl-2-like cell-death inhibitors and to induce programmed cell death,
however, is regulated at the posttranslationallevel through the phosphorylation of Bad at a critical serine residue (reviewed by Franke and
Cantley 1997). The BH3-only containing protein Bid is also regulated at
the posttranslational level, in this case through proteolytic cleavage at
specific sites (Luo et al. 1998; Li et al. 1998).
45
As expected from results obtained with the mammalian BH3-only
containing proteins, the EGL-l protein interacts with the Bcl-2-like
cell-death inhibitor CED-9 in a BH3-dependent manner in vitro and in a
yeast two-hybrid system (Conradt and Horvitz 1998). This finding suggests a molecular mechanism for the initiation of the programmed
cell-death process in C. elegans (Fig. 2B). egl-l initiates programmed
cell death in C. elegans in a ced-4- and ced-3-dependent manner. Furthermore, egl-l acts through ced-9. It is therefore likely that the EGL-l
protein induces programmed cell death by binding to the CED-9 protein, thereby negatively regulating the ability of CED-9 to inhibit CED4. How the binding of EGL-l to CED-9 might negatively regulate
CED-9 is not known. However, it has been suggested that the binding of
EGL-l to CED-9 results in the release of CED-4 from the membranebound complex (del Peso et al. 1998) (Fig. 2B). CED-4 could, for
example, be displaced if EGL-l and CED-4 competed for the same
binding site or if the binding of EGL-l to CED-9 resulted in a conformational change in the CED-9 protein which disrupts the interaction between CED-9 and CED-4.
3.7 Cell-Death Initiation Might Be Regulated
by Cell-Type Specific Factors
The EGL-l protein can be regarded as the initiator of programmed cell
death in the C. elegans soma. But how is EGL-l itself regulated? The
mammalian BH3-only containing proteins appear to be regulated by
diverse mechanisms. The removal of nerve growth factor from cultures
of sympathetic neurons, for instance, results in the transcriptional
upregulation of the BH3-only containing protein DPS (lmaizumi et al.
1997). The availability of growth factors also regulates the activity of
the BH3-only containing protein Bad. The ability of Bad to bind to
Bcl-2-like cell-death inhibitors and to induce programmed cell death,
however, is regulated at the posttranslationallevel through the phosphorylation of Bad at a critical serine residue (reviewed by Franke and
Cantley 1997). The BH3-only containing protein Bid is also regulated at
the posttranslational level, in this case through proteolytic cleavage at
specific sites (Luo et al. 1998; Li et al. 1998).