42
B. Conradt
is required for proCED-3 activation (Chaudhary et al. 1998). Interestingly, the insertion into the P-Ioop region of 24 amino acids in the
CED-4L protein results in the disruption of this specific interaction and
the inability of the CED-4L protein to activate proCED-3 (Chaudhary et
al. 1998). CED-4 also interacts with the cell-death inhibitor protein
CED-9 (Spector et al. 1997; Chinnaiyan et al. 1997a; Wu et al. 1997a;
Seshagiri and Miller 1997; Ottilie et al. 1997), the latter being membrane-associated due to a hydrophobic region at the C-terminus (Wu et
al. 1997a; Chaudhary et al. 1998; Hisahara et al. 1998). The presence of
CED-9 blocks the CED-4-dependent activation of proCED-3 (Chinn aiyan et al. 1997a; Seshagiri and Miller 1997; Wu et al. 1997b). It is
therefore likely that, by binding to CED-4, CED-9 inhibits the ability of
CED-4 to activate proCED-3. CED-9 might block the oligomerization
of CED-4 or disrupt the interaction of the P-Ioop region of CED-4 with
proCED-3 (Yang et al. 1998; Chaudhary et al. 1998). CED-9, CED-4,
and proCED-3 possibly form a ternary complex (Chinnaiyan et al.
1997a; Wu et al. 1997b) which has been proposed to be present in all
cells during C. elegans development (Vaux 1997; Hengartner 1997a).
The programmed death of cells would be blocked as long as the inhibitory interaction between CED-9 and CED-4 is maintained. The possibility that CED-9, CED-4, and proCED-3 are present not only in cells
destined to die is supported by the following observations: loss-of-function mutations in the ced-9 gene cause cells that normally survive to die
in a ced-3- and ced-4-dependent manner (Hengartner et al. 1992); and
mutations in ced-9, ced-3, or ced-4 influence the efficiency with which
the overexpression of either ced-4 or ced-3 in C. elegans can kill cells
that normally survive (Shaham and Horvitz 1996a).
A number of the molecular events just described also appear to occur
in vertebrates. It has been shown, for example, that Apaf-I binds to, and
is required for, the activation of Caspase 9 (Li et al. 1997). In addition,
the Apaf-l-dependent activation of Caspase 9 in vitro appears to involve
the oligomerization of Apaf-l (Srinivasula et al. 1998) and is blocked by
the Bc1-2-like cell-death inhibitor Bc1-x which can interact with Apaf-I
(panetal. 1998; Huetal. 1998).
B. Conradt
is required for proCED-3 activation (Chaudhary et al. 1998). Interestingly, the insertion into the P-Ioop region of 24 amino acids in the
CED-4L protein results in the disruption of this specific interaction and
the inability of the CED-4L protein to activate proCED-3 (Chaudhary et
al. 1998). CED-4 also interacts with the cell-death inhibitor protein
CED-9 (Spector et al. 1997; Chinnaiyan et al. 1997a; Wu et al. 1997a;
Seshagiri and Miller 1997; Ottilie et al. 1997), the latter being membrane-associated due to a hydrophobic region at the C-terminus (Wu et
al. 1997a; Chaudhary et al. 1998; Hisahara et al. 1998). The presence of
CED-9 blocks the CED-4-dependent activation of proCED-3 (Chinn aiyan et al. 1997a; Seshagiri and Miller 1997; Wu et al. 1997b). It is
therefore likely that, by binding to CED-4, CED-9 inhibits the ability of
CED-4 to activate proCED-3. CED-9 might block the oligomerization
of CED-4 or disrupt the interaction of the P-Ioop region of CED-4 with
proCED-3 (Yang et al. 1998; Chaudhary et al. 1998). CED-9, CED-4,
and proCED-3 possibly form a ternary complex (Chinnaiyan et al.
1997a; Wu et al. 1997b) which has been proposed to be present in all
cells during C. elegans development (Vaux 1997; Hengartner 1997a).
The programmed death of cells would be blocked as long as the inhibitory interaction between CED-9 and CED-4 is maintained. The possibility that CED-9, CED-4, and proCED-3 are present not only in cells
destined to die is supported by the following observations: loss-of-function mutations in the ced-9 gene cause cells that normally survive to die
in a ced-3- and ced-4-dependent manner (Hengartner et al. 1992); and
mutations in ced-9, ced-3, or ced-4 influence the efficiency with which
the overexpression of either ced-4 or ced-3 in C. elegans can kill cells
that normally survive (Shaham and Horvitz 1996a).
A number of the molecular events just described also appear to occur
in vertebrates. It has been shown, for example, that Apaf-I binds to, and
is required for, the activation of Caspase 9 (Li et al. 1997). In addition,
the Apaf-l-dependent activation of Caspase 9 in vitro appears to involve
the oligomerization of Apaf-l (Srinivasula et al. 1998) and is blocked by
the Bc1-2-like cell-death inhibitor Bc1-x which can interact with Apaf-I
(panetal. 1998; Huetal. 1998).