Programmed Cell Death and Its Regulation in C. e/egans
39
ced-3. ced-9, ced-4, and ced-3 therefore appear to act in a simple
pathway in which ced-9 negatively regulates ced-4 and ced-4 positively
regulates ced-3 (Fig. lA).
The programmed cell-death pathway, however, is probably more
complex. ced-9 loss-of-function mutations, for instance, enhance the
cell-death defect caused by weak loss-of-function mutations in either
ced-3 or ced-4, suggesting that ced-9 not only has a cell-death protective
function but also a killing function (Hengartner and Horvitz 1994b;
Conradt and Horvitz 1998). In addition, the gene products of ced-9 and
ced-3 might interact directly (see below). Also, the ced-4 message is
alternatively spliced (Shaham and Horvitz 1996b). This results in the
production of the major "short" transcript, ced-4s, and a minor "long"
transcript, ced-41, which contains an additional 72 nucleotides in the
center of the message. Whereas the overexpression of the ced-4s message induces killing in C. elegans, the overexpressing of ced-41 blocks
programmed cell death (Shaham and Horvitz 1996b).
3.4 The Programmed Cell-Death Pathway
Has Been Conserved Through Evolution
The cloning of the ced-9 gene confirmed that the process of programmed cell death is conserved not only at the cellular level but also at
the molecular level (Hengartner and Horvitz 1994a). ced-9 was found to
encode a protein with structural and functional similarity to the mammalian oncoprotein and cell-death inhibitor Bcl-2, the prototype of the
growing family of Bcl-2-like cell-death regulators (reviewed by Chao
and Korsmeyer 1998; Adams and Cory 1998). The bcl-2 gene was
originally identified at the breakpoint of the t(l4; 18) translocation present in the majority of individuals with follicular lymphomas. The
t( 14; 18) translocation results in the inappropriate overexpression of the
bcl-2 gene in B cells and the extended survival of these cells. It has since
been shown that the overexpression of bcl-2 in a number of cell types
prolongs survival by blocking programmed cell death (Chao and Korsmeyer 1998; Adams and Cory 1998). The cloning of the ced-3 gene
revealed a role for proteolysis in the cell-death process. ced-3 encodes a
cysteine protease similar to ICE, the interleukin-l ~-converting enzyme
(Yuan et a1. 1993). A large number of CED-3IICE-like proteases with
39
ced-3. ced-9, ced-4, and ced-3 therefore appear to act in a simple
pathway in which ced-9 negatively regulates ced-4 and ced-4 positively
regulates ced-3 (Fig. lA).
The programmed cell-death pathway, however, is probably more
complex. ced-9 loss-of-function mutations, for instance, enhance the
cell-death defect caused by weak loss-of-function mutations in either
ced-3 or ced-4, suggesting that ced-9 not only has a cell-death protective
function but also a killing function (Hengartner and Horvitz 1994b;
Conradt and Horvitz 1998). In addition, the gene products of ced-9 and
ced-3 might interact directly (see below). Also, the ced-4 message is
alternatively spliced (Shaham and Horvitz 1996b). This results in the
production of the major "short" transcript, ced-4s, and a minor "long"
transcript, ced-41, which contains an additional 72 nucleotides in the
center of the message. Whereas the overexpression of the ced-4s message induces killing in C. elegans, the overexpressing of ced-41 blocks
programmed cell death (Shaham and Horvitz 1996b).
3.4 The Programmed Cell-Death Pathway
Has Been Conserved Through Evolution
The cloning of the ced-9 gene confirmed that the process of programmed cell death is conserved not only at the cellular level but also at
the molecular level (Hengartner and Horvitz 1994a). ced-9 was found to
encode a protein with structural and functional similarity to the mammalian oncoprotein and cell-death inhibitor Bcl-2, the prototype of the
growing family of Bcl-2-like cell-death regulators (reviewed by Chao
and Korsmeyer 1998; Adams and Cory 1998). The bcl-2 gene was
originally identified at the breakpoint of the t(l4; 18) translocation present in the majority of individuals with follicular lymphomas. The
t( 14; 18) translocation results in the inappropriate overexpression of the
bcl-2 gene in B cells and the extended survival of these cells. It has since
been shown that the overexpression of bcl-2 in a number of cell types
prolongs survival by blocking programmed cell death (Chao and Korsmeyer 1998; Adams and Cory 1998). The cloning of the ced-3 gene
revealed a role for proteolysis in the cell-death process. ced-3 encodes a
cysteine protease similar to ICE, the interleukin-l ~-converting enzyme
(Yuan et a1. 1993). A large number of CED-3IICE-like proteases with