Programmed Cell Death and Its Regulation in C. e/egans
3.6 The Gene Product of egl-l Initiates
Programmed Cell Death in C. elegans
43
The emerging molecular model raises a number of questions, such as
what substrates of the CED-3 caspase are required to bring about cell
death. While a number of potential substrates have been identified for
vertebrate caspases (reviewed by Porter et al. 1997), the only C. elegans
substrate of CED-3 characterized so far is the protein CED-9 (Xue and
Horvitz 1997). It is possible that the CED-3-dependent cleavage of
CED-9 is required for the progression of the cell-death process but it is
also possible that, by being a substrate for CED-3, CED-9 acts as a
competitive inhibitor of CED-3; this would constitute a safeguard
mechanism against inappropriately activated CED-3 molecules in cells
destined to survive. Another question raised by the emerging model is
how programmed cell death is initiated in cells destined to die. The
recent identification of another C. elegans gene required for programmed cell death in the soma, egl-l (egl, egg-laying defective), has
provided some clues to the mechanism of cell-death initiation.
Just like loss-of-function mutations in ced-3 or ced-4, a loss-of-function mutation in the gene egl-l blocks most if not all somatic cell death
events (Conradt and Horvitz 1998). However, unlike loss-of-function
mutations in ced-3 or ced-4, the egl-lloss-of-function mutation fails to
suppress ced-9 loss-of-function mutations. In animals carrying both an
egl-l loss-of-function mutation and a ced-9 loss-of-function mutation,
ectopic cell death still occurs resulting in lethality. This suggests that
egl-l is acting upstream of, or in parallel to, ced-9. The egl-l loss-offunction mutation can enhance the cell-death defect caused by weak
ced-3 loss-of-function mutations. However, this ability of the egl-l
loss-of-function mutation is dependent on the presence of a functional
ced-9 gene; in the absence of ced-9, the egl-Iloss-of-function mutation
fails to enhance a weak ced-3 If mutation. This indicates that egl-l acts
through ced-9 and that it normally functions to negatively regulate ced-9
(Conradt and Horvitz 1998) (Fig. 2A). The overexpression of egl-l in C.
elegans in cells that normally survive causes these cells to undergo
programmed cell death. This indicates that, like ced-3 and ced-4, the
egl-l gene acts in a cell-autonomous manner. egl-l-induced killing is
suppressed by the gain-of-function mutation in ced-9 and by loss-offunction mutations in either ced-4 or ced-3 which provides further
3.6 The Gene Product of egl-l Initiates
Programmed Cell Death in C. elegans
43
The emerging molecular model raises a number of questions, such as
what substrates of the CED-3 caspase are required to bring about cell
death. While a number of potential substrates have been identified for
vertebrate caspases (reviewed by Porter et al. 1997), the only C. elegans
substrate of CED-3 characterized so far is the protein CED-9 (Xue and
Horvitz 1997). It is possible that the CED-3-dependent cleavage of
CED-9 is required for the progression of the cell-death process but it is
also possible that, by being a substrate for CED-3, CED-9 acts as a
competitive inhibitor of CED-3; this would constitute a safeguard
mechanism against inappropriately activated CED-3 molecules in cells
destined to survive. Another question raised by the emerging model is
how programmed cell death is initiated in cells destined to die. The
recent identification of another C. elegans gene required for programmed cell death in the soma, egl-l (egl, egg-laying defective), has
provided some clues to the mechanism of cell-death initiation.
Just like loss-of-function mutations in ced-3 or ced-4, a loss-of-function mutation in the gene egl-l blocks most if not all somatic cell death
events (Conradt and Horvitz 1998). However, unlike loss-of-function
mutations in ced-3 or ced-4, the egl-lloss-of-function mutation fails to
suppress ced-9 loss-of-function mutations. In animals carrying both an
egl-l loss-of-function mutation and a ced-9 loss-of-function mutation,
ectopic cell death still occurs resulting in lethality. This suggests that
egl-l is acting upstream of, or in parallel to, ced-9. The egl-l loss-offunction mutation can enhance the cell-death defect caused by weak
ced-3 loss-of-function mutations. However, this ability of the egl-l
loss-of-function mutation is dependent on the presence of a functional
ced-9 gene; in the absence of ced-9, the egl-Iloss-of-function mutation
fails to enhance a weak ced-3 If mutation. This indicates that egl-l acts
through ced-9 and that it normally functions to negatively regulate ced-9
(Conradt and Horvitz 1998) (Fig. 2A). The overexpression of egl-l in C.
elegans in cells that normally survive causes these cells to undergo
programmed cell death. This indicates that, like ced-3 and ced-4, the
egl-l gene acts in a cell-autonomous manner. egl-l-induced killing is
suppressed by the gain-of-function mutation in ced-9 and by loss-offunction mutations in either ced-4 or ced-3 which provides further