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Drosophila apoptosis and Bcl-2 genes: outliers fly in.

Chen P, Abrams JM - J. Cell Biol. (2000)

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.

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In C. elegans, both Ced-3 and Ced-4 are required for all PCD during worm development... Ced-3 encodes a founding member of the caspase family (cysteine proteases) while Ced-4 promotes the activation of Ced-3 through direct physical interaction... How do the mammalian Bcl-2 proteins function to regulate cell death? Since human Bcl-2 can partially reverse cell death defects found in Ced-9 mutant worms, Ced-9 and Bcl-2 are thought to share at least some functional properties (Vaux et al. 1992; Hengartner and Horvitz 1994)... This is an attractive model, easily reconciled with the relationship between Egl-1, Ced-9, Ced-4, and Ced-3 in C. elegans... However, when native Bcl-2 proteins were directly examined, the predicted associations with Apaf-1 were not found, raising doubts as to whether the Apaf-1/Bcl-2 overexpression studies truly reflect the physiological condition (Moriishi et al. 1999)... In cell culture and in transgenic animals, directed expression of Debcl provokes extensive cell death which required an intact BH3 domain and was suppressible by the virally derived caspase inhibitor, p35... Colussi et al. 2000 also used the RNA interference technique, a relatively new method of blocking gene expression, to validate a pro-apoptotic function for Debcl and demonstrate a requirement for this gene during embryonic cell death... A concurrent paper by Igaki et al. 2000 characterizes the same gene, which they refer to as Drob-1... They used a clone that is 25 residues longer at the NH2 terminus and found that Drob-1, like Debcl, was pro-apoptotic... Another discrepancy is that although expression of Debcl/Drob-1 provoked caspase activation, Colussi et al. 2000 found that p35 was able to suppress accompanying cell death (in cultured cells and the animal) whereas Igaki et al. 2000 report that it was not (only cultured cells were tested)... How does Debcl/Drob-1 fit into our current view of cell death genetics in flies? Although it is far too early for a well-focused picture, the similarities to pro-death Bcl-2 genes combined with epistasis data connecting Debcl to existing players of the Drosophila cell death pathway suggests a tentative molecular order for gene action (see Colussi et al. 2000, and Fig. 2)... In contrast, cell killing by Debcl was insensitive to the dosage of the death activators Rpr, Grim, and Hid, suggesting that the protein either functions downstream or parallel to these genes... While the pathways in Fig. 2 (and Colussi et al. 2000) offer a reasonable interpretation of the current data, the usual caution and caveats apply since the position of the fly Bcl-2 proteins is largely based upon dominant phenotypes resulting from directed overexpression studies.

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Conserved elements of the cell death machinery in nematodes, mammals and flies are presented in schematic form. The order of gene action is based on precedents established in the nematode, C. elegans.
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Figure 1: Conserved elements of the cell death machinery in nematodes, mammals and flies are presented in schematic form. The order of gene action is based on precedents established in the nematode, C. elegans.

Mentions: Central components of the apoptosis machinery in worms, mammals and flies are schematized in Fig. 1. In C. elegans, both Ced-3 and Ced-4 are required for all PCD during worm development. Ced-3 encodes a founding member of the caspase family (cysteine proteases) while Ced-4 promotes the activation of Ced-3 through direct physical interaction. The upstream death regulator, Ced-9, protects cells from death by forming a complex with Ced-4, thus preventing the activation of Ced-3 by Ced-4. A pro-apoptotic protein with limited Bcl-2 similarity, Egl-1, can interact with Ced-9 to derepress Ced-4 and permit activation of Ced-3 (reviewed in Metzstein et al. 1998; Gumienny et al. 1999; Horvitz 1999).


Drosophila apoptosis and Bcl-2 genes: outliers fly in.

Chen P, Abrams JM - J. Cell Biol. (2000)

Conserved elements of the cell death machinery in nematodes, mammals and flies are presented in schematic form. The order of gene action is based on precedents established in the nematode, C. elegans.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169364&req=5

Figure 1: Conserved elements of the cell death machinery in nematodes, mammals and flies are presented in schematic form. The order of gene action is based on precedents established in the nematode, C. elegans.
Mentions: Central components of the apoptosis machinery in worms, mammals and flies are schematized in Fig. 1. In C. elegans, both Ced-3 and Ced-4 are required for all PCD during worm development. Ced-3 encodes a founding member of the caspase family (cysteine proteases) while Ced-4 promotes the activation of Ced-3 through direct physical interaction. The upstream death regulator, Ced-9, protects cells from death by forming a complex with Ced-4, thus preventing the activation of Ced-3 by Ced-4. A pro-apoptotic protein with limited Bcl-2 similarity, Egl-1, can interact with Ced-9 to derepress Ced-4 and permit activation of Ced-3 (reviewed in Metzstein et al. 1998; Gumienny et al. 1999; Horvitz 1999).

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In C. elegans, both Ced-3 and Ced-4 are required for all PCD during worm development... Ced-3 encodes a founding member of the caspase family (cysteine proteases) while Ced-4 promotes the activation of Ced-3 through direct physical interaction... How do the mammalian Bcl-2 proteins function to regulate cell death? Since human Bcl-2 can partially reverse cell death defects found in Ced-9 mutant worms, Ced-9 and Bcl-2 are thought to share at least some functional properties (Vaux et al. 1992; Hengartner and Horvitz 1994)... This is an attractive model, easily reconciled with the relationship between Egl-1, Ced-9, Ced-4, and Ced-3 in C. elegans... However, when native Bcl-2 proteins were directly examined, the predicted associations with Apaf-1 were not found, raising doubts as to whether the Apaf-1/Bcl-2 overexpression studies truly reflect the physiological condition (Moriishi et al. 1999)... In cell culture and in transgenic animals, directed expression of Debcl provokes extensive cell death which required an intact BH3 domain and was suppressible by the virally derived caspase inhibitor, p35... Colussi et al. 2000 also used the RNA interference technique, a relatively new method of blocking gene expression, to validate a pro-apoptotic function for Debcl and demonstrate a requirement for this gene during embryonic cell death... A concurrent paper by Igaki et al. 2000 characterizes the same gene, which they refer to as Drob-1... They used a clone that is 25 residues longer at the NH2 terminus and found that Drob-1, like Debcl, was pro-apoptotic... Another discrepancy is that although expression of Debcl/Drob-1 provoked caspase activation, Colussi et al. 2000 found that p35 was able to suppress accompanying cell death (in cultured cells and the animal) whereas Igaki et al. 2000 report that it was not (only cultured cells were tested)... How does Debcl/Drob-1 fit into our current view of cell death genetics in flies? Although it is far too early for a well-focused picture, the similarities to pro-death Bcl-2 genes combined with epistasis data connecting Debcl to existing players of the Drosophila cell death pathway suggests a tentative molecular order for gene action (see Colussi et al. 2000, and Fig. 2)... In contrast, cell killing by Debcl was insensitive to the dosage of the death activators Rpr, Grim, and Hid, suggesting that the protein either functions downstream or parallel to these genes... While the pathways in Fig. 2 (and Colussi et al. 2000) offer a reasonable interpretation of the current data, the usual caution and caveats apply since the position of the fly Bcl-2 proteins is largely based upon dominant phenotypes resulting from directed overexpression studies.

Show MeSH