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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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Programmed cell death pathways in Drosophila. In Drosophila, all embryonic PCD requires the activities of three closely linked genes, Rpr, Grim, and Hid. Expression of these apoptosis regulators initiates multiple downstream pathways to activate caspases and kill cells. Rpr, Grim, and Hid may induce formation of an apoptosome complex consisting of cytochrome c (cyt. c), Dark (Kanuka et al. 1999; Rodriguez et al. 1999; Zhou et al. 1999), and apical caspases such as Dronc (Loretta et al. 1999) and Dredd (Chen et al. 1998), which in turn promotes caspase activation and propagation of proteolytic activity to downstream, effector caspases (Abrams 1999). Alterations in cyt. c (Varkey et al. 1999) could be regulated by Scythe, a protein that binds all three death activators (Thress et al. 1999, Thress et al. 1998). Rpr, Grim, and Hid also engage caspases via one or more Dark-independent pathways. These involve derepression of native caspase inhibitors such as Diap1 (Wang et al. 1999). The pro-apoptotic Bcl-2 proteins (Drob-1/Debcl) probably function downstream of Rpr, Grim, and Hid and might directly engage caspases or function through Dark/cyt. c to propagate death signals. Currently, no pro-survival Bcl-2 gene has been reported in Drosophila.
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Figure 2: Programmed cell death pathways in Drosophila. In Drosophila, all embryonic PCD requires the activities of three closely linked genes, Rpr, Grim, and Hid. Expression of these apoptosis regulators initiates multiple downstream pathways to activate caspases and kill cells. Rpr, Grim, and Hid may induce formation of an apoptosome complex consisting of cytochrome c (cyt. c), Dark (Kanuka et al. 1999; Rodriguez et al. 1999; Zhou et al. 1999), and apical caspases such as Dronc (Loretta et al. 1999) and Dredd (Chen et al. 1998), which in turn promotes caspase activation and propagation of proteolytic activity to downstream, effector caspases (Abrams 1999). Alterations in cyt. c (Varkey et al. 1999) could be regulated by Scythe, a protein that binds all three death activators (Thress et al. 1999, Thress et al. 1998). Rpr, Grim, and Hid also engage caspases via one or more Dark-independent pathways. These involve derepression of native caspase inhibitors such as Diap1 (Wang et al. 1999). The pro-apoptotic Bcl-2 proteins (Drob-1/Debcl) probably function downstream of Rpr, Grim, and Hid and might directly engage caspases or function through Dark/cyt. c to propagate death signals. Currently, no pro-survival Bcl-2 gene has been reported in Drosophila.

Mentions: 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). Debcl-associated death phenotypes were sensitive to the dosage of DIAP1 and Dark (the APAF-1/Ced4 ortholog) indicating that the protein functions upstream, or parallel to, the action of these genes. Expression of Debcl/Drob-1 also provoked caspase activation which (at least in the animal) was reversed by the broad-spectrum caspase inhibitor, p35. 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. Nevertheless, given the attention these genes are likely to receive, we can expect rigorous testing of the model for years to come. In this regard, the isolation of mutations in these genes and the identification of an anti-apoptotic ortholog are perhaps the highest priorities.


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

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

Programmed cell death pathways in Drosophila. In Drosophila, all embryonic PCD requires the activities of three closely linked genes, Rpr, Grim, and Hid. Expression of these apoptosis regulators initiates multiple downstream pathways to activate caspases and kill cells. Rpr, Grim, and Hid may induce formation of an apoptosome complex consisting of cytochrome c (cyt. c), Dark (Kanuka et al. 1999; Rodriguez et al. 1999; Zhou et al. 1999), and apical caspases such as Dronc (Loretta et al. 1999) and Dredd (Chen et al. 1998), which in turn promotes caspase activation and propagation of proteolytic activity to downstream, effector caspases (Abrams 1999). Alterations in cyt. c (Varkey et al. 1999) could be regulated by Scythe, a protein that binds all three death activators (Thress et al. 1999, Thress et al. 1998). Rpr, Grim, and Hid also engage caspases via one or more Dark-independent pathways. These involve derepression of native caspase inhibitors such as Diap1 (Wang et al. 1999). The pro-apoptotic Bcl-2 proteins (Drob-1/Debcl) probably function downstream of Rpr, Grim, and Hid and might directly engage caspases or function through Dark/cyt. c to propagate death signals. Currently, no pro-survival Bcl-2 gene has been reported in Drosophila.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Programmed cell death pathways in Drosophila. In Drosophila, all embryonic PCD requires the activities of three closely linked genes, Rpr, Grim, and Hid. Expression of these apoptosis regulators initiates multiple downstream pathways to activate caspases and kill cells. Rpr, Grim, and Hid may induce formation of an apoptosome complex consisting of cytochrome c (cyt. c), Dark (Kanuka et al. 1999; Rodriguez et al. 1999; Zhou et al. 1999), and apical caspases such as Dronc (Loretta et al. 1999) and Dredd (Chen et al. 1998), which in turn promotes caspase activation and propagation of proteolytic activity to downstream, effector caspases (Abrams 1999). Alterations in cyt. c (Varkey et al. 1999) could be regulated by Scythe, a protein that binds all three death activators (Thress et al. 1999, Thress et al. 1998). Rpr, Grim, and Hid also engage caspases via one or more Dark-independent pathways. These involve derepression of native caspase inhibitors such as Diap1 (Wang et al. 1999). The pro-apoptotic Bcl-2 proteins (Drob-1/Debcl) probably function downstream of Rpr, Grim, and Hid and might directly engage caspases or function through Dark/cyt. c to propagate death signals. Currently, no pro-survival Bcl-2 gene has been reported in Drosophila.
Mentions: 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). Debcl-associated death phenotypes were sensitive to the dosage of DIAP1 and Dark (the APAF-1/Ced4 ortholog) indicating that the protein functions upstream, or parallel to, the action of these genes. Expression of Debcl/Drob-1 also provoked caspase activation which (at least in the animal) was reversed by the broad-spectrum caspase inhibitor, p35. 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. Nevertheless, given the attention these genes are likely to receive, we can expect rigorous testing of the model for years to come. In this regard, the isolation of mutations in these genes and the identification of an anti-apoptotic ortholog are perhaps the highest priorities.

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