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First published online April 28, 2005
doi: 10.1242/10.1242/jcs.02377

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Apoptosis in Drosophila: neither fish nor fowl (nor man, nor worm)

¹ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
² CBRC, Massachusetts General Hospital/Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA

View larger version (28K): [in a new window]   Fig. 1. Models of apoptosome regulation. (A) In vertebrate cells, a variety of apoptotic stimuli induce release of cytochrome c from the mitochondria. Once released, cytochrome c binds to Apaf-1, promoting a conformational change that leads to the exposure of the CARD domain and consequent recruitment of pro-caspase-9 into the active oligomerized apoptosome; caspase-9 can then cleave and activate effector caspases. Cytochrome c release from the mitochondria is promoted by pro-apoptotic Bcl-2-family members such as Bax and Bak and is antagonized by anti-apoptotic members of the family such as Bcl-2 and Bcl-xL. Red rectangles, Apaf-1; light-blue circles, caspase-9; green stars, cytochrome c. (B) In Drosophila cells, it is possible that cytochrome c, or some other intramitochondrial factor (represented here by brown triangles) is released from mitochondria in response to apoptotic stimuli, to promote the activation of the Dark/Dronc apoptosome (red rectangles and blue circles, respectively). This might stimulate oligomerization or enhance activation of the already oligomerized structure. (C) If the fly Bcl-2-family members do not act at the level of cytochrome c release from the mitochondria as in vertebrates, it is possible that pro-apoptotic Debcl protein (yellow rectangles) interacts in some way with the apoptosome to promote its activation. (D) By analogy to the worm system, it is possible that the anti-apoptotic Bcl-2-family protein, Buffy, binds to and inhibits the apoptosome (either at the mitochondrial surface or elsewhere). One possible scenario is that pro-apoptotic Debcl facilitates apoptosome activation by dimerizing with and thereby removing Buffy from the apoptosome. (E) The C. elegans apoptosome is held in check by binding of Ced-9 to Ced-4. This repression is relieved following Egl-1 production and interaction with Ced-9. Red bars, Ced-4; light-blue circles, Ced-3.

View larger version (15K): [in a new window]   Fig. 2. Apoptosis through the fly's eye. In our current understanding of apoptosis in Drosophila, DIAP1 acts as a central brake on apoptosis, inhibiting activated caspases (reviewed by Hay, 2000). Caspase binding to DIAP1 can result in sequestration of the caspase away from its targets or in caspase degradation. The IBM proteins Rpr, Grim, Hid and Skl compete with caspases for binding to DIAP1 and promote apoptosis. Rpr and Grim can also suppress DIAP1 translation (Holley et al., 2002; Yoo et al., 2002). This is the fundamental mechanism of apoptosis induction in fly development, as well as in response to stress such as DNA damage (red bars) (White et al., 1994; Nordstrom et al., 1996; Brodsky et al., 2004). DIAP1 also has other functions: it can promote its own degradation and the degradation of IBM proteins (Hay, 2000). DIAP1 may also regulate the levels of other IAPs (broken arrows and bars are speculative). Caspase activity also contributes to DIAP1 degradation (Ditzel et al., 2003; Yokokura et al., 2004). No role for mitochondrial factors has been definitively demonstrated in Drosophila apoptosis, although Rpr and Grim can release cytochrome c in heterologous systems (Thress et al., 1999; Claveria et al., 2004). Dark is required to activate the apical caspase Dronc (Kanuka et al., 1999; Rodriguez et al., 1999; Zhou et al., 1999), and could be regulated by cytochrome c, although this has not been demonstrated. It is clear that the other IAP-like proteins in flies, DIAP2, deterin and dBRUCE, can suppress apoptosis, but their role and mechanism of regulation has yet to be fully explored (Hay et al., 1995; Jones et al., 2000; Vernooy et al., 2002; Arama et al., 2003). Developmental and other environmental inputs (open arrows) can influence the apoptotic pathway at several points, including the transcription and activity of the IBM proteins, the synthesis of Dark and some of the caspases, and the synthesis of some of the IAPs (White et al., 1994; Zhou et al., 1999; Dorstyn et al., 1999a; Jiang et al., 2000).