Interaction of CED-4 with CED-3 and CED-9: A Molecular Framework for Cell Death

Chinnaiyan, Arul M.; O’Rourke, Karen; Lane, Brian R.; Dixit, Vishva M.

doi:10.1126/science.275.5303.1122

Cited by 605 publications

(422 citation statements)

References 21 publications

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“…However, there is no obvious molecular mechanism linking anti-apoptotic Bcl-2 family members with the classical type 1 CD95/ FADD/caspase-8 pathway. Although it has been suggested that Bcl-2 and Bcl-X L directly (Boise and Thompson, 1997) or indirectly (Chinnaiyan et al, 1997;Han et al, 1997;Ng et al, 1997;Hu et al, 1998) bind caspase-8 and so modulate its activation (Medema et al, 1998), a recent report indicates that, in a system in which Bcl-X L e ectively suppresses CD95-induced apoptosis, Bcl-X L neither interacts with caspase-8 nor inhibits its recruitment or activation (Medema et al, 1998). This ®nding seems to leave little room for a role for Bad as an intermediary modulating activation of caspase-8 by FADD.…”

Section: Discussionmentioning

confidence: 99%

The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis

et al. 1998

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Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in their absence; this dual capacity ensures that cell growth is restricted to the correct paracrine environment and is thereby strictly controlled. Recently our laboratory demonstrated that cMyc-induced apoptosis requires the CD95 death receptor pathway and that insulin-like growth factor (IGF-1) signalling suppresses this killing. To investigate further the links between c-Myc and IGF-1 pathways in CD95-induced apoptosis, we examined the e ects of c-Myc and a downstream IGF-1 survival kinase, Akt, on killing mediated by CD95 and its recruited e ector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-caspase-8, which narrows the point at which cMyc exerts its action downstream of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8. These results restrict the possible mechanisms by which CD95-induced apoptosis is modulated by death signals and survival factors.

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Section: Discussionmentioning

confidence: 99%

The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis

et al. 1998

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“…34,35 While the activation of CED-3 appears to be autocatalytic in nature, it does require association of the zymogen with oligomerized CED-4, likely forming a worm version of the apoptosome, which in mammals consists of at least three proteins -caspase-9, Apaf-1, and cytochrome c. 36 In cells that should survive, formation of the apoptosome is prevented, at least in part because CED-4 is bound to and sequestered by CED-9 in a stable complex on the surface of mitochondria. 37 Cells fated to die appear to be marked for apoptosis through the expression of EGL-1.…”

Section: Developmental Cell Deathmentioning

confidence: 99%

Death and more: DNA damage response pathways in the nematode C. elegans

2003

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Genotoxic stress is a threat to our cells' genome integrity. Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale genomic instability. Because such changes may have tumorigenic potential, damaged cells are often eliminated via apoptosis. Loss of this apoptotic response is actually one of the hallmarks of cancer. Towards the effort to elucidate the DNA damage-induced signaling steps leading to these biological events, an easily accessible model system is required, where the acquired knowledge can reveal the mechanisms underlying more complex organisms. Accumulating evidence coming from studies in Caenorhabditis elegans point to its usefulness as such. In the worm's germline, DNA damage can induce both cell cycle arrest and apoptosis, two responses that are spatially separated. The latter is a tightly controlled process that is genetically indistinguishable from developmental programmed cell death. Upstream of the central death machinery, components of the DNA damage signaling cascade lie and act either as sensors of the lesion or as transducers of the initial signal detected. This review summarizes the findings of several studies that specify the elements of the DNA damage-induced responses, as components of the cell cycle control machinery, the repairing process or the apoptotic outcome. The validity of C. elegans as a tool to further dissect the complex signaling network of these responses and the high potential for it to reveal important links to cancer and other genetic abnormalities are addressed.

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“…Some caspases have long prodomains (Ϸ200 amino acids) and colleagues have short ones (Ϸ20 amino acids). The long prodomains of caspase-8, CED-3 (caspase of C. elegans) and caspase-9 bind to FADD, CED-4 and Apaf-1 (CED-4 of mammals), respectively (Boldin et al 1996;Fernandes-Alnemri et al 1996;Muzio et al 1996;Chinnaiyan et al 1997;Zou et al 1997). The prodomains of caspase-3, -6 and -7 are short, and these prodomains were not shown to interact with any molecules regulating apoptosis.…”

Section: Introductionmentioning

confidence: 99%