Caenorhabditis elegans CED-4 stimulates CED-3 processing and CED-3-induced

Seshagiri, Somasekar; Miller, Lois K.

doi:10.1016/s0960-9822(06)00216-8

Cited by 171 publications

(128 citation statements)

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“…66,67 Although Bcl-2 can mimic the death protective effect of CED-9 in worms and vice versa, the two proteins appear to function slightly differently. 66 ± 68 While CED-9 directly binds to CED-4 and prevents the latter from activating CED-3, 11,12,26,27 Bcl-2 does not avidly interact with the CED-4 homolog Apaf-1 (own observation) but prevents the release of cytochrome c from mitochondria thereby blocking caspase-9/-3 activation upstream or independently of Apaf-1 ( Figure 1). 57,58 How Bcl-2 performs this peculiar action on mitochondria has remained elusive.…”

Section: Apoptosis: a Cell-intrinsic Molecular Guillotinementioning

confidence: 99%

Apoptosis without caspases: an inefficient molecular guillotine?

1999

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Since the discovery that the cysteine protease CED-3 was essential for developmental death in the nematode C. elegans, the search has been on to identify homologous proteases governing mammalian apoptosis. Fourteen of these proteases, now called caspases, have been found to date, and studies with natural or chemical inhibitors, and more recently knock-out mice, confirmed the involvement of at least a subset of these proteases in various forms of mammalian apoptosis. However, there has been recent evidence that some apoptotic morphologies, such as cell shrinkage, membrane blebbing and nuclear condensation, are not blocked by caspase inhibitors and that the cells continue to die in a protracted and inefficient manner. This has led to the notion that caspases are not required for all aspects of apoptosis in mammals. Here we review the current knowledge about caspase-independent apoptosis, discuss the strengths and weaknesses of the reasoning that led to its proposition and provide insights into its possible regulation and physiological significance.

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Section: Apoptosis: a Cell-intrinsic Molecular Guillotinementioning

confidence: 99%

Apoptosis without caspases: an inefficient molecular guillotine?

1999

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“…On a molecular level, expression of CED-4 was shown to enhance both the processing of CED-3 zymogen and CED-3-induced apoptosis in insect cells. 27 Furthermore, these effects depended on an intact CED-3 prodomain, 27 suggesting that CED-4 acts through CED-3 to cause cell death, perhaps through a direct interaction requiring the CED-3 prodomain. Indeed, CED-4 was found to interact physically with both the CED-3 prodomain and protease domain in cells, 28,29 and purified CED-4 could mediate CED-3 autoprocessing in vitro in a prodomaindependent fashion.…”

Section: Elegans Caspasesmentioning

confidence: 99%

Caspases: an ancient cellular sword of Damocles

2003

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Caspases are a family of cysteine proteases homologous to the Caenorhabditis elegans programmed cell death gene product CED-3. Caspases and their distant relatives, metaand paracaspases, have been found in phylogenetically distant nonmetazoan groups, including plants, fungi and prokaryotes. This review summarizes the current information on the mechanisms and functions of non-mammalian caspases and their relatives in apoptotic and nonapoptotic processes, and explores the possible evolutionary origin of the caspase family.

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“…The NBD of Apaf-1 and Ced-4 is homologous to the ABC-ATP/GTPase module that is present in a large number of proteins with diverse biological function (Walker et al, 1982). Both the ABC domain present in these ATP/GTPases and the NBD of Apaf-1/Ced-4 contain conserved binding sites for nucleotide (P-loop or Walker's A box) and Mg 2+ (Walker's B box) (Walker et al, 1982;Seshagiri and Miller, 1997;Chinnaiyan et al, 1997b;Chaudhary et al, 1998;Jaroszewski et al, 2000). In addition, the NBD of both Apaf-1 and CED-4 mediates protein homooligomerization, a function that is critical for Apaf-1/Ced-4 activity (Chaudhary et al, 1998;Yang et al, 1998;Hu et al, 1998a;Srinivasula et al, 1998).…”

Section: Introductionmentioning

confidence: 99%