Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins

Verhagen, A. M. W.; Ekert, Paul G.; Pakusch, Miha; Silke, John; Connolly, Lisa; Reid, Gavin E.; Moritz, Robert L.; Simpson, Richard J.; Vaux, David L.

doi:10.1016/s0092-8674(00)00009-x

Cited by 2,146 publications

(1,540 citation statements)

References 34 publications

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“…the nucleus, lysosomes, the endoplasmic reticulum, or the cytosol) converge on mitochondria where they favor mitochondrial membrane permeabilization (MMP) [7][8][9]. Upon permeabilization of the mitochondrial outer membrane (OM), intermembrane space (IMS) proteins, that include caspase activators such as cytochrome c (Cyt c) [10], Omi/HtrA2 (Omi stress-regulated endoprotease/High temperature requirement protein A 2) [11,12] and Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with a low pI) [13,14], as well as caspase-independent death effectors like apoptosis-inducing factor (AIF) [15,16] and endonuclease G (EndoG) [17], are released into the cytosol. Cyt c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome (together with the apoptosis protease activating factor-1, i.e.…”

Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

“…Cyt c promotes the activation of the initiator caspase-9 in a direct fashion via the assembly of the apoptosome (together with the apoptosis protease activating factor-1, i.e. APAF-1, and ATP/dATP) [18], while Omi/HtrA2 [11,12] and Smac/Diablo [13,14] favor the caspase cascade indirectly, by antagonizing the activity of endogenous inhibitors of caspases, i.e. the inhibitor of apoptosis proteins (IAPs).…”

Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

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Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

et al. 2007

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Mitochondrial membrane permeabilization (MMP) is considered as the "point-of-no-return" in numerous models of programmed cell death. Indeed, mitochondria determine the intrinsic pathway of apoptosis, and play a major role in the extrinsic route as well. MMP affects the inner and outer mitochondrial membranes (IM and OM, respectively) to a variable degree. OM permeabilization culminates in the release of proteins that normally are confined in the mitochondrial intermembrane space (IMS), including caspase activators (e.g. cytochrome c) and caspase-independent death effectors (e.g. apoptosis-inducing factor). Partial IM permeabilization disrupts mitochondrial ion and volume homeostasis and dissipates the mitochondrial transmembrane potential ( m ). The assessment of early mitochondrial alterations allows for the identification of cells that are committed to die but have not displayed yet the apoptotic phenotype. Several

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Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

et al. 2007

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“…3 Mitochondrial membrane potential is rapidly lost and there is a massive release of proapoptotic factors into the cytosol, including cytochrome c, apoptosis-inducing factor, second mitochondria-derived activator of caspase (Smac)/ Diablo, endonuclease G, and the serine protease Omi/HtrA. [4][5][6][7][8] Released cytochrome c, along with Apaf-1 and procaspase 9, forms the apoptosome, 9,10 causing the proteolytic autoactivation of caspase 9, which in turn cleaves and activates effector caspases 3 and 7. [11][12][13][14] Smac release is necessary for the effective activation of caspases through interactions with inhibitor of apoptosis proteins (IAPs).…”

Section: Introductionmentioning

confidence: 99%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

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“…Recently though, Smac/Diablo and the serine protease HtrA2/Omi were defined as functional Reaper homologues in human, in that they possess IAP binding and neutralisation function. [21][22][23] Both proteins are released from mitochondria in response to apoptotic stimuli. They are synthesised as precursors with an extensive mitochondrial targeting sequence at their amino terminus.…”

Section: Introductionmentioning

confidence: 99%

“…14,25 In mammalian cells, however, removal of IAP-mediated inhibition sensitises cells to apoptosis but does not trigger caspase activation and apoptosis. 21,22 An additional signal is required for caspase activation. In line with the existence of another pro-apoptotic mechanism, at least in Reaper and Grim, deletion of their IBM did not significantly affect their capacity to induce apoptosis in human breast carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of action of Drosophila Reaper in mammalian cells: Reaper globally inhibits protein synthesis and induces apoptosis independent of mitochondrial permeability

et al. 2004

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Drosophila Reaper can bind inhibitor of apoptosis proteins (IAP) and thereby rescue caspases from proteasomal degradation. In insect cells, this is sufficient to induce apoptosis. Reaper can also induce apoptosis in mammalian cells, in which caspases need to be activated, usually via the mitochondrial pathway. Nevertheless, we find that Reaper efficiently induces apoptosis in mammalian cells in the absence of mitochondrial permeabilisation and cytochrome c release. Moreover, this capacity was only marginally affected by deletion of Reaper's amino-terminal IAP-binding motif. Independent of this motif, Reaper could globally suppress protein synthesis. Deletion of 20 amino acids from the carboxy-terminus of Reaper fully abrogated its potential to inhibit protein synthesis and to induce apoptosis in the absence of IAP-binding. Our findings indicate that the newly identified capacity of Reaper to suppress protein translation can operate in mammalian cells and may be key to its proapoptotic activity.

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Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins

Cited by 2,146 publications

References 34 publications

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Mechanism of action of Drosophila Reaper in mammalian cells: Reaper globally inhibits protein synthesis and induces apoptosis independent of mitochondrial permeability

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