Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors

Luo, Xu; Budihardjo, Imawati; Zou, Hua; Slaughter, Clive A.; Wang, Xiaodong

doi:10.1016/s0092-8674(00)81589-5

Cited by 3,249 publications

(2,605 citation statements)

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“…6,12 For instance, following the induction of apoptosis, we and others 18,19 have noted the stark lack of an appropriate precursor-product relationship between the proenzyme and the mature (p17) subunit of caspase-3. As shown by immunoblot analysis this phenomenon is readily observed in HeLa cells induced by staurosporine treatment to undergo apoptosis ( Figure 1).…”

Section: Resultsmentioning

confidence: 98%

“…In response to numerous proapoptotic stimuli procaspase-3 is rapidly processed to generate a large (p17) and small (p12) polypeptide subunit, and two copies of each subunit form a catalytically active tetrameric complex. 5,12 Work from our lab and that of others 18,19 demonstrates that the active form of caspase-3 is highly labile and is rapidly turned over relative to its proenzyme form. In addition, we show that turnover of caspase-3 is dependent on its catalytic activity and that as a consequence of inhibition, caspase inhibitors act to efficiently stabilize the active form of the enzyme.…”

Section: Discussionmentioning

confidence: 95%

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Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

et al. 2004

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The activation of caspase-3 represents a critical step in the pathways leading to the biochemical and morphological changes that underlie apoptosis. Upon induction of apoptosis, the large (p17) and small (p12) subunits, comprising active caspase-3, are generated via proteolytic processing of a latent proenzyme dimer. Two copies of each individual subunit are generated to form an active heterotetramer. The tetrameric form of caspase-3 cleaves specific protein substrates within the cell, thereby producing the apoptotic phenotype. In contrast to the proenzyme, once activated in HeLa cells, caspase-3 is difficult to detect due to its rapid degradation. Interestingly, however, enzyme stability and therefore detection of active caspase-3 by immunoblot analysis can be restored by treatment of cells with a peptide-based caspase-3 selective inhibitor, suggesting that the active form can be stabilized through protein-inhibitor interaction. The heteromeric active enzyme complex is necessary for its stabilization by inhibitors, as expression of the large subunit alone is not stabilized by the presence of inhibitors. Our results show for the first time, that synthetic caspase inhibitors not only block caspase activity, but may also increase the stability of otherwise rapidly degraded mature caspase complexes. Consistent with these findings, experiments with a catalytically inactive mutant of caspase-3 show that rapid turnover is dependent on the activity of the mature enzyme. Furthermore, turnover of otherwise stable active site mutants of capase-3 is rescued by the presence of the active enzyme suggesting that turnover can be mediated in trans.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 95%

Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

et al. 2004

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“…For example, cleavage of the BH3-only protein Bid by caspase-8 results in its acquisition of a proapoptotic function (Luo et al, 1998). Similarly, p53 has been shown to enhance mitochondrial depolarization and augment apoptosis after cleavage by caspase-3 (Sayan et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

Sayan

Gogvadze

et al. 2008

Oncogene

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The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcriptionindependent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.

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“…[21][22][23] The Bcl-2 family member Bid is cleaved by caspase 8 and targeted to the mitochondria, where it induces cytochrome c release and unleashes the intrinsic apoptotic machinery, providing a direct link between both apoptotic pathways. 24,25 In addition, caspase 8 can be activated independently of death receptor-mediated signals by certain anticancer drugs. 26,27 Retinoids regulate important biological functions through the activation of the nuclear retinoid receptors, retinoic acid receptors (RARs) and retinoid X receptors.…”

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.

show abstract

Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors

Cited by 3,249 publications

References 50 publications

Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

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

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