Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

Yasuhara, Noriko; Sahara, Setsuko; Kamada, Shinji; Eguchi, Yawara; Tsujimoto, Yoshihide

doi:10.1038/sj.onc.1201370

Cited by 24 publications

(21 citation statements)

References 22 publications

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“…HeLa cells have been shown to behave as type II cells since overexpression of Bcl-2 prevents CD95-mediated apoptosis (23,36). Treatment of these cells with agonistic anti-Fas/CD95 induced apoptosis in the large majority of cells; however, prior infection with T. gondii significantly blocked Fas/CD95-triggered cell death, as was expected from previous results ( Fig.…”

Section: T Gondii Inhibits Apoptosis In Fas-triggered Type II Cellssupporting

confidence: 75%

Fas/CD95-Mediated Apoptosis of Type II Cells Is Blocked byToxoplasma gondiiPrimarily via Interference with the Mitochondrial Amplification Loop

et al. 2008

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The intracellular protozoan Toxoplasma gondii induces persistent infections in various hosts and is an important opportunistic pathogen of humans with immature or deficient immune responses. The ability to survive intracellularly largely depends on the blocking of different proapoptotic signaling cascades of its host cell. Fas/CD95 triggers an apoptotic cascade that is crucial for immunity and the outcome of infectious diseases. We have determined the mechanism by which T. gondii counteracts death receptor-mediated cell death in type II cells that transduce Fas/CD95 ligation via caspase 8-mediated activation of the mitochondrial amplification loop. The results showed that infection with T. gondii significantly reduced Fas/CD95-triggered apoptosis in HeLa cells by inhibiting the activities of initiator caspases 8 and 9 and effector caspase 3/7. Parasitic infection dose dependently diminished cleavage of caspase 8, the BH3-only protein Bid, and the downstream caspases 9 and 3. Importantly, interference with Fas/CD95-triggered caspase 8 and caspase 3/7 activities after parasitic infection was largely dependent on the presence of caspase 9. Within the mitochondrial amplification loop, T. gondii significantly inhibited the Fas/CD95-triggered release of cytochrome c into the host cell cytosol. These results indicate that T. gondii inhibits Fas/CD95-mediated apoptosis in type II cells primarily by decreasing the apoptogenic function of mitochondria.

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Section: T Gondii Inhibits Apoptosis In Fas-triggered Type II Cellssupporting

confidence: 75%

Fas/CD95-Mediated Apoptosis of Type II Cells Is Blocked byToxoplasma gondiiPrimarily via Interference with the Mitochondrial Amplification Loop

et al. 2008

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“…Cleavage of Bcl-2 might be a means of effectively removing the anti-apoptotic effect of Bcl-2. Current results favour the notion that Bcl-2 functions upstream of caspase activation and prevents apoptosis by suppressing caspase 3 [27][28][29]. Our results have demonstrated that Bcl-2 can act as a downstream substrate of caspase 3 or a caspase-3-like protease, raising the possibility that the cleaved 22 kDa fragment might have a direct role in mediating the amplification of the death effects during apoptosis [22].…”

Section: Discussionsupporting

confidence: 56%

Inhibition of ubiquitin-proteasome pathway activates a caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells

Zhang

Lin

Chen

et al. 1999

Biochemical Journal

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The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. Here we examine the possibility that ubiquitin-proteasome is involved in regulating the levels of Bcl-2, which is abundantly expressed in M-07e cells, a granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent human leukaemic cell line. Apoptosis in M-07e cells, induced by GM-CSF withdrawal, was associated with a gradual cleavage of Bcl-2 into a 22 kDa fragment. Treatment of M-07e cells with benzyloxycarbonyl-Leu-Leu-L-leucinal (Z-LLL-CHO; MG-132), a reversible ubiquitin-proteasome inhibitor, markedly accelerated the cleavage of Bcl-2 and promoted cell death through the apoptotic pathway. The cleavage of Bcl-2 was inhibited by a caspase-3 (CPP32)-specific inhibitor [acetyl-Asp-Glu-Val-Asp-CHO (DEVD-CHO)] but not caspase 1 inhibitor (acetyl-Tyr-Val-Ala-Asp-CHO), suggesting that Bcl-2 is a proteolytic substrate of a caspase-3-like protease activated during apoptosis. The simultaneous addition of recombinant human GM-CSF (rhGM-CSF) to M-07e cultures delayed the activation of caspase 3 and Bcl-2 cleavage triggered by Z-LLL-CHO, suggesting that the activation of the GM-CSF signalling pathway can partly overcome the apoptotic effect induced by Z-LLL-CHO. Apoptosis induced by inhibition of the proteasome pathway was verified in studies with lactacystin, a highly specific and irreversible proteasome inhibitor. Lactacystin-induced apoptosis in M-07e cells was remarkably similar to that induced by Z-LLL-CHO, which included caspase 3 activation, cleavage of Bcl-2 into a 22 kDa fragment and, ultimately, cell death. These results showed that inhibition of the ubiquitin-proteasome pathways can lead to the activation of a DEVD-CHO-sensitive caspase and induces Bcl-2 cleavage, which might have a role in mediating apoptosis in M-07e cells.

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“…Cheng et al [23] have proposed that the cleaved product is capable of acting as a Bax-like death effector. This notion is somewhat controversial in that Bcl-2 is thought to act upstream of caspase-3 activation [29], therefore suggesting that the cleavage of Bcl-2 during apoptosis is a means of preventing its antiapoptotic effects after caspase-3 activation rather than inducing proapoptotic activity. Whether Bcl-2 cleavage to a proapoptotic form during apoptosis does indeed act to amplify the apoptotic response should be an interesting topic for future study.…”

Section: Discussionmentioning

confidence: 99%

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

Kurland

Meyn

2001

Intl Journal of Cancer

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SUMMARY The proteasome pathway is important for the turnover of many regulatory proteins. This pathway has recently become a target for antitumor agents and several research groups have demonstrated that inhibitors with specificities for the proteasome are potent apoptosis-inducing agents. Many mechanisms by which proteasome inhibitors exert their effects have been suggested, including inhibition of NF-B activity and stabilization of the p53 tumor suppressor protein. We investigated the ability of inhibitors with specificities for the proteasome and for another protein degradation enzyme, calpain, to sensitize a murine B-cell lymphoma with constitutive NF-B1 homodimer activity and high expression of Bcl-2 protein to radiation-induced apoptosis. Protease inhibitors tested were calpain inhibitor I, calpain inhibitor II, calpeptin, MG132, and Lactacystin. All five inhibitors induced apoptosis and sensitized cells to radiation despite the maintenance of Bcl-2 protein levels throughout the course of treatment. An electrophoretic migration shift assay for NF-B1 activity provided evidence that reversal of NF-B activity was not required for induction of cell death; however, p53 levels were elevated for all inhibitors tested. HL-60 cells, devoid of p53, could not be sensitized to radiation by MG132 treatment, suggesting that p53 was important for cell death induced by combined treatment with protease inhibitors and radiation. We concluded that protease inhibitors are capable of overcoming the protective effects of Bcl-2 to induce apoptosis and suggest that protease inhibitor treatment, when combined with ionizing radiation, leads to p53-mediated apoptosis.

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Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

Cited by 24 publications

References 22 publications

Fas/CD95-Mediated Apoptosis of Type II Cells Is Blocked byToxoplasma gondiiPrimarily via Interference with the Mitochondrial Amplification Loop

Fas/CD95-Mediated Apoptosis of Type II Cells Is Blocked byToxoplasma gondiiPrimarily via Interference with the Mitochondrial Amplification Loop

Inhibition of ubiquitin-proteasome pathway activates a caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

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