Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members

Certo, Michael; Moore, Victoria Del Gaizo; Nishino, Mari; Wei, Guo; Korsmeyer, Stanley J.; Armstrong, Scott A.; Letaï, Anthony

doi:10.1016/j.ccr.2006.03.027

Cited by 1,117 publications

(1,405 citation statements)

References 47 publications

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“…Hence, Beclin-1 is an atypical BH3-domain-containing protein in that its expression in cells that depend for survival on overexpressed Bcl-2 is not sufficient to induce apoptosis. This result contrasts with overexpression of Puma, for example, which led to rapid apoptosis of untreated HeLa cells , showing that the cells are 'primed' and competent to die (Certo et al, 2006). Why Beclin-1 is different from other BH3-only proteins is still unclear.…”

Section: Discussionmentioning

confidence: 93%

“…Beclin-1 was first identified as a protein that interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL, but not with Bax/Bak (Liang et al, 1998), and classified recently as a BH3-only protein (Oberstein et al, 2007;Maiuri et al, 2007b). BH3-only proteins are pro-apoptotic regulators of apoptosis, the binding of which to anti-apoptotic Bcl-2 members is one mechanism of facilitating the activation of Bax/Bak, crucial mediators of the mitochondrial pathway of apoptosis (Scorrano and Korsmeyer, 2003;Certo et al, 2006;Adams and Cory, 2007). Like other BH3-only proteins, the BH3 domain of Beclin-1 binds to anti-apoptotic Bcl-2 family proteins within their hydrophobic groove (Feng et al, 2007;Oberstein et al, 2007;Maiuri et al, 2007b;Ku et al, 2008;Sinha et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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The binding of Bcl-2 to Beclin-1 reduces Beclin-1's capacity to induce autophagy. Here, we have tested whether the interaction is reciprocated by loss of Bcl-2's anti-apoptotic function. We targeted Bcl-2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis using several apoptotic stimuli that initiate ER and/or mitochondrial signaling pathways (UV radiation, TNF and cycloheximide, staurosporine, thapsigargin and tunicamycin). When Beclin-1 and Bcl-2 were expressed together in HeLa cells, Beclin-1 (but not Beclin-1 lacking the Bcl-2-binding domain) followed Bcl-2 to the appropriate organelle with complete or near-complete overlap (comprising 60 and 30% of cells, respectively). The interaction between Beclin-1 and Bcl-2 was verified by immunoprecipitation, and a membrane-proximate localization of Beclin-1 was shown by immunoelectron microscopy. Apoptosis was followed by measuring changes in nuclear morphology, caspase-3 activity, poly-ADP-ribose polymerase cleavage or punctation of mRFP-Bax on mitochondria. Binding of Beclin-1 to Bcl-2 did not modify apoptosis irrespective of Bcl-2 concentration, location or apoptotic stimulus. A similar result was obtained in Atg5À/À cells that are autophagy-deficient, arguing against compensation for the loss of protection by Bcl-2 by autophagy-mediated survival induced by Beclin-1. Hence, although Beclin-1 contains a BH3-only motif typical of pro-apoptotic proteins, it is a negligible modulator of Bcl-2's anti-apoptotic function.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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“…35 Although Bcl-2 antagonizes Puma, Bcl-2 has an extremely low affinity for Noxa. 36,37 Instead, both Mcl-1 and A1 have a higher affinity for Noxa. 36,37 Noxa is activated by nutrient deprivation, potentially through maintenance of Mcl-1, 38 and can contribute to T-cell contraction in some model systems.…”

Section: Discussionmentioning

confidence: 99%

“…36,37 Instead, both Mcl-1 and A1 have a higher affinity for Noxa. 36,37 Noxa is activated by nutrient deprivation, potentially through maintenance of Mcl-1, 38 and can contribute to T-cell contraction in some model systems. 16,39 Further, we recently showed that Mcl-1 was critical for effector T-cell survival and that the additional loss of Bim failed to restore Mcl-1-deficient effector T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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During the effector CD8 þ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8 þ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8 þ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.

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“…However, the results so far obtained from combined treatment seem to suggest that the apoptosis resistance pathway could be not completely related to BCL-2, BCL-XL or MCL-1 inactivation, and that the inhibition of BCL-2 protein family is necessary but not sufficient to achieve a complete overcoming of resistance. Recent papers have shown that, although the MCL-1 levels may well influence the ABT-737 sensitivity, on the other hand, its lack unlikely causes sensitivity to BCL-2 antagonism nor the most critical in lymphoma and in solid tumors [33,42].…”

Section: Discussionmentioning

confidence: 99%

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid

Romani

Desenzani

Morganti

et al. 2010

Cancer Chemother Pharmacol

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Purpose: In TFK-1 and EGI-1 cholangiocarcinoma cell lines zoledronic acid (ZOL) determines a S-phase block without apoptosis. Here we investigated the occurrence of apoptosis stigmata when ZOL is associated to the BH3-mimetic ABT-737. Methods:In EGI-1 and TFK-1 cholangiocarcinoma cell lines untreated or treated with ABT-737 alone or in combination with ZOL, the pro-survival proteins pattern (BCL-2, BCL-XL, MCL-1, HSP72, HSP27) was investigated by biochemical criteria along with the occurrence of mitochondrial damage evaluated by cytofluorimetric analysis using a cationic dye.Results: ABT-737 induced growth inhibition and significantly affected the colony-forming ability of both EGI-1 and TFK-1 cells. However, activated PARP-1 or/and caspase-3 cleavage (apoptosis markers) were detected only at the highest ABT-737 concentrations used. Combined treatment showed synergistic effect by converting the predominant cytostatic effect of ZOL into a cytotoxic one as shown by striking increment of mitochondrial-harmed cells along with PARP-1 activation and caspase-3 cleavage. Conclusion:The lacking of apoptosis following ZOL treatment in these cholangiocarcinoma cell lines appears to be multifactorial and could be ascribed to the large constitutive expression of prosurvival proteins. The efficacy of ZOL treatment requires a concomitant unleashing of apoptosis by using a selective BH3-mimetic as ABT-737. The rational targeting of specific components of the apoptotic pathway may appear a useful approach to improve the treatment of refractory or relapsed cholangiocarcinoma. Combined treatment could be further explored in vivo tumor model of cholangiocarcinoma

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Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members

Cited by 1,117 publications

References 47 publications

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid

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