VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis

Cheng, Emily H.; Sheiko, Tatiana; Fisher, Jill K.; Craigen, William J.; Korsmeyer, Stanley J.

doi:10.1126/science.1083995

Cited by 740 publications

(783 citation statements)

References 27 publications

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“…Mouse embryonic fibroblasts (MEF) lacking both Bcl-2-associated X protein (Bax) and Bcl-2 antagonist/killer (Bak), two tumor-suppressor gene products from the proapoptotic arm of the Bcl-2 family, are resistant to different types of apoptotic stimuli Boya et al, 2005) and are more susceptible to rat sarcoma viral oncogene homolog (Ras)-mediated transformation than control cells . Bak is normally associated with OM, where it interacts with the voltage-dependent anion channel isoform 2 (VDAC2), which prevents its activation (Cheng et al, 2003). Upon apoptosis induction Bak fully inserts into OM, as a result of a conformational change.…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

“…Of note, there are several VDAC isoforms (VDAC1, VDAC2, VDAC3). Although there is no systematic study that has addressed the contribution of VDAC isoforms to apoptosis, it appears that VDAC1 is proapoptotic (Zaid et al, 2005), while VDAC2 might be antiapoptotic, acting as an endogenous inhibitor of Bak (Cheng et al, 2003).…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

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Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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“…However, both Bax and Bcl-2 are implicated in direct, or at least functional interactions with ANT, and are suggested to have opposite effects on ANT function (Belzacq et al, 2002;Verrier et al, 2004;Kroemer and Martin, 2005). In addition, Bak was shown to bind directly to VDAC2 (Cheng et al, 2003). Together with complex V (F 1 F 0 ATP synthase), ANT and VDAC are thought to coordinately exchange ADP and ATP across both mitochondrial membranes.…”

Section: The Victim Mitochondrionmentioning

confidence: 99%

Mitochondrial factors with dual roles in death and survival

Berman

Ivanovska

et al. 2006

Oncogene

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At least in mammals, we have some understanding of how caspases facilitate mitochondria-mediated cell death, but the biochemical mechanisms by which other factors promote or inhibit programmed cell death are not understood. Moreover, most of these factors are only studied after treating cells with a death stimulus. A growing body of new evidence suggests that cell death regulators also have 'day jobs' in healthy cells. Even caspases, mitochondrial fission proteins and pro-death Bcl-2 family proteins appear to have normal cellular functions that promote cell survival. Here, we review some of the supporting evidence and stretch beyond the evidence to seek an understanding of the remaining questions.

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“…Nevertheless, recent evidence delineates that Bax and Bak exert also nonredundant activities Cartron et al, 2003;Gillissen et al, 2003;von Haefen et al, 2004;Wendt et al, 2005). At the molecular level, this may be reflected by the fact that Bax and Bak are differentially controlled by additional factors such as VDAC2 (Cheng et al, 2003;Chandra et al, 2005). Furthermore, the proapoptotic activity of Bax and Bak is hold in check by distinct antiapoptotic Bcl-2 family members.…”

Section: Introductionmentioning

confidence: 99%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis

Cited by 740 publications

References 27 publications

Mitochondria as therapeutic targets for cancer chemotherapy

Mitochondria as therapeutic targets for cancer chemotherapy

Mitochondrial factors with dual roles in death and survival

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

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