Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway

Gillissen, Bernhard; Eßmann, Frank; Graupner, Vilma; Stärck, Lilian; Radetzki, Silke; Dörken, Bernd; Schulze‐Osthoff, Klaus; Daniel, Peter T.

doi:10.1093/emboj/cdg343

Cited by 110 publications

(150 citation statements)

References 37 publications

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“…To corroborate the impact of Bax reexpression in p53/Bax-deficient DU145 prostate cancer cells, we tested a panel of mock-and Bax-transfected stable clones (Gillissen et al, 2003) and studied caspase activation, cytochrome c release and dissipation of the mitochondrial membrane potential. To this end, DU145 cells either deficient (clones mock #2 and mock #4) or reconstituted for Bax (clones bax #3 and bax #10) were infected with an increasing multiplicity of infection (m.o.i.)…”

Section: Resultsmentioning

confidence: 99%

“…However, DU145 are wild type for Bak (Gillissen et al, 2003), which may functionally rescue for Bax deficiency during the activation of mitochondria and subsequent activation of caspases, that is, caspase-9 and caspase-3/7. Therefore, we studied the capacity of p14 ARF to induce caspase-9-like (LEHDase) and caspase-3/7-like (DEVDase) activities.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the fact that DU145 cells are void of functional p53, which may translate into a failure of DU145 cells to upregulate certain BH3-only proteins during p14 ARF -induced apoptosis must be put into account. There is in fact evidence for such differential regulation of Bax and Bak by BH3-only proteins (Gillissen et al, 2003;Yu et al, 2003). In turn, this may have profound effects on the apoptosis sensitivity of p53-deficient cells in general and, at the same time, alter the selectivity of certain apoptotic stimuli for Baxindependent versus Bax-dependent pathways of mitochondrial activation.…”

Section: Discussionmentioning

confidence: 99%

“…Most studies addressing the impact of Bax and Bak on apoptosis sensitivity of cancer cells therefore suggest that both proteins are partially redundant. 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).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the proapoptotic activity of Bax and Bak is hold in check by distinct antiapoptotic Bcl-2 family members. Finally, BH3-only proteins have recently been shown to preferentially activate either Bax-or Bak-dependent events in human cells Gillissen et al, 2003;Yu et al, 2003;Willis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase‐9 activation

et al. 2004

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Various routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase-3 processing have suggested that antigen receptor (BCR)-mediated apoptosis may involve a zVAD-insensitive initiator protease(s). In search of the events leading to caspase-3 activation, we now establish that both CD95-and BCRmediated apoptosis depend on Bax activation and cytochrome C (cytC) release. Nevertheless, the timing and caspase-dependence of mitochondrial membrane depolarization differed considerably after CD95-or BCR-triggering. To delineate events subsequent to cytC release, we compared apoptosis induced via BCR triggering and via direct mitochondrial depolarization by CCCP. In both cases, partial processing of caspase-3 was observed in the presence of zVAD. By expression in 293 cells we addressed the potential of candidate initiator caspases to function in the presence of zVAD, and found that caspase-9 efficiently processed caspase-3, while caspase-2 or -8 were inactive. Finally, retroviral expression of dominant-negative caspase-9 inhibited both CD95-and BCR-mediated apoptosis. In conclusion, we obtained no evidence for involvement of a BCR-specific protease. Instead, our data show for the first time that the BCR-signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release. Subsequent caspase-9 activation can solely account for events further downstream.

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Necrotic death but not irradiation abolishes costimulation of T‐cell effector functions and survival by CD80‐expressing tumor cells

Stärck

Schölz

Blankenstein

et al. 2005

Intl Journal of Cancer

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Tumor vaccination by the use of gene‐modified cancer cells that provide costimulatory signals has been successfully applied in preclinical animal models and is currently evaluated in a variety of clinical settings. In previous work, we demonstrated the efficacy of B7.1/CD80 to promote tumor immunity in syngeneic murine models and to prevent deletion of activated T cells by activation‐induced cell death (AICD). In clinical trials, tumor cell vaccines are generally inactivated to avoid transfer of live tumor cells, i.e., additional tumor burden. Previous data indicated, however, that inactivation of tumor cells by lethal ionizing irradiation abrogates tumor vaccination by CD80‐expressing cells. Here, we compare living and irradiated allogeneic tumor cells regarding their capacity to induce T‐cell effector functions and their propensity to interfere with T‐cell deletion by apoptosis. Both lethally irradiated and nonirradiated tumor cells facilitated T‐cell proliferation, tumor cell lysis, and interfered with T‐cell AICD to a similar extent. In contrast, necrotic tumor cells failed to costimulate T‐cell effector functions. Thus, irradiation does not seem to hamper tumor cell‐mediated costimulation of T‐cell effector functions. In contrast, necrosis of gene‐modified tumor cells abrogates costimulation of T cells by CD80‐expressing cells. © 2005 Wiley‐Liss, Inc.

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Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway

Cited by 110 publications

References 37 publications

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

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

Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase‐9 activation

Necrotic death but not irradiation abolishes costimulation of T‐cell effector functions and survival by CD80‐expressing tumor cells

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