Apoptosis and the conformational change of Bax induced by proteasomal inhibition of PC12 cells are inhibited by bcl-xL and bcl-2

Lang-Rollin, Isabelle; Maniati, Matina; Jabado, Omar; Vekrellis, Kostas; Papantonis, S.; Rideout, Hardy J.; Stefanis, Leonidas

doi:10.1007/s10495-005-0378-5

Cited by 31 publications

(15 citation statements)

References 54 publications

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“…However, in Bcl-2 over-expressed TR9-7 cells (which otherwise express moderate level of Bcl-2) apoptosis was significantly decreased despite of Bax up-regulation and translocation to mitochondria in the presence of theaflavins. The underlying cause may be that, Bcl-2 prevents conformational change of Bax, which is required for its pro-apoptotic activity [30]. In conformity, when Bax was restored in the absence of normal p53 transcriptional activity or in p53-null cells, these cells regained their sensitivity towards theaflavins.…”

Section: Discussionmentioning

confidence: 99%

Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis

et al. 2008

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Theaflavins, the bioactive flavonoids of black tea, have been demonstrated to inhibit proliferation and induce apoptosis in a variety of cancer cells. However, the contribution of p53 in mammary epithelial carcinoma cell apoptosis by theaflavins remains unclear. It has been reported that p53 triggers apoptosis by inducing mitochondrial outer membrane permeabilization through transcription-dependent and -independent mechanisms. Using wild-type and mutant p53-expressing as well as p53-null cells we found a strong correlation between p53 status and theaflavin-induced breast cancer cell apoptosis. Apoptogenic effect was more pronounced in functional p53-expressing cells in which theaflavins raised p53 protein levels that harmonized with Bax up-regulation and migration to mitochondria. However, in the same cells, when p53-mediated transactivation was inhibited by pifithrin-alpha, theaflavins not only failed to increase transcription but also to induce apoptosis although p53 up-regulation was not altered. In contrast, Bax over-expression restored back theaflavin-induced apoptosis in pifithrin-alpha-inhibited/dominant-negative p53-expressing cells. Inhibition of Bax by RNA-interference also reduced theaflavin-induced apoptosis. These results not only indicated the requirement of p53-mediated transcriptional activation of Bax but also its role as down-stream effecter in theaflavin-induced apoptosis. Bax up-regulation resulted in mitochondrial transmembrane potential loss and cytochrome c release followed by activation of caspase cascade. In contrast, mitochondrial translocation of p53 and its interaction with Bcl-2 family proteins or activation of caspase-8 could not be traced thereby excluding the involvement of p53-mediated transcription-independent pathways. Together these findings suggest that in breast cancer cells, p53 promotes theaflavin-induced apoptosis in a transcription-dependent manner through mitochondrial death cascade.

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Section: Discussionmentioning

confidence: 99%

Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis

et al. 2008

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“…This model yielded a plausible tertiary structure without major constraints and proved useful to model the interaction between vMIA and Bax. One important difference between vMIA and Bcl-X L , in functional terms, is that vMIA recruits Bax to mitochondria, causing its oligomerization and membrane insertion , while Bcl-X L functionally counteracts Bax, hindering it from inserting into the outer mitochondrial membrane Lang-Rollin et al, 2005). This difference may be dictated by the nature of the Bax-vMIA and Bax-Bcl-X L interactions.…”

Section: Discussionmentioning

confidence: 99%

Structure–function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA

et al. 2007

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The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X L . In contrast to Bcl-X L , however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an a-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membraneinserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Baxbinding function. We found that D131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIAD131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIAD131-147 suggest that vMIA forms homooligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.

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“…Recent studies suggested that Bax promotes apoptosis through several interdependent mechanisms, including translocation of Bax from the cytoplasm to the mitochondria, Bax conformational changes, and oligomerization of Bax and Bak (13,(16)(17)(18). Bax expression is closely related to cellular sensitivity to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

MutantPIK3CA-Bearing Colon Cancer Cells Display Increased Metastasis in an Orthotopic Model

et al. 2007

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Mutations in the PIK3CA gene are common in human cancers, including colon cancer. We compared two pairs of colon cancer cells (HCT116 and DLD1) bearing only the wild-type (WT) or mutant (MUT) PIK3CA allele for their survival capacity under stress conditions in vitro as well as their metastatic properties in an in vivo orthotopic model. When subjected to growth factor deprivation stress (GFDS), the MUT PIK3CA cells displayed resistance to GFDS-induced apoptosis relative to the WT cells. Phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT were constitutively activated during stress conditions in the MUT PIK3CA cells but not in the WT cells. The MUT cells showed hypersensitivity to PI3K inhibition. Moreover, the proapoptotic protein Bax was expressed at a very high level in the WT PIK3CA cells, whereas it was almost undetectable in the MUT cells. Inhibition of Bax expression by small interfering RNA protected the WT PIK3CA cells from GFDS-induced apoptosis, suggesting an important role of Bax in GFDS-induced apoptosis. These results indicated that the MUT PI3K confers resistance to GFDS-induced apoptosis and that the MUT cells are more dependent on the PI3K pathway for survival. In vivo studies showed that the MUT PIK3CA-bearing cells were more metastatic than the WT cells in an orthotopic model of colon cancer. Taken together, these results suggest that MUT PI3K imparts a more aggressive phenotype in colon cancer cells and could be a potential therapeutic target for treatment of colon cancer patients bearing PIK3CA mutations. [Cancer Res 2007;67(12):5851-8]

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Apoptosis and the conformational change of Bax induced by proteasomal inhibition of PC12 cells are inhibited by bcl-xL and bcl-2

Cited by 31 publications

References 54 publications

Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis

Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis

Structure–function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA

MutantPIK3CA-Bearing Colon Cancer Cells Display Increased Metastasis in an Orthotopic Model

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