Translocation of Bax and Bid to Mitochondria, Endoplasmic Reticulum and Nuclear Envelope: Possible Control Points in Apoptosis

Gajkowska, B; Wojewódzka, Urszula; Gajda, Joanna

doi:10.1023/b:hijo.0000020900.86650.89

Cited by 27 publications

(23 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…U937 tumor cells treated with P-OH + PTX exhibited increased expression of Bcl-2 and Bax protein and apoptosis. Based on our observations and the current concepts about the activities of Bcl-2 and Bax [28,29] , we propose that these proteins are involved in the effects we observed in our system. However, we cannot rule out other possible mechanisms to explain the effects of P-OH and PTX, and further experiments with inhibitors of Bcl-2 and Bax protein expression are needed.…”

Section: Discussionsupporting

confidence: 61%

In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression

et al. 2006

View full text Add to dashboard Cite

Background: Chemotherapy is effective against a wide variety of tumor cells, although its use is limited by side effects. In vitro experiments and phase I and II trials have shown that phytochemicals such as perillyl alcohol (P-OH) have antitumor effects. Pentoxifylline (PTX), a synthetic methylxanthine used mainly to treat pathologies associated with hematological diseases, sensitizes tumor cells to chemotherapy. The aim of this study was to determine whether PTX amplifies the antitumor effects of P-OH in U937 human myelomonocytic leukemia cells. Methods: Apoptosis was measured by the loss of mitochondrial membrane potential determined by flow cytometry using dihexyloxacarbocyanine iodide (DiOC₆) and propidium iodide. Bcl-2 and Bax protein expression was also assessed by Western blot analysis. Results: P-OH and PTX induced loss of the mitochondrial membrane potential in U937 cells in vitro. Culturing the cells in the presence of both compounds caused a significant increase (p < 0.001) in apoptosis and expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins. However, despite their coexistence, Bax expression prevailed in our experiments. These data suggest that the effects of PTX might be attributable to changes in the mitochondrial membrane potential. Conclusion: PTX sensitizes tumor cells to the anti-neoplastic action of P-OH. These observations may have clinical relevance in the treatment of cancer patients.

show abstract

Section: Discussionsupporting

confidence: 61%

In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Thus, we observed a significant reduction in the expression of the antiapoptotic proteins Bcl-2 (9.0 fold) and Bcl XL (3.5 fold). These proteins also prevent oligomerization of Bax and tBid on the mitochondria and stabilize the outer mitochondrial membrane surface, thus preventing cyt c release (17). From these observations, we infer that LKT generally mobilizes proapoptotic proteins and downregulates antiapoptotic proteins that control mitochondrial damage and cyt c release.…”

Section: Discussionmentioning

confidence: 73%

Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway

Atapattu

Czuprynski

2005

Infect Immun

View full text Add to dashboard Cite

Mannheimia haemolytica is a key pathogen in the bovine respiratory disease complex. It produces a leukotoxin (LKT) that is an important virulence factor, causing cell death in bovine leukocytes. The LKT binds to the ␤ 2 integrin CD11a/CD18, which usually activates signaling pathways that facilitate cell survival. In this study, we investigated mechanisms by which LKT induces death in bovine lymphoblastoid cells (BL-3). Incubation of BL-3 cells with a low concentration of LKT results in the activation of caspase-3 and caspase-9 but not caspase-8. Similarly, the proapoptotic proteins Bax and BAD were significantly elevated, while the antiapoptotic proteins Bcl-2, Bcl XL and Akt-1 were downregulated. Following exposure to LKT, we also observed a reduction in mitochondrial cytochrome c and corresponding elevation of cytosolic cytochrome c, suggesting translocation from the mitochondrial compartment to the cytosol. Consistent with this observation, tetramethylrhodamine ethyl ester perchlorate staining revealed that mitochondrial membrane potential was significantly reduced. These data suggest that LKT induces apoptosis of BL-3 cells via a caspase-9-dependent mitochondrial pathway. Furthermore, scanning electron micrographs of mitochondria from LKT-treated BL-3 cells revealed lesions in the outer mitochondrial membrane, which are larger than previous reports of the permeability transition pore through which cytochrome c is usually released.Mannheimia (Pasteurella) haemolytica is the principal bacterial pathogen of the bovine respiratory disease complex (23,49). Among the most important virulence factors produced by this pathogen is a 104-kDa leukotoxin (LKT) that both activates and kills bovine leukocytes (2, 41). The M. haemolytica LKT is a member of the "repeats in toxin" (RTX) family of gram-negative bacterial exotoxins (34). It has been demonstrated that M. haemolytica LKT binds to the ␤ 2 integrin CD11a/CD18 (also known as leukocyte functional antigen 1 [LFA-1]) (2, 15, 21). Paradoxically, LFA-1 is usually a survival receptor whose signaling pathways protect cells against death (31,37,41). It is not clear how binding of LKT to LFA-1 results in apoptosis of bovine leukocytes.The molecular mechanisms leading to apoptosis are complex. There are two major pathways that initiate apoptosis in cells (3,7,14). The first involves ligand binding to a death receptor (e.g., Fas or tumor necrosis factor receptor) that initiates a signaling pathway, which activates caspase-8 (5, 19). The second pathway involves mitochondrial activation of caspase-9. Both activated caspase-8 and caspase-9 can then activate the effector caspase-3 that cleaves macromolecules, leading to apoptotic cell death (35,42). The caspase-9-dependent mitochondrial pathway is induced by cellular stress, which results in deployment of an array of proapoptotic members of the Bcl-2 family of proteins (e.g., BAD and Bax) to the outer mitochondrial membrane (OMM) (4,52,54). This destabilizes the membrane, resulting in pore formation and release of cytochrome c (c...

show abstract

“…Since part of Bax had previously been reported to reside on the NE, 24,25 we envisaged the possibility that it might trigger SIGRUNB from that site. We therefore used a Bax variant that was targeted to the outer surface of the ONM of the NE via the KASH domain.…”

Section: Bax Mediates Sigrunb Via Distinct Domainsmentioning

confidence: 99%

“…Nonetheless a NE localization of Bax has been reported in both healthy [42][43][44] and apoptotic cells. 24,25,45 Thus, we postulate that in response to apoptotic stimuli, Bax not only causes permeabilization of the mitochondrial and ER membranes 46 to release apoptogenic factors, but may also acts, at least in part, on the NE to trigger SIGRUNB. Interestingly, the LINC complex matefin/SUN1 protein in Caenorhabditis elegans has been shown to be required to recruit the pro-apoptotic protein CED-4 to the NE.…”

Section: The Role Of Apoptotic Molecules In Sigrunbmentioning

confidence: 99%

Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release

Lindenboim

Sasson

Worman

et al. 2014

Nucleus

View full text Add to dashboard Cite

Cellular stress triggers many pathways including nuclear protein redistribution. We previously discovered that this process is regulated by Bax but the underlying mechanism has not yet been studied. Here we define this mechanism by showing that apoptotic stimuli cause Bax-regulated disturbances in lamin A/C and nuclear envelope (NE)-associated proteins which results in the generation and subsequent rupture of nuclear protein-containing bubbles. The bubbles do not contain DNA and are encapsulated by impaired nuclear pore-depleted NE. Stress-induced generation and rupture of nuclear bubbles ultimately leads to the discharge of nuclear proteins into the cytoplasm. This process precedes morphological changes of apoptosis and occurs independently of caspases. Rescue experiments revealed that this Bax effect is non-canonical, i.e. it requires the BH3 domain and a-helices 5 and 6 but it is not inhibited by Bcl -x L . Targeting Bax to the NE by the Klarsicht/ANC-1/Syne-1 homology (KASH) domain effectively triggers the generation and rupture of nuclear bubbles. Overall, our findings provide evidence for a novel stress-response, which is regulated by a non-canonical action of Bax on the NE.

show abstract

Translocation of Bax and Bid to Mitochondria, Endoplasmic Reticulum and Nuclear Envelope: Possible Control Points in Apoptosis

Cited by 27 publications

References 30 publications

In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression

In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression

Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway

Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release

Contact Info

Product

Resources

About