Interaction of E1B 19K with Bax is required to block Bax-induced loss of mitochondrial membrane potential and apoptosis

Han, Jeonghoon; Modha, Digant; White, Eileen

doi:10.1038/sj.onc.1202215

Cited by 55 publications

(46 citation statements)

References 32 publications

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“…However, the situation bears some resemblance to the inhibition of apoptosis and SAPK activation associated with the E1B19K protein of adenovirus (33). This viral protein up-regulates SAPK activity but also inhibits Fas-mediated apoptosis by binding to BAX, APAF1, and FADD/caspase 8 in the signal transduction pathway (31,93). It is not known whether HBx also interacts directly with components in the Fas pathway, with mitochondrial membrane proteins, or indirectly influences the apoptotic signal transduction pathway by activating SAPK.…”

Section: Discussionmentioning

confidence: 99%

X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway

Diao

Khine

Sarangi

et al. 2001

Journal of Biological Chemistry

157

121

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The X protein from a chronic strain of hepatitis B virus (HBx) was determined to inhibit Fas-mediated apoptosis and promote cell survival. Fas-mediated apoptosis is the major cause of hepatocyte damage during liver disease. Experiments demonstrated that cell death caused by anti-Fas antibodies was blocked by the expression of HBx in human primary hepatocytes and mouse embryo fibroblasts. This effect was also observed in mouse erythroleukemia cells that lacked p53, indicating that protection against Fas-mediated apoptosis was independent of p53. Components of the signal transduction pathways involved in this protection were studied. The SAPK/JNK pathway has previously been suggested to be a survival pathway for some cells undergoing Fasmediated apoptosis, and kinase assays showed that SAPK activity was highly up-regulated in cells expressing the HBx protein. Normal mouse fibroblasts expressing HBx were protected from death, whereas identical fibroblasts lacking the SEK1 component from the SAPK pathway succumbed to Fas-mediated apoptosis, whether HBx was present or not. Assays showed that caspase 3 and 8 activities and the release of cytochrome c from mitochondria were inhibited, in the presence of HBx, following stimulation with anti-Fas antibodies. Coprecipitation and confocal immunofluorescence microscopy experiments demonstrated that HBx localizes with a cytoplasmic complex containing MEKK1, SEK1, SAPK, and 14-3-3 proteins. Finally, mutational analysis of HBx demonstrated that a potential binding region for 14-3-3 proteins was essential for induction of SAPK/JNK activity and protection from Fas-mediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway

Diao

Khine

Sarangi

et al. 2001

Journal of Biological Chemistry

157

121

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“…Bax in healthy HeLa cells is apparently not in a conformation that will permit E1B 19K binding (7,10). Since Bax BH3 is necessary and sufficient for E1B 19K binding to Bax (11,38), Bax BH3 may not be in a configuration in the absence of a death stimulus to permit E1B 19K binding. Once tBid is bound to Bax and has altered the conformation of the Bax amino terminus adjacent to BH3, this may expose the E1B 19K-binding domain to permit Bax-E1B 19K complex formation.…”

Section: E1b 19k Inhibits Bax-bak Interaction 45126mentioning

confidence: 99%

“…The Sephacryl S-300 gel filtration chromatography was carried out as previously described (10). Fractions were analyzed by SDS-PAGE and Western blotting as previously described (33) and probed with the Bax- (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) or Bak NT antibodies.…”

Section: Methodsmentioning

confidence: 99%

Tumor Necrosis Factor-α Induces Bax-Bak Interaction and Apoptosis, Which Is Inhibited by Adenovirus E1B 19K

Sundararajan¹,

Cuconati²,

Nelson³

et al. 2001

Journal of Biological Chemistry

Self Cite

108

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Tumor necrosis factor (TNF)-␣-mediated death signaling induces oligomerization of proapoptotic Bcl-2 family member Bax into a high molecular mass protein complex in mitochondrial membranes. Bax complex formation is associated with the release of cytochrome c, which propagates death signaling by acting as a cofactor for caspase-9 activation. The adenovirus Bcl-2 homologue E1B 19K blocks TNF-␣-mediated apoptosis by preventing cytochrome c release, caspase-9 activation, and apoptosis of virus-infected cells. TNF-␣ induces E1B 19K-Bax interaction and inhibits Bax oligomerization. Oligomerized Bax may form a pore to release mitochondrial proteins, analogous to the homologous pore-forming domains of bacterial toxins. E1B 19K can also bind to proapoptotic Bak, but the functional significance is not known. TNF-␣ signaling induced Bak-Bax interaction and both Bak and Bax oligomerization. E1B 19K was constitutively in a complex with Bak, and blocked the Bak-Bax interaction and oligomerization of both. The TNF-␣-mediated cytochrome c and Smac/DIABLO release from mitochondria was inhibited by E1B 19K expression in adenovirus-infected cells. Since either Bax or Bak is essential for death signaling by TNF-␣, the interaction between E1B 19K and both Bak and Bax may be required to inhibit their cooperative or independent oligomerization to release proteins from mitochondria which promote caspase activation and cell death.

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“…As a Bcl-2 functional homologue, E1B-19kD is able to inhibit apoptosis by interrupting FADD oligomerization and by binding to Bax and Bak. 11,12 E1B-19kD appears capable of inhibiting apoptosis from both receptormediated death signaling pathways and via the mitochondrial pathway. 13 In addition, E1B-19kD is also able to indirectly counteract the function of the E3 protein ADP in preventing premature viral release.…”

Section: Introductionmentioning

confidence: 99%

Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus

et al. 2005

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Replication-selective oncolytic adenoviruses hold promise, but novel mechanisms must be identified to maximize intratumoral virus persistence, spread and therapeutic transgene-carrying capacity while maintaining safety. One of the main approaches to engineering cancer-selectivity has been to delete a viral gene that is theoretically expendable in cancer cells. Results with this approach have been mixed, however, as evidenced by controversy over Onyx-015 (E1B-55kD(À)) selectivity. We hypothesized that the functional redundancy between viral gene products might limit selectivity and/or potency with this approach. Antiviral immune inducers of apoptosis (eg TNF-a) have not been thoroughly investigated in previous studies. We therefore explored whether deletion of functionally redundant viral genes, E1B-19kD and E3B, both independently antagonize TNF-a, could lead to enhanced oncolytic potency while maintaining selectivity. Since tumors have numerous blocks in apoptotic pathways, we hypothesized that deletion of one or both gene regions would result in cancer-selectivity in the presence of TNF-a. We have previously shown that the E1B-19kD deletion resulted in enhanced viral spread in vitro and in immunocompetent tumor models in vivo. In contrast, the impact of E3B deletion, especially its in vitro selectivity and potency, was not thoroughly characterized, although it resulted in rapid immune-mediated viral clearance in vivo. Furthermore, previous publications indicated that doubledeleted mutants have selectivity but unsatisfactory efficacy. We compared the selectivity and potency of E1B-19kD(À), E3B(À) and E1B-19kD(À)/E3B(À) mutants to wild-type adenovirus. In cancer cells, the E1B-19kD(À) mutant had superior replication, spread and cytolysis (+) or (À) TNF-a; deletion of both E1B-19kD and E3B was relatively deleterious. In normal cells without TNF-a, similar results were obtained. In contrast, all three mutants were significantly inhibited in the presence of TNF-a. In immunocompetent mice, all three mutants were significantly inhibited in normal tissue. In tumors, only the E1B-19kD(À) mutant demonstrated enhanced replication, spread and antitumoral efficacy. Therefore, E1B-19kD deletion and E3B retention should be incorporated in oncolytic adenoviruses for enhanced safety and efficacy. In addition, functional redundant viral genes and their biological mediators/targets need to be carefully examined for the next generation of gene-deleted oncolytic viruses.

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Interaction of E1B 19K with Bax is required to block Bax-induced loss of mitochondrial membrane potential and apoptosis

Cited by 55 publications

References 32 publications

X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway

X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway

Tumor Necrosis Factor-α Induces Bax-Bak Interaction and Apoptosis, Which Is Inhibited by Adenovirus E1B 19K

Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus

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