Viral pro-survival proteins block separate stages in Bax activation but changes in mitochondrial ultrastructure still occur

Cross, Justin R.; Postigo, Antonio; Blight, Ken; Downward, Julian

doi:10.1038/cdd.2008.14

Cited by 19 publications

(19 citation statements)

References 41 publications

(56 reference statements)

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“…We conclude that BHRF1 must exert its anti-apoptotic effect at the level of, or prior to, Bax and Bak activation, consistent with a report that BHRF1 prevented Bax and Bak conformational change, oligomerization and activation of the initiator caspase, caspase-9 [17]. How then might BHRF1 inhibit activation of these essential cell death mediators?…”

Section: Resultssupporting

confidence: 90%

Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1

et al. 2010

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Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.

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Section: Resultssupporting

confidence: 90%

Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1

et al. 2010

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“…The biological function of E1B19K is to inhibit receptor-induced signaling at the time of cell death by preventing the Bax-Bak association, thus intrinsically inhibiting induced apoptosis through the p53-dependent and p53-independent mechanisms. The effect can be observed, for example, in the cellular response to viral E1A proteins (31)(32)(33)(34). The anti-apoptotic E1B19K protein promotes viral replication, allowing it to propagate throughout the tumor.…”

Section: Discussionmentioning

confidence: 99%

Combination of oncolytic adenovirus and endostatin inhibits human retinoblastoma in an in vivo mouse model

Wang

Wei

et al. 2012

International Journal of Molecular Medicine

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Abstract. There is a critical need for new paradigms in retinoblastoma (RB) treatment that would more efficiently inhibit tumor growth while sparing the vision of patients. Oncolytic adenoviruses with the ability to selectively replicate and kill tumor cells are a promising strategy for cancer gene therapy. Exploration of a novel targeting strategy for RB utilizing combined oncolytic adenovirus and anti-angiogenesis therapy was applied over the course of the current study with positive results. The oncolytic adenoviruses Ad-E2F1 p-E1A and Ad-TERT p-E1 were constructed. The E1 region was regulated by the E2F-1 promoter or the human telomerase reverse transcriptase (hTERT) promoter, respectively. Effects on both replication and promotion of enhanced green fluorescent protein (EGFP) expression were observed in the replicationdefective adenovirus Ad-EGFP in diverse cancer cell lines, HXO-RB44, Y79, Hep3B, NCIH460, MCF-7 and HLF. The cancer cell death induced by these agents was also explored. The in situ RB model demonstrated that mice with tumors treated with the oncolytic adenovirus and replication-defective adenovirus Ad-endostatin exhibited notable cancer cell death. This anticancer effect was further examined by stereo microscope, and the survival rate of experimental mice was determined. Both Ad-E2F1 p-E1A and Ad-TERT p-E1 replicated specifically in cancer cells in vitro and promoted EGFP expression in Ad-EGFP, although Ad-E2F1 p-E1A demonstrated superior EGFP promotion activity than Ad-TERT p-E1. In Hep3B, NCIH460 and MCF-7 cells, the number of Ad-TERT p-E1 copies was observed to exceed of the number of Ad-E2F1 p-E1A copies by a minimum of 10-fold. Furthermore, Ad-TERT p-E1 demonstrated significantly superior oncolytic effects in the RB mouse model, and Ad-endostatin effectively suppressed tumor growth and extended the overall lifespan of subjects; however, the Ad-E2F1 p-E1A was clearly less effective in attaining these goals. Most notably, the antitumor effect and survival rate of subjects in the combined Ad-TERT p-E1 + Ad-endostatin group were higher than those treated with either single Ad-TERT p-E1 (p= 0.097, p= 0.022, respectively) or Ad-endostatin (p=0.037, p=0.006, respectively). In conclusion, application of transcription factor E2F-1 and human telomerase reverse transcriptase (hTERT) promoters to control E1 offer some guarantee that not only is RB gene therapy effective, but it is also safe. Combination therapy using the oncolytic adenovirus Ad-TERT p-E1 and replication-defective adenovirus Ad-endostatin demonstrates desirable oncolysis in the in situ RB mouse model. Additionally, E1B19K is important in the RB tumor suppression effect of oncolytic adenoviruses.

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“…16 E1B-19 kDa, a functional Bcl-2 homolog, directly binds Bax, Bak-inhibiting oligomerization, and mitochondrial pore-formation intrinsically inhibiting E1A-induced apoptosis through the p53-dependent and p53-independent mechanisms. [17][18][19][20] The anti-apoptotic E1B-19 kDa protein promotes viral replication, allowing it to propagate throughout the tumor. Matsushita et al also found that adeno-associated virus production would be reduced by at least 100-fold when adenovirus-bearing mutated E1B-19 kDa was used as a helper virus.…”

Section: Discussionmentioning

confidence: 99%