The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins.

Rao, Lakshmi G.; Debbas, Michael; Sabbatini, Peter; Hockenbery, David M.; Korsmeyer, Stanley J.; White, Eileen

doi:10.1073/pnas.89.16.7742

Cited by 620 publications

(463 citation statements)

References 47 publications

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“…We presume that the smaller Ad E1B proteins protect from cell death. Indeed, it has previously been demonstrated that the E1B 19K component is a somewhat more potent anti-apoptosis agent than the larger E1B protein (Rao et al, 1992). Moreover, expression of E1B 19K by large E1B-null mutant adenoviruses overcomes an abortive infection by inhibiting premature Ad-induced apoptosis, and thus facilitating viral replication (Turnell et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Consequences of disruption of the interaction between p53 and the larger adenovirus early region 1B protein in adenovirus E1 transformed human cells

et al. 2000

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The adenovirus early region 1B (Ad E1B) genes have no transforming capability of their own but markedly increase the transformation frequency of Ad E1A following co-transfection into mammalian cells. The larger E1B proteins of both Ad2/5 and Ad12 bind to p53 and inhibit its ability to transcriptionally activate other genes. We have previously demonstrated that synthetic peptides identical to the binding sites for p53 on both the Ad2 and Ad12 E1B proteins will disrupt the interaction in vivo and in vitro. In the work presented here we have examined the e ects of complex dissociation on Ad E1-transformed human cells. It has been shown, using confocal microscopy, that when the peptide identical to the p53 binding site was added to Ad5 E1-transformed cells it initally located in the cytoplasmic dense bodies where it caused disruption of the p53/E1B complex. Peptide and p53 then translocated to the nucleus. In Ad12 E1-transformed cells the peptide localized in the nucleus directly and there caused a reorganization of p53 staining from a highly organized,¯e cked' distribution to one in which nuclear staining was homogeneous and di use. Peptides added to either Ad5 E1 or Ad12 E1 transformed cells resulted in the release of transcriptionally active p53. Interestingly, the level of p53 then fell presumably as a result of proteasomal action -this was probably a re¯ection of the short halflife of`free' (i.e. dissociated) p53 compared to that of the bound protein. Free p53 did not cause apoptosis in target cells probably due to the presence of the smaller (19K) E1B proteins. However, addition of peptide leads to a signi®cant reduction in cell growth rate. We have further demonstrated that a signi®cant proportion of those cells which had taken up peptide had ceased DNA synthesis, probably due to a p53-induced cell cycle arrest. The role of the larger E1B protein during transformation is considered in view of these data. Oncogene (2000) 19, 452 ± 462.

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Section: Discussionmentioning

confidence: 99%

“…The two major Ad E1B proteins can produce this e ect either separately or together (Rao et al, 1992). Ad E1B 19K is a Bcl-2 homologue and appears to function in an analogous manner, binding to Bax and other functional homologues and neutralizing their proapoptotic properties (reviewed White, 1996White, , 1998Chinnadurai, 1998).…”

Section: Introductionmentioning

confidence: 99%

Consequences of disruption of the interaction between p53 and the larger adenovirus early region 1B protein in adenovirus E1 transformed human cells

et al. 2000

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“…Although such a possibility can not be excluded for Rb, it was recently reported that ectopic expression of DRb is not su cient to induce apoptosis (Janicke et al, 1996;Tan et al, 1997). There is strong evidence that Rb can exert a potent antiapoptotic activity: Rb-de®cient cells are more sensitive to apoptosis than cells expressing Rb (Berry et al, 1996;Clarke et al, 1992;Fan et al, 1996;Jacks et al, 1992;Lee et al, 1992), and the production of viral oncoproteins such as E1A and E7, which inhibit Rb by binding to the B pocket, enhances susceptibility to apoptosis (Howes et al, 1994;Rao et al, 1992). In addition to Rb cleavage, TGFb-mediated apoptosis was always associated with a large decrease of total Rb expression consistent with Rb having a protective e ect ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

et al. 1999

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In this study, we investigated the involvement of caspases in TGFb-induced apoptosis in human B cells. Our results show that TGFb-mediated nuclear fragmentation, observed in the Epstein ± Barr virus-negative Burkitt's Lymphoma cell line BL41, was abolished in the presence of the tripeptide caspase inhibitor ZVAD-fmk or the speci®c caspase-3 inhibitor DEVD-fmk. Other apoptotic manifestations such as cell shrinkage, surface phosphatidylserine expression and chromatin condensation were strongly inhibited by ZVAD-fmk but only partially by DEVD-fmk. This suggests that other caspases in addition to caspase-3 control these apoptotis-associated features. Speci®c activation of caspase-3 during TGFbinduced apoptosis was demonstrated by the DEVD-fmksensitive expression of the active p17 subunit of caspase-3 and by in vivo cleavage of PARP. In addition, TGFb treatment of BL41 promoted the expression of both dephosphorylated and truncated forms of the retinoblastoma protein. Inhibition of caspase-3 activity abolished both nuclear fragmentation and expression of the truncated retinoblastoma protein, without modifying the G1 cell cycle arrest induced by TGFb. Our data thus demonstrate that TGFb-induced apoptosis of lymphoma B lymphocytes is dependent on caspase activation and involves caspase-dependent cleavage of the retinoblastoma protein.

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“…It is thought that E1B19K prevents E1A-induced apoptosis by interfering with the actions of the proapoptotic proteins, Bak and Bax. 6,13,14 Through the action of these E1b-encoded proteins, premature cell death is prevented and viral replication is maximized.…”

Section: T O Induce the Cells Into S-phase For Effective Viralmentioning

confidence: 99%

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

et al. 2004

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Apoptotic pathways are initiated as a cellular defense mechanism to eliminate adenovirus-infected cells. We have investigated how E1A-induced apoptosis interferes with viral replication in cancer cells. We found that E1B19K alone can efficiently suppress E1A-induced apoptosis in cancer cells. Viruses deleted for both E1B19K and E1B55K resulted in cellular DNA degradation. However, less than 20% of human lung cancer cells infected with a virus deleted for both E1B19K and E1B55 K had evidence of chromatin condensation and multiple-micronuclei formation (apoptotic hallmarks); these cells could not produce infectious viral particles. The majority of cancer cells infected with viruses deleted for the entire E1b gene did not undergo extended apoptosis and produced abundant viral progeny. Thus, only a fraction of cancer cells underwent apoptosis and did not allow E1b-deleted viruses to replicate, while the majority of cancer cells were resistant to E1A-induced apoptosis and could support virus-selective replication. The results of this study imply that, in addition to inhibiting E1A-induced apoptosis, E1B proteins may contribute other important roles in the viral life cycle. Our results also suggest that combining virus-induced apoptosis and selective viral replication into one vector will be a novel approach to destroy cancer cells.

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The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins.

Cited by 620 publications

References 47 publications

Consequences of disruption of the interaction between p53 and the larger adenovirus early region 1B protein in adenovirus E1 transformed human cells

Consequences of disruption of the interaction between p53 and the larger adenovirus early region 1B protein in adenovirus E1 transformed human cells

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

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