Regulation of Apoptosis by Adenovirus E1A and E1B Oncogenes

White, Eileen

doi:10.1006/smvy.1998.0155

Cited by 73 publications

(42 citation statements)

References 96 publications

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“…Phase I clinical trials are presently underway using ONYX-015, an Ad-mutant that does not express the E1B-55K protein (59). E1B-55K partially inhibits the p53-dependent apoptosis induced by E1A-expression (60). The deletion of E1B-55K may enable ONYX-015 to replicate and induce apoptosis in p53-deficient human cancer cells but may leave normal (p53 positive) cells intact (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

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Ryan²,

Clase³

et al. 2000

The Journal of Immunology

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Expression of the adenovirus serotype 5 (Ad5) E1A oncogene sensitizes cells to apoptosis by TNF-α and Fas-ligand. Because TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar manner as TNF-α and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by TRAIL. To test this hypothesis, we examined TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following either infection with Ad5 or stable transfection with Ad5-E1A. E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-induced killing, but Ad5-infected cells expressing equally high levels of E1A protein remained resistant to TRAIL. Infection of A2058-E1A cells with Ad5 reduced their sensitivity to TRAIL-dependent killing. Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity to TRAIL-induced killing conferred by transfection with E1A. E1B and E3 gene products have been shown to inhibit TNF-α- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined by using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptible to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A2058-E1A cells was not inhibited by infection with H5dl327. Infection with H5dl250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection. In summary, expression of Ad5-E1A gene products sensitizes cells to TRAIL-dependent killing, whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.

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Section: Discussionmentioning

confidence: 99%

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Routes

Ryan²,

Clase³

et al. 2000

The Journal of Immunology

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“…It has been suggested that the major role of Ad E1B proteins is to neutralize the e ect of the increased levels of p53, thus inhibiting apoptosis (White, 1996(White, , 1998. The two major Ad E1B proteins can produce this e ect either separately or together (Rao et al, 1992).…”

Section: Introductionmentioning

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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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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“…The E1B proteins function to inhibit apoptosis, and are not absolutely required for replication. 4,5 The E3 proteins protect infected cells from attack by the immune system, and they, too, are not essential for replication. 4,6 RC vectors destroy cells as part of the virus life cycle.…”

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confidence: 99%

Adenovirus replication–competent vectors (KD1, KD3) complement the cytotoxicity and transgene expression from replication-defective vectors (Ad-GFP, Ad-Luc)

et al. 2002

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The successful clinical application of adenovirus ( Ad ) in cancer control has been of limited success because of the current inability to infect the majority of cancer cells with a large amount of vector. In this study, we show that when human lung tumors growing in immunodeficient nude mice were coinfected with a replication -defective ( RD ) Ad vector expressing green fluorescent protein and a replication -competent ( RC ) Ad vector named KD3, KD3 enhanced the expression of green fluorescent protein throughout the tumor. Also, KD3 and another RC vector named KD1 complemented the expression of luciferase from a RD vector in a human liver tumor xenotransplant in nude mice. Altogether, these results suggest that the combination of a RD vector with a RC vector might be a more effective treatment for cancer than either vector alone due to more widespread dissemination of the virus. Cancer Gene Therapy ( 2002 ) 9, 651 -654 doi:10.1038/sj.cgt.7700481Keywords: gene therapy; cancer; adenovirus; p53; Ad E1B -deleted; dl1520; Ad -p53; KD1; KD3 H uman adenovirus serotype 5 ( Ad5 ) offers great promise in cancer gene therapy. It is benign, primarily causing asymptomatic or mild respiratory infections in young children, followed by long -term effective immunity. 1 Fatalities are extremely rare. It transduces genes with high efficacy.There are two general types of Ad5 -based vectors, replication-defective (RD ) and replication -competent (RC). 2,3 RD vectors lack the Ad E1A, E1B, and E3 transcription units. The E1A proteins deregulate the cell cycle so that Ad DNA can replicate efficiently, and they also induce transcription of other Ad genes. 4 The deleted E1A and E1B regions (known collectively as E1 ) are usually replaced by an expression cassette where a therapeutic gene, e.g., p53, is expressed from a foreign promoter, e.g., the human cytomegalovirus ( CMV ) immediate early promoter. Vectors that lack E1A are defective for replication because Ad genes are not transcribed. The E1B proteins function to inhibit apoptosis, and are not absolutely required for replication. 4,5 The E3 proteins protect infected cells from attack by the immune system, and they, too, are not essential for replication. 4,6 RC vectors destroy cells as part of the virus life cycle. The Ad mutant dl1520, 7 which has been named ONYX -015 by ONYX Pharmaceuticals (Richmond, CA) has been used as an RC vector. 8 -10 This virus has a deletion in the Ad5 E1B region that removes the gene for a protein named E1B -55K. 7 The E1B -55K protein binds p53, 11,12 blocks transcription from p53-responsive promoters, 13,14 and inhibits p53-induced apoptosis and allows the cell cycle to be deregulated. 5 E1B -55K can also interact with the Ad protein named E4ORF6 coded by the Ad E4 transcription unit to induce degradation of p53. 15 -17 E1B -55K and E4ORF6 also act together to facilitate transport of Ad mRNA from the nucleus. 18 Because of these many functions of E1B -55K, complete deletion mutants of E1B -55K ( such as dl1520 ) are somewhat defective for replication...

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Regulation of Apoptosis by Adenovirus E1A and E1B Oncogenes

Cited by 73 publications

References 96 publications

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

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

Adenovirus replication–competent vectors (KD1, KD3) complement the cytotoxicity and transgene expression from replication-defective vectors (Ad-GFP, Ad-Luc)

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