Mutational analysis of the transforming and apoptosis suppression activities of the adenovirus E1 B 175R protein

Subramanian, T.; Taródi, B; Govindarajan, R.; Boyd, Janice M.; Yoshida, Kôichi; Chinnadurai, G.

doi:10.1016/0378-1119(93)90391-f

Cited by 38 publications

(34 citation statements)

References 52 publications

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“…The suppression of apoptosis by E1B 19 kDa was also demonstrated by earlier reports in which the investigators reported that the E1B 19 kDa protein efficiently prevents cisplatin -induced apoptosis. 46 Taken together, the replicating adenoviruses deleted in E1B 19 kDa function may serve as an improved vector for anticancer gene therapy in combination with other apoptosis -inducing modalities such as chemotherapeutic agents and radiation therapy.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy

et al. 2002

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Gene -attenuated replication -competent adenoviruses are emerging as a promising new modality for the treatment of cancer. For the aim of improving adenoviral vectors for cancer gene therapy, we have constructed genetically attenuated adenoviral vectors with different combinations of E1B genes and investigated the possibility of enhanced oncolytic and replication effects of these engineered replication -competent adenoviruses. We show here that the cytolytic potency of each gene -attenuated replicating adenovirus differed significantly depending on the presence or deletion of E1B 55 kDa and E1B 19 kDa function. More specifically, among the constructed vectors ( Ad -ÁE1B19, Ad -ÁE1B55, Ad -ÁE1B19 / 55, and Ad -wt ), E1B 19 kDa -inactivated adenovirus ( Ad -ÁE1B19 ) was the most potent against all tumor cells tested, inducing the largest -sized plaques and marked CPE. Further, cells infected with either Ad -ÁE1B19 or E1B19 / 55 kDa -deleted adenovirus ( Ad -ÁE1B19 / 55 ) showed complete cell lysis with disintegrated cellular structure, whereas cells infected with Ad -wt maintained intact cellular and nuclear membrane with properly structured organelles. TUNEL and DNA fragmentation assay also revealed that the Ad -ÁE1B19 or Ad -ÁE1B19 / 55 adenovirus -infected cells showed more profound induction of apoptosis in comparison to wild -type adenovirus -infected cells. The presence of E1B 55 kDa gene was required for efficient viral replication and deletion of E1B 19 kDa function in replicating adenovirus -induced apoptosis, leading to increased cytopathic effects. Moreover, Ad -ÁE1B19 adenovirus showed a better antitumor effect than other E1B -attenuated adenoviruses. Taken together, the replicating adenoviruses deleted in E1B 19 kDa function may serve as an improved vector for anticancer gene therapy in combination with apoptosis -inducing modalities such as chemotherapeutic agents and radiation therapy.

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Section: Discussionmentioning

confidence: 99%

Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy

et al. 2002

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“…Ad2 mutant dl250 defective in coding the E1B-19K protein has been described previously (Subramanian et al, 1984(Subramanian et al, , 1995b. Ad5 mutants dl309 (phenotypic wt, but deficient for E3-14.7K, 14.5K and 10.4K proteins.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…The Microsoft Excel software was used for calculations. The extent of cell death was also assed on the basis of analysis of low molecular weight DNA extracted from infected cells essentially as described (Subramanian et al, 1995b) and was quantified using the ImageQuant software.…”

Section: Cell Death Assays and Statistical Analysismentioning

confidence: 99%

“…The 19K protein is a viral homolog of the cellular antiapoptosis protein BCL-2, since BCL-2 can efficiently substitute for E1B-19K during viral replication Chiou et al, 1994;Subramanian et al, 1995b), they both interact with a common set of cellular proapoptotic proteins (Boyd et al, 1994(Boyd et al, , 1995Farrow et al, 1995;Chen et al, 1996a;Han et al, 1996a, b) and share limited aminoacid sequence homology over certain conserved domains (Chiou et al, 1994;Subramanian et al, 1995a). In addition to suppressing apoptosis during viral infection, expression of 19K can efficiently overcome apoptosis mediated by ectopic overexpression of p53 (Debbas and White, 1993) and by stimuli such as DNA-damaging agents that cause activation of p53 Tarodi et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial localization of p53 during adenovirus infection and regulation of its activity by E1B-19K

2005

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Recent results have revealed that the p53 tumor suppressor protein possesses a direct transcription-independent apoptotic activity. During apoptosis induced by genotoxic stress, a small fraction of p53 is targeted to mitochondria where it initiates apoptosis by causing mitochondrial dysfunction. In adenovirus-infected cells, the expression of E1A protein enhances the accumulation of p53 during early phases of infection and during late times after infection, it is targeted for degradation by the combined action of E1B-55K and E4-orf6 proteins. The functional significance of E1A-mediated accumulation of p53 during early phases of viral replication is not known. Our studies with isogenic epithelial cell lines that differ only on the status of p53 indicate that Ad infection induces apoptosis by p53-dependent and -independent pathways and both pathways are suppressed by E1B-19K. We show that during early phase of Ad infection, a fraction of p53 is targeted to the mitochondria. In virus infected cells, a large fraction of the viral antiapoptosis protein E1B-19K is also localized in mitochondria during early and late phases of infection. Coimmunoprecipitation analysis has revealed that p53 and E1B-19K form a complex in mitochondria. The interaction of 19K involves two noncontiguous regions located around amino-acid residues 14-15 and 123-124. On p53, the mutations within the DNA-binding domain reduce interaction with E1B-19K. Our studies also suggest that 19K may additionally complex with the multidomain mitochondrial proapoptotic protein BAK, thereby reducing the level of p53 interaction with BAK. We suggest that p53-induced apoptosis may be important for efficient cell lysis and viral spread and that E1B-19K may neutralize the apoptotic activity of p53 at multiple levels.

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“…However, the mechanism(s) underlying the anti-apoptotic behaviour of these proteins is currently not completely understood. Similar to Bcl-2, the E1B 19K protein is membrane-localized (Subramanian et al, 1993). Some of the anti-apoptotic eects of E1B 19K can be explained by functional interactions with the proapoptotic proteins Bax and Nbk/Bik (Han et al, 1996).…”

mentioning

confidence: 99%

Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-κB

et al. 1999

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Mutational analysis of the transforming and apoptosis suppression activities of the adenovirus E1 B 175R protein

Cited by 38 publications

References 52 publications

Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy

Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy

Mitochondrial localization of p53 during adenovirus infection and regulation of its activity by E1B-19K

Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-κB

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