Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A

Savelyeva, Irina; Dobbelstein, Matthias

doi:10.1038/onc.2010.461

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…It increased sensitivity to different categories of anticancer drug in multiple clinical trials [20]. Here we identified that this mE1A affected tumor cell cycle distribution in a different way as that in normal cells and induced cell apoptosis in a p53-independent manner (Figures 4&5).…”

Section: Discussionmentioning

confidence: 75%

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A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

et al. 2016

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The conserved regions (CR) of adenoviral E1A had been shown to be necessary for disruption of pRb-E2F transcription factor complexes and induction of the S phase. Here we constructed a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa and 120-127aa deletion, mE1A) and investigated its antitumor capacities in vitro and in vivo. The mE1A suppressed the viability of tumor cells as efficiently as the wild type E1A, and there was no cytotoxic effect on normal cells. Although the mE1A arrested tumor cell cycle with the same manner as E1A, the former played a different role on cell cycle regulation compared with E1A in normal cells, which might contribute to its selective antitumor activity. E1A and mE1A had accumulated inactive p53, decreased the expression of mdm2, Cdkn1a (also named p21), increased p21's nuclear distribution and induced tumor cell apoptosis in a p53-indenpent manner. Further, E1A or mE1A significantly suppressed tumor growth in subcutaneous hepatocellular carcinoma xenograft models. Especially, tumor-bearing mice treated with mE1A had higher survival rate than those treated with E1A. Our data demonstrated that mutant adenoviral E1A significantly induced tumor cell apoptosis in a p53-indenpednt manner and had selective tumor suppressing ability. The observations of adenoviral E1A mutant had provided a novel mechanism for E1A's complex activities during infection.

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Section: Discussionmentioning

confidence: 75%

“…The other possible pathway of p53 regulation was needed to investigate upon adenovirus infecting. Although there is research about E1A had been involved in p53 regulation [8–20], the understanding of E1A mediated tumor suppression activity remains limited.…”

Section: Introductionmentioning

confidence: 99%

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

et al. 2016

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“…The E1A p300/CBP complex acts as a scaffold to TFIID preventing transcription factor binding to TATA domains [28], [44]. Lack of p300/CBP binding to E1A12S (AdE1A1104) attenuates protein degradation and increases the levels of c-myc and E2F, while lack of p400 binding (AdE1A1102) would result in increased protein degradation through higher expression of HDM2 and ubiquitination [45]. Overall, binding of either p400 or p300/CBP to E1A12S inhibits p21-mediated cell cycle arrest and promotes cell cycling in the presence of DNA-damage ultimately resulting in apoptotic death [11], [28], [30], [31].…”

Section: Discussionmentioning

confidence: 99%

“…The E1A-p300/CBP complex also represses p53-dependent transcription, in turn preventing cell cycle arrest to support high levels of viral replication [45], [47]. A trend towards lower levels of replication for dl 1104 was noted in the p53-positive 22Rv cells.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region

Miranda

Pineda²,

Öberg³

et al. 2012

PLoS ONE

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Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922–947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922–947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics.

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“…Indeed, mutations in the p300/Cbp-binding region of E1A have been reported to partially restore expression of the p53-dependent p21 gene in infected cells that do not synthesize the E1B 55-kDa protein (121).…”

Section: Discussionmentioning

confidence: 99%

Impact of the Adenoviral E4 Orf3 Protein on the Activity and Posttranslational Modification of p53

DeHart

Perlman

Flint

2015

J Virol

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Our previous studies have established that the p53 populations that accumulate in normal human cells exposed to etoposide or infected by an E1B 55-kDa protein-null mutant of human adenovirus type 5 carry a large number of posttranslational modifications at numerous residues (C. J. DeHart, J. S. Chahal, S. J. Flint, and D. H. Perlman, Mol Cell Proteomics 13:1-17, 2014, http: //dx.doi.org/10.1074/mcp.M113.030254). In the absence of this E1B protein, the p53 transcriptional program is not induced, and it has been reported that the viral E4 Orf3 protein inactivates p53 (C. Soria, F. E. Estermann, K. C. Espantman, and C. C. O'Shea, Nature 466:1076 -1081, 2010, http://dx.doi.org/10.1038/nature09307). As the latter protein disrupts nuclear Pml bodies, sites at which p53 is modified, we used mass spectrometry to catalogue the posttranscriptional modifications of the p53 population that accumulates when neither the E1B 55-kDa nor the E4 Orf3 protein is made in infected cells. Eighty-five residues carrying 163 modifications were identified. The overall patterns of posttranslational modification of this population and p53 present in cells infected by an E1B 55-kDa-null mutant were similar. The efficiencies with which the two forms of p53 bound to a consensus DNA recognition sequence could not be distinguished and were lower than that of transcriptionally active p53. The absence of the E4 Orf3 protein increased expression of several p53-responsive genes when the E1B protein was also absent from infected cells. However, expression of these genes did not attain the levels observed when p53 was activated in response to etoposide treatment and remained lower than those measured in mock-infected cells. T he cellular p53 protein was discovered by virtue of its interaction with the major product of the simian virus 40 oncogene, large T antigen (1, 2). The p53 tumor suppressor is a master regulator of cellular responses to internal and external stresses, when it can induce inhibition of cell cycle progression, apoptosis, or other responses, such as changes in metabolism. Under normal conditions, the human p53 protein is maintained at low concentrations, for example, as a result of its targeting for proteasomal degradation by the E3 ubiquitin ligase Hdm2 (3-5). Once stabilized and activated in response to genotoxic and other forms of stress, p53 binds to specific promoter sequences to activate or repress the transcription of numerous target genes (6-10) and can also operate in the cytoplasm to induce apoptosis by transcription-independent mechanisms (reviewed in references 11 to 14).One of the first interactions between human adenovirus type 5 (Ad5) and cellular proteins to be identified was the association of the viral E1B 55-kDa protein with p53 (15). In view of its crucial roles in regulating cell survival and other aspects of cellular physiology, considerable effort has since been devoted to elucidation of the impacts of adenoviral gene products on the activities and properties of p53. The viral immediate-early E1A prote...

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Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A

Cited by 15 publications

References 47 publications

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region

Impact of the Adenoviral E4 Orf3 Protein on the Activity and Posttranslational Modification of p53

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