The adenovirus E1A domains required for induction of DNA rereplication in G2/M arrested cells coincide with those required for apoptosis

Sakurai-Yageta, Mika; Tsunoda, Haruki; T, Yamanaka; Nakajima, Takuma; Tomooka, Yasuhiro; Tsuchida, Nobuo; Oda, Kinichiro

doi:10.1038/sj.onc.1203063

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…It has been known for some time that the E1A proteins can induce apoptosis by both p53-dependent and p53-independent mechanisms (14,45,47,56,65,82). Induction of p53-dependent apoptosis is accompanied by accumulation of the p53 protein and requires the E1A sequences that are also necessary for transformation and mitogenesis (11,54,55,89). However, the E1B 55-kDa protein can counter these effects by several mechanisms.…”

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confidence: 99%

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

Miller

Rickards

Mashiba

et al. 2009

J Virol

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The human adenovirus type 5 (Ad5) E1B 55-kDa protein modulates several cellular processes, including activation of the tumor suppressor p53. Binding of the E1B protein to the activation domain of p53 inhibits p53-dependent transcription. This activity has been correlated with the transforming activity of the E1B protein, but its contribution to viral replication is not well understood. To address this issue, we used microarray hybridization methods to examine cellular gene expression in normal human fibroblasts (HFFs) infected by Ad5, the E1B 55-kDa-protein-null mutant Hr6, or a mutant carrying substitutions that impair repression of p53-dependent transcription. Comparison of the changes in cellular gene expression observed in these and our previous experiments (D. L. Miller et al., Genome Biol. 8:R58, 2007) by significance analysis of microarrays indicated excellent reproducibility. Furthermore, we again observed that Ad5 infection led to efficient reversal of the p53-dependent transcriptional program. As this same response was also induced in cells infected by the two mutants, we conclude that the E1B 55-kDa protein is not necessary to block activation of p53 in Ad5-infected cells. However, groups of cellular genes that were altered in expression specifically in the absence of the E1B protein were identified by consensus k-means clustering of the hybridization data. Statistical analysis of the enrichment of genes associated with specific functions in these clusters established that the E1B 55-kDa protein is necessary for repression of genes encoding proteins that mediate antiviral and immune defenses.The genomes of human subgroup C adenoviruses, such as adenovirus type 5 (Ad5), encode more than 20 proteins that are made prior to the onset of viral DNA synthesis in infected cells (reviewed in reference 1). The great majority of these immediate-early and early viral gene products interact with cellular proteins to optimize expression of viral genes or to block potentially deleterious host responses to infection. The 289R and 243R E1A proteins are prime examples of the former class. The larger E1A protein binds via a unique internal sequence to a specific subunit of the host cell mediator, a component of the RNA polymerase II transcriptional machinery, to stimulate transcription from viral early promoters by this enzyme in vitro and in infected cells (7,77,85). The 243R E1A protein interacts with the Rb protein and the related family members p107 and p130 to liberate transcriptional regulators of the E2F family, which are required for efficient transcription from the viral E2 early promoter (2, 13). This interaction is also crucial for the mitogenic and transforming activities of the E1A proteins. Adenoviral proteins that protect infected cells against antiviral defenses include E3 gene products, such as the 19-kDa glycoprotein that sequesters major histocompatibility complex class I molecules in the endoplasmic reticulum and several small proteins that prevent induction of apoptosis in response to external signa...

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mentioning

confidence: 99%

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

Miller

Rickards

Mashiba

et al. 2009

J Virol

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“…Moreover, E1a protein has been shown to provoke endoreduplication of DNA and drive cells to apoptosis from cells in G2 cell cycle phase. 28 The TK system has also been studied with replicative-conditional adenovirus trying to enhance the effects of both antitumoral strategies. In fact, Wildner 30 using an E3 -deleted adenoviral vector containing the HSVTK -suicide gene driven by the endogenous E3 promoter.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus E1a protein enhances the cytotoxic effects of the herpes thymidine kinase-ganciclovir system

et al. 2003

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Cancer gene therapy based on the use of suicide genes, such as the thymidine kinase gene, is not producing satisfactory results. Several approaches have been delineated to enhance the therapeutic responses, including augmentation of the bystander effect, the combination of the herpes simplex virus thymidine kinase -ganciclovir ( HSVTK -GCV ) system into replication competent adenoviruses and others. Moreover, because usually less than 20% of human malignant cells are in S -phase, the HSVTK -GCV system is not as efficient as expected. To increase the cytotoxic effects of the HSVTK -GCV system, we hypothesized that concomitant expression of E1a protein, which drives cells to proliferation and S -phase, could increase the effects of the HSVTK -GCV system. Several retroviruses were constructed carrying bicistronic sequences of TK and E1a 12S genes under the control of the CMV promoter. The constructions were tested in murine ( NIH -3T3, MSC11A5 ) and human cells ( IMR90, HeLa, MDA -MB435 ). A clear increase of the HSVTK -GCV system killing effect in nonconfluent cells was observed in the cells studied, especially in NIH -3T3, MSC11A5, IMR90, and MDA -MB435 expressing cells. In confluence, the NIH3T3 and IMR90 E1a -TK -expressing cells were also very sensitive and most malignant E1a -TK -expressing cells showed an irreversible G2 -M cell cycle arrest. Moreover, the concomitant expression of adenovirus E1a and the HSVTK -GCV system increased the sensitivity to anticancer agents such as cisplatin. These results show that adenovirus E1a protein expression clearly enhances the cytotoxic effects of the HSVTK -GCV system and the response to treatment with cisplatin.

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“…10 More importantly, Id-1 was found to bind to the N-terminal region of the adenovirus protein E1A and augment its effect on induction of cellular apoptosis. 11 These findings suggested that Id-1 might be a common cellular target of viral proteins.…”

Section: Introductionmentioning

confidence: 97%

Id-1 Induces Proteasome-dependent Degradation of the HBX Protein

Ling

Chiu

Lee

et al. 2008

Journal of Molecular Biology

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The adenovirus E1A domains required for induction of DNA rereplication in G2/M arrested cells coincide with those required for apoptosis

Cited by 12 publications

References 35 publications

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

Adenovirus E1a protein enhances the cytotoxic effects of the herpes thymidine kinase-ganciclovir system

Id-1 Induces Proteasome-dependent Degradation of the HBX Protein

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