How adenovirus strives to control cellular gene expression

Zhao, Hongxing; Granberg, Fredrik; Pettersson, Ulf

doi:10.1016/j.virol.2007.02.013

Cited by 51 publications

(74 citation statements)

References 71 publications

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“…Cellular RNAs that specify proteins implicated in progression through the cell cycle and proliferation have been observed to increase substantially in concentration following Ad5 infection of quiescent human foreskin and lung fibroblasts and the diploid fibroblast line WI38 (51,66,94). Comparison of the alterations in expression of such genes, particularly as exemplified by cyclin E1, induced by infection with Ad5 or the E1B mutant Adhz60 or dl1520 (Onyx-015), led to the conclusion FIG.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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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“…Recent gene expression analysis has confirmed that infection of normal human cells with group C adenoviruses causes changes in the expression of vast numbers of genes (at least 1,000-2,000) and that many of these genes are involved in the control of the cell cycle (10,11). Genes related to S-phase induction (including cyclins D2 and E1/2, cdk4, and cdk2) were prominent, and our results are entirely in keeping with this, emphasizing the importance of the G 1 -S transition for viral function.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown its therapeutic potential in ovarian cancer (9), and a phase I trial in women with relapsed ovarian cancer is imminent. Efficient production of viral progeny necessitates profound modulation of host cell gene transcription (10,11). The adenovirus must force the cell into S phase to ensure optimal conditions for viral replication while counteracting antiviral defense and cell death mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

Connell

Wheatley

McNeish³

2008

Cancer Research

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Survivin (BIRC5) promotes cell division and survival with roles as chromosomal passenger protein and inhibitor of apoptosis protein (IAP). It is overexpressed in many cancers and is associated with resistance to chemotherapy and radiation. Previously, we showed that expression of survivin within the nucleus of HeLa cells accelerates its degradation and blocks apoptosis inhibition without affecting localization during mitosis. Here, we have investigated the effects of survivin on cell cycle control and potential therapeutic consequences using HeLa and IGROV1 cells expressing wildtype and nuclear-targeted survivin. We show that overexpression of survivin, especially within the nucleus, increases control over G 1 -S checkpoint via increased nuclear accumulation of cyclin D and cyclin-dependent kinase 4 and subsequent pRb phosphorylation. We investigated the influence of survivin on the activity of the E1A CR2-deleted oncolytic adenovirus dl922-947, which depends critically on an aberrant G 1 -S checkpoint. Nuclear expression of survivin augments virus-induced S-phase induction and increases viral protein expression and overall viral replication. There is a consequent increase in antitumor activity both in vitro and in vivo. The increased dl922-947 activity is restricted to malignant cells and is not associated with induction of apoptosis, nor does it rely on the role of survivin as an IAP. In addition, we observe the appearance of a large z4N population coincident with multiple mitotic defects in dl922-947-infected cells, both of which are significantly increased by nuclear survivin. This indicates that adenoviral activity is facilitated by abrogation of multiple cell cycle checkpoints and can be enhanced by expression of survivin within the nucleus.

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“…A number of reports have shown that adenovirus infection leads to alterations in the transcription of several hundreds, if not thousands, of genes. The differentially expressed genes belong to several Gene Ontology groups and are altered during various stages of viral infection (33,47). One of the genes that are downregulated during adenovirus infection is MYC (27,47).…”

mentioning

confidence: 99%

Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

Ben-Israel

Sharf

Rechavi

et al. 2008

J Virol

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The adenovirus E4 open reading frame 4 (E4orf4) protein is a multifunctional viral regulator that is involved in the temporal regulation of viral gene expression by modulating cellular and viral genes at the transcription and translation levels and by controlling alternative splicing of adenoviral late mRNAs. When expressed individually, E4orf4 induces apoptosis in transformed cells. Using oligonucleotide microarray analysis, validated by quantitative real time PCR, we found that MYC (also known as c-Myc) is downregulated early after the induction of E4orf4 expression. As a result, Myc protein levels are reduced in E4orf4-expressing cells. MYC downregulation is observed both when E4orf4 is expressed individually and within the context of viral infection. E4orf4 reduces MYC transcription but does not affect transcriptional elongation or RNA stability. An interaction with the PP2A-B55 subunit is required for the downregulation of MYC by E4orf4. Since Myc overexpression was previously shown to inhibit adenovirus replication, the downregulation of Myc by E4orf4 would contribute to efficient virus infection.

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How adenovirus strives to control cellular gene expression

Cited by 51 publications

References 71 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

Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis

Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

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