Inhibition of Cell Division by the Human Cytomegalovirus IE86 Protein: Role of the p53 Pathway or Cyclin-Dependent Kinase 1/Cyclin B1

Song, Yoon‐Jae; Stinski, Mark F.

doi:10.1128/jvi.79.4.2597-2603.2005

Cited by 56 publications

(60 citation statements)

References 60 publications

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“…Indeed, IE2-86 expression led to Ser15 phosphorylation on p53 as well (Fig. 4) (68). Our attempt to discern the contributions of each IE protein to p53 phosphorylation during HCMV infection were not fruitful because the UL123 (IE1-72) mutant used did not express either IE protein.…”

Section: Discussionmentioning

confidence: 97%

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Castillo¹,

Frame

Rogoff³

et al. 2005

J Virol

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Human cytomegalovirus (HCMV) encodes several proteins that can modulate components of the cell cycle machinery. The UL123 gene product, IE1-72, binds the Rb-related, p107 protein and relieves its repression of E2F-responsive promoters; however, it is unable to induce quiescent cells to enter S phase in wild-type (p53 ؉/؉ ) cells. IE1-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19Arf and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IE1-72 expression alone or HCMV infection is found to be dependent on the ataxia-telangiectasia mutated kinase. IE2-86 expression leads to p53 phosphorylation and may contribute to this phenotype in HCMV-infected cells. We also found that IE1-72 promotes p53 nuclear accumulation by abrogating p53 nuclear shuttling. These events result in the stimulation of p53 activity, leading to a p53-and p21-dependent inhibition of cell cycle progression from G 1 to S phase in cells transiently expressing IE1-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell.

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Section: Discussionmentioning

confidence: 97%

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Castillo¹,

Frame

Rogoff³

et al. 2005

J Virol

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“…Furthermore, many reports have described a viral connection between TP53 and cell cycle arrest. Herpesviruses, such as herpes simplex virus (40), human herpesvirus 6 (41), and human cytomegalovirus (42)(43)(44), cause cell cycle arrest via the TP53 pathway; however, the viral proteins responsible for TP53 stabilization and the precise mechanisms and significance of cell cycle arrest remain unknown. The data in this study might provide a clue to the mechanism and the significance of cell cycle arrest induced by these viruses.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Izumi

Io²,

Matsui³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the Nterminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.AIDS | NL4-3 | HXB2 | APOBEC3G | infectivity

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“…There, or indeed also in G 0 cells, HCMV stimulates proproliferative cellular pathways by activating the S-phase-promoting cyclin E-Cdk2-Rb-E2F pathway (6,9,18,21,24,26,28,41,49,56,64,67,69) and the M-phase-promoting cyclin B1-Cdk1 complex (26,52,61,65,67). However, once infected cells reach the G 1 /S transition, the viral IE2 protein inhibits further cell cycle progression by specifically blocking cellular DNA synthesis (8,15,34,38,46,48,57,66). Together, these viral activities lead to a profoundly deregulated cell cycle state of HCMV-infected cells, where the initiation of cellular DNA replication is selectively inhibited (4,68) but other features of S-phase-cells, such as an active nucleotide metabolism and the expression of replication factors, are induced.…”

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confidence: 99%

Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G ₁ and G ₂ Arrest in Murine Cytomegalovirus-Infected Cells

Wiebusch

Neuwirth

Grabenhenrich

et al. 2008

J Virol

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The infectious cycle of human cytomegalovirus (HCMV) is intricately linked to the host's cell cycle. Viral gene expression can be initiated only in G 0 /G 1 phase. Once expressed, the immediate-early gene product IE2 prevents cellular DNA synthesis, arresting infected cells with a G 1 DNA content. This function is required for efficient viral replication in vitro. A prerequisite for addressing its in vivo relevance is the characterization of cell cycle-regulatory activities of CMV species for which animal models have been established. Here, we show that murine CMV (MCMV), like HCMV, has a strong antiproliferative capacity and arrests cells in G 1 . Unexpectedly, and in contrast to HCMV, MCMV can also block cells that have passed through S phase by arresting them in G 2 . Moreover, MCMV can also replicate in G 2 cells. This is made possible by the cell cycle-independent expression of MCMV immediate-early genes. Transfection experiments show that of several MCMV candidate genes, only immediate-early gene 3 (ie3), the homologue of HCMV IE2, exhibits cell cycle arrest activity. Accordingly, an MCMV ie3 deletion mutant has lost the ability to arrest cells in either G 1 or G 2 . Thus, despite interspecies variations in the cell cycle dependence of viral gene expression, the central theme of HCMV IE2-induced cell cycle arrest is conserved in the murine counterpart, raising the possibility of studying its physiological relevance at the level of the whole organism.Cytomegaloviruses (CMVs), the prototypical members of the betaherpesvirus subfamily, are ubiquitous, species-specific pathogens that typically establish an asymptomatic, lifelong infection in the immunocompetent host. In the immunocompromised host, CMV can reactivate and cause severe or even life-threatening disease. Consequently, human CMV (HCMV) infections are particularly hazardous in neonates as well as transplant recipients and AIDS patients.During their evolution, CMVs have evolved many ways to functionally interfere with their host's biology in order to ensure their replication and survival (43). In this respect, the analysis of cell cycle regulation by HCMV has been a constant focus of interest over recent years and by now has been studied to some extent mainly in lytically infected fibroblasts (2,12,16,29,55). These studies revealed a complex interplay between HCMV and the cell cycle state of the host cell. HCMV can infect cells throughout the cell cycle, but for unknown reasons viral de novo gene expression is initiated only in G 0 and early to mid-G 1 phases (17, 51). In later cell cycle phases, viral entry takes place, but viral gene expression is delayed until cells have divided and reentered the following G 1 phase (17, 51). There, or indeed also in G 0 cells, HCMV stimulates proproliferative cellular pathways by activating the S-phase-promoting cyclin E-Cdk2-Rb-E2F pathway (6,9,18,21,24,26,28,41,49,56,64,67,69) and the M-phase-promoting cyclin B1-Cdk1 complex (26,52,61,65,67). However, once infected cells reach the G 1 /S transition, the viral IE...

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Inhibition of Cell Division by the Human Cytomegalovirus IE86 Protein: Role of the p53 Pathway or Cyclin-Dependent Kinase 1/Cyclin B1

Cited by 56 publications

References 60 publications

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G ₁ and G ₂ Arrest in Murine Cytomegalovirus-Infected Cells

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Inhibition of Cell Division by the Human Cytomegalovirus IE86 Protein: Role of the p53 Pathway or Cyclin-Dependent Kinase 1/Cyclin B1

Cited by 56 publications

References 60 publications

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G 1 and G 2 Arrest in Murine Cytomegalovirus-Infected Cells

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Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G ₁ and G ₂ Arrest in Murine Cytomegalovirus-Infected Cells