Oncogenic Transformation by Cellular DNA Isolated from Human Cytomegalovirus-lnfected Cells

Boldogh, István; Huang, Eng Shang; Baskar, John F.; Gergely, Lajos; Albrecht, Thomas

doi:10.1159/000150264

Cited by 11 publications

(4 citation statements)

References 24 publications

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“…Studies of HCMV infection in nonpermissive rodent cells indicate that the virus can act as a mutagen (1,5,78). In fact, in permissive human cells expression of the immediate-early (IE) gene products by themselves can drive cells into S phase (57).…”

mentioning

confidence: 99%

Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection

Luo

Rosenke

Czornak

et al. 2007

J Virol

113

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Many viruses (herpes simplex virus type 1, polyomavirus, and human immunodeficiency virus type 1) require the activation of ataxia telangiectasia mutated protein (ATM) and/or Mre11 for a fully permissive infection. However, the longer life cycle of human cytomegalovirus (HCMV) may require more specific interactions with the DNA repair machinery to maximize viral replication. A prototypical damage response to the double-stranded ends of the incoming linear viral DNA was not observed in fibroblasts at early times postinfection (p.i.). Apparently, a constant low level of phosphorylated ATM was enough to phosphorylate its downstream targets, p53 and Nbs1. p53 was the only cellular protein observed to relocate at early times, forming foci in infected cell nuclei between 3.5 and 5.5 h p.i. Approximately half of these foci localized with input viral DNA, and all localized with viral UL112/113 prereplication site foci. No other DNA repair proteins localized with the virus or prereplication foci in the first 24 h p.i. When viral replication began in earnest, between 24 and 48 h p.i., there were large increases in steady-state levels and phosphorylation of many proteins involved in the damage response, presumably triggered by ATM-Rad3-related kinase activation. However, a sieving process occurred in which only certain proteins were specifically sequestered into viral replication centers and others were particularly excluded. In contrast to other viruses, activation of a damage response is neither necessary nor detrimental to infection, as neither ATM nor Mre11 was required for full virus replication and production. Thus, by preventing simultaneous relocalization of all the necessary repair components to the replication centers, HCMV subverts full activation and completion of both double-stranded break and S-phase checkpoints that should arrest all replication within the cell and likely lead to apoptosis.Human cytomegalovirus (HCMV) is the major viral cause of birth defects. Each year approximately 1 to 2% of all newborns are congenitally infected, and of these infants, 5 to 10% manifest signs of serious neurological defects (6,8,16,31). HCMV infection is also a major medical problem in immunocompromised individuals (8).Recent literature points to HCMV as a potential causative agent for the development of certain types of cancers including malignant gliomas, prostate carcinomas, and colorectal cancers (17,35,74). Studies of HCMV infection in nonpermissive rodent cells indicate that the virus can act as a mutagen (1,5,78). In fact, in permissive human cells expression of the immediate-early (IE) gene products by themselves can drive cells into S phase (57). This has led to the suggestion that the IE proteins of HCMV may cause "hit-and-run" mutagenesis. In addition, our earlier findings showed that 15% of fibroblasts infected in S phase were specifically broken in the long arm of chromosome 1 when analyzed during the subsequent mitosis (28). Due to the clinical ramifications of HCMV infection, the study of its interactions w...

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confidence: 99%

Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection

Luo

Rosenke

Czornak

et al. 2007

J Virol

113

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“…Because p53(ΔCp44) is abundant at points in the HCMV replication cycle in which the virus is modifying the cell to support HCMV proliferation, p53(ΔCp44) may have some role in the cellular pathogenesis of HCMV, [eg, cell cycle deregulation, 37-39 susceptibility to gene mutation, 106,107 chromosome aberration, 108-110 oncogenic transformation, [111][112][113] and/or HCMV replication]. In vitro calpain cleavage studies suggest that m-calpain is largely responsible for the generation of p53 N-terminal fragments, particularly p53(ΔCp44), in HCMV-infected LU cells.…”

Section: Chen Et Almentioning

confidence: 99%

“…In vitro calpain cleavage studies suggest that m-calpain is largely responsible for the generation of p53 N-terminal fragments, particularly p53(ΔCp44), in HCMV-infected LU cells. Because p53(ΔCp44) is abundant at points in the HCMV replication cycle in which the virus is modifying the cell to support HCMV proliferation, p53(ΔCp44) may have some role in the cellular pathogenesis of HCMV, [eg, cell cycle deregulation, [37][38][39] susceptibility to gene mutation, 106,107 chromosome aberration, 108-110 oncogenic transformation, [111][112][113] and/or HCMV replication]. The biological activities of p53(ΔCp44) during HCMV infection remain to be studied, particularly because the p53 C-terminal sequences reportedly participate in virtually every aspect of p53 function as a transcription factor, including DNA binding, cofactor recruitment, and protein stabilization.…”

Section: Chen Et Almentioning

confidence: 99%

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

et al. 2018

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Endogenous fragments of p53 protein were identified in human cytomegalovirus (HCMV)‐infected human lung fibroblasts, particularly a 44‐kDa N‐terminal fragment [hereafter referred to as p53(ΔCp44)], generated via calpain cleavage. The fragment abundance increased in a biphasic manner, peaking at 6‐9 hours and 48 hours post infection. Treatment of LU cells with calpain inhibitors eliminated most detectable p53 fragments. In cell‐free experiments, exogenous m‐calpain cleavage generated p53(ΔCp44). Attempts to preserve p53 proteins by treating cells with the calpain inhibitor E64d for 6 hours before harvesting increased the sensitivity of p53 to calpain cleavage. p53 in mock‐infected cell lysates was much more sensitive to cleavage and degradation by exogenous calpain than that in HCMV‐infected cells. The proteasome inhibitor MG132 stabilized p53(ΔCp44), particularly in mock‐infected cells. p53(ΔCp44) appeared to be tightly associated with a chromatin‐rich fraction. The abundance of p53β was unchanged over a 96‐h time course and very similar in mock‐ and HCMV‐infected cells, making it unlikely that p53(ΔCp44) was p53β. The biological activities of this and other fragments lacking C‐terminal sequences are unknown, but deserve further investigation, given the association of p53(ΔCp44) with the chromatin‐rich (or buffer C insoluble) fraction in HCMV‐infected cells.

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“…In the light of these findings, it appears that CMV-induced cellular genetic alterations (chromosome aberration(s), mutations, incorporation of transforming viral DNA sequences) could contribute to the develop ment of human malignancies. Consistent with this view, earlier studies have demonstrated that the cellular DNA extracted from CMV-infected cells has transforming ac tivity after introduction into normal diploid cells [ 18],…”

Section: Introductionmentioning

confidence: 61%

Alteration in the Coding Potential and Expression of H-ras in Human Cytomegalovirus-Transformed Cells

et al. 1994

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CMV-transformed cell lines demonstrated a greater level of H-ras RNA (7.5-to 9.5-fold) relative to the level for H-ras in parental cells. Nuclear run off assays showed that the RNA levels for the H-ras gene were regulated at the level of transcriptional initiation. The increased RNA levels for H-ras correlated with the level of p21^rasVal-12 in transformed cells, while p21^raíVal-12 was below the level of detection in nontransformed cells using Western blot analysis. In addition, an activating mutation was identified in both alleles of the first exon, codon 12 of H-ras resulting in a G:C to T:A transversion in all transformed cell lines examined in this study. These results suggest that the mutated H-ras may be one of the components by which an oncogenic phenotype is maintained in these CMV-transformed cells.

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Oncogenic Transformation by Cellular DNA Isolated from Human Cytomegalovirus-lnfected Cells

Cited by 11 publications

References 24 publications

Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection

Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

Alteration in the Coding Potential and Expression of H-ras in Human Cytomegalovirus-Transformed Cells

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