Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: A DNA microarray analysis

Song, Yoon‐Jae; Stinski, Mark F.

doi:10.1073/pnas.052010099

Cited by 108 publications

(105 citation statements)

References 42 publications

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“…Hypophosphorylated (active) pRb prevents the expression of E2F-responsive genes (1). Previous work has shown that HCMV infection induces E2F-responsive gene expression (25)(26)(27), but the viral protein(s) responsible have not been conclusively identified. In subconfluent, serum-starved cells, we found that the re-addition of serum or WT infection caused an increase in the steady state levels of transcripts encoding thymidylate synthase (TS) and uracil monophosphate synthase (UMPS) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Kamil¹,

Hume

Jurak³

et al. 2009

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

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Several different families of DNA viruses encode proteins that inactivate the cellular retinoblastoma tumor suppressor protein (pRb), which normally functions to bind E2F transcription factors and restrict expression of genes necessary for cellular processes including DNA replication. Human cytomegalovirus (HCMV) UL97, a protein kinase functionally orthologous to cellular cyclin-dependent kinases, phosphorylates pRb on inactivating residues during HCMV infection. To assess if such phosphorylation is biologically relevant, we tested whether the human papillomavirus type 16 E7 protein, which inactivates pRb family proteins by direct binding and destabilization, could substitute for UL97 during HCMV infection. In the absence of UL97, expression of wild-type E7 protein, but not a mutant E7 unable to bind pRb family proteins, restored E2F-responsive cellular gene expression, late viral gene expression, and viral DNA synthesis to levels normally observed during wildtype virus infection of quiescent cells. UL97-null mutants exhibited more pronounced defects in virus production and DNA synthesis in quiescent cells as compared to serum-fed, cycling cells. E7 expression substantially enhanced infectious virus production in quiescent cells, but did not complement the defects observed during UL97-null virus infection of cycling cells. Thus, a primary role of UL97 is to inactivate pRb family proteins during infection of quiescent cells, and this inactivation likely abets virus replication by induction of cellular E2F-responsive genes. Our findings have implications for human cytomegalovirus disease and for drugs that target UL97.E2F ͉ cyclin-dependent kinase ͉ cell cycle ͉ antiviral drugs ͉ retinoblastoma protein

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Section: Resultsmentioning

confidence: 99%

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Kamil¹,

Hume

Jurak³

et al. 2009

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

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“…HCMV productively infects terminally differentiated cells that are in the G 0 /G 1 phase of the cell cycle and low in nucleotide triphosphate precursors for DNA synthesis. Although HCMV induces human foreskin fibroblast (HFF) cells to express genes required for S phase entry, cellular DNA synthesis does not occur in HFF cells (4,7,12,24,26,29,54,56).The viral immediate-early (IE) protein of approximately 86 kDa (IE86) is encoded by the IE2 gene (UL122) of HCMV and is a strong transactivator of viral and cellular promoters. The IE86 protein interacts with the cellular basal transcription factors to activate transcription (9, 25, 30, 31).…”

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confidence: 99%

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

Song

Stinski

2005

J Virol

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The human cytomegalovirus (HCMV) IE86 protein induces the human fibroblast cell cycle from G 0 /G 1 to G 1 /S, where cell cycle progression stops. Cells with a wild-type, mutated, or null p53 or cells with null p21 protein were transduced with replication-deficient adenoviruses expressing HCMV IE86 protein or cellular p53 or p21. Even though S-phase genes were activated in a p53 wild-type cell, IE86 protein also induced phosphoSer 15 p53 and p21 independent of p14ARF but dependent on ATM kinase. These cells did not enter the S phase. In human p53 mutant, p53 null, or p21 null cells, IE86 protein did not up-regulate p21, cellular DNA synthesis was not inhibited, but cell division was inhibited. Cells accumulated in the G 2 /M phase, and there was increased cyclin-dependent kinase 1/cyclin B1 activity. Although the HCMV IE86 protein increases cellular E2F activity, it also blocks cell division in both p53؉/؉ and p53 ؊/؊ cells.The DNA tumor viruses such as adenovirus, simian virus 40, and the papillomaviruses have the ability to transform cells (38). These viruses inactivate the Rb family of proteins to induce E2F-responsive gene expression (11,23,49). For regulation of cellular proliferation, the Rb pathway is functionally linked to the p53 pathway (50). Deregulated E2F activity induces the p53 pathway to inhibit cell cycle progression or to induce apoptosis. By doing so, the growth and development of cancerous cells are prevented. The DNA tumor viruses interfere with the activity of p53 and escape a cellular checkpoint system induced by deregulated E2F activity (11,23,49). p53 transactivates a set of genes that promote antiproliferative responses, including cell cycle arrest either at the G 1 /S transition or at G 2 before mitosis (1,5,13,43). The cyclindependent kinase (cdk) inhibitor p21 (Cip1) is one of the p53-responsive genes that play an important role in regulation of cellular proliferation (21,51,52,60). Besides cdk inhibition, p21 also binds to proliferating cell nuclear antigen and inhibits DNA polymerase delta (14,59,60).Human cytomegalovirus (HCMV), a member of the Betaherpesvirus family, has various effects on cellular physiology, including the cell cycle (7,26,56). HCMV productively infects terminally differentiated cells that are in the G 0 /G 1 phase of the cell cycle and low in nucleotide triphosphate precursors for DNA synthesis. Although HCMV induces human foreskin fibroblast (HFF) cells to express genes required for S phase entry, cellular DNA synthesis does not occur in HFF cells (4,7,12,24,26,29,54,56).The viral immediate-early (IE) protein of approximately 86 kDa (IE86) is encoded by the IE2 gene (UL122) of HCMV and is a strong transactivator of viral and cellular promoters. The IE86 protein interacts with the cellular basal transcription factors to activate transcription (9, 25, 30, 31). The IE86 protein also interacts with Rb, inhibits Rb-mediated repression of transcription (16,20), and consequently up-regulates the expression of E2F-responsive genes (7,26,56). Despite up-regulated E2F-r...

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“…Recent studies of global host gene expression using DNA microarrays show that HCMV infection dramatically changes the gene expression profile of the host cell (7,77,79,100). HCMV infection alters the expression of numerous host cell genes, including genes that regulate cell cycle progression, cellular proliferation, cell adhesion, and genes encoding transcription factors (7,79,100).…”

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confidence: 99%

“…HCMV infection alters the expression of numerous host cell genes, including genes that regulate cell cycle progression, cellular proliferation, cell adhesion, and genes encoding transcription factors (7,79,100). Human cells respond to HCMV infection by altering transcription in an attempt to antagonize viral replication and spread (7,61).…”

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Evaluation of the host transcriptional response to human cytomegalovirus infection

Challacombe

Rechtsteiner

Gottardo

et al. 2004

Physiological Genomics

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Gene expression data from human cytomegalovirus (HCMV)-infected cells were analyzed using DNA-Chip Analyzer (dChip) followed by singular value decomposition (SVD) and compared with a previous analysis of the same data that employed GeneChip software and a fold change filtering approach. dChip and SVD analysis revealed two clusters of coexpressed human genes responding differently to HCMV infection: one containing some genes identified previously, and another that was largely unique to this analysis. Annotating these genes, we identified several functional categories important to host cell responses to HCMV infection. These categories included genes involved in transcriptional regulation, oncogenesis, and cell cycle regulation, which were more prevalent in cluster 1, and genes involved in immune system regulation, signal transduction, and cell adhesion, which were more prevalent in cluster 2. Within these categories, we found genes involved in the host response to HCMV infection (mainly in cluster 1), as well as genes targeted by HCMV’s immune evasion strategies (mainly in cluster 2). As the second group of genes identified by the dChip and SVD approach was statistically and biologically significant, our results point out the advantages of using different methods to analyze gene expression data.

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Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: A DNA microarray analysis

Cited by 108 publications

References 42 publications

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

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

Evaluation of the host transcriptional response to human cytomegalovirus infection

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