Infection of Cells with Human Cytomegalovirus during S Phase Results in a Blockade to Immediate-Early Gene Expression That Can Be Overcome by Inhibition of the Proteasome

Fortunato, Elizabeth A.; Sánchez, Verónica; Yen, Judy; Spector, Deborah H.

doi:10.1128/jvi.76.11.5369-5379.2002

Cited by 74 publications

(92 citation statements)

References 57 publications

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“…p14 ARF binds to Hdm2 to antagonize its function and to free p53 (50). ATM kinase induces the phosphorylation of p53 at serine 15 to stabilize and activate p53 (1). Both p14 ARF and ATM are E2F-responsive genes, and deregulated E2F activity induces p14…”

Section: Resultsmentioning

confidence: 99%

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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

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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Section: Resultsmentioning

confidence: 99%

“…(ii) HCMV prevents the S phase because during S phase viral IE gene expression is inhibited (15). The virus also activates the ATM pathway, which stabilizes p53 (48).…”

Section: Discussionmentioning

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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“…Expression of IE proteins can be detected in cells infected in G 0 /G 1 by 1 to 2 h p.i. (15,25). Cells infected in S phase fail to express IE proteins until cells divide and cycle to the next G 1 phase; however, addition of a proteasome inhibitor was able to relieve this block in IE gene expression (15,52).…”

Section: Resultsmentioning

confidence: 99%

“…(15,25). Cells infected in S phase fail to express IE proteins until cells divide and cycle to the next G 1 phase; however, addition of a proteasome inhibitor was able to relieve this block in IE gene expression (15,52). Thus, infection of an asynchronous cell population would likely result in asynchronous viral gene expression.…”

Section: Resultsmentioning

confidence: 99%

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Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Tran

Mahr

Spector

2010

J Virol

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We have continued studies to further understand the role of the ubiquitin-proteasome system (UPS) in human cytomegalovirus (HCMV) infection. With specific inhibitors of the proteasome, we show that ongoing proteasome activity is necessary for facilitating the various stages of the infection. Immediate-early protein 2 expression is modestly reduced with addition of proteasome inhibitors at the onset of infection; however, both early and late gene expression are significantly delayed, even if the inhibitor is removed at 12 h postinfection. Adding the inhibitor at later times during the infection blocks the further accumulation of viral early and late gene products, the severity of which is dependent on when the proteasome is inhibited. This can be attributed primarily to a block in viral RNA transcription, although DNA synthesis is also partially inhibited. Proteasome activity and expression increase as the infection progresses, and this coincides with the relocalization of active proteasomes to the periphery of the viral DNA replication center, where there is active RNA transcription. Interestingly, one 19S subunit, Rpn2, is specifically recruited into the viral DNA replication center. The relocalization of the subunits requires viral DNA replication, but their maintenance around or within the replication center is not dependent on continued viral DNA synthesis or the proteolytic activity of the proteasome. These studies highlight the importance of the UPS at all stages of the HCMV infection and support further studies into this pathway as a potential antiviral target.

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Function of Human Cytomegalovirus MicroRNAs and Potential Roles in Latency

Reynolds

Pavelin

Grey

2013

MicroRNAs in Medicine

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Infection of Cells with Human Cytomegalovirus during S Phase Results in a Blockade to Immediate-Early Gene Expression That Can Be Overcome by Inhibition of the Proteasome

Cited by 74 publications

References 57 publications

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

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

Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Function of Human Cytomegalovirus MicroRNAs and Potential Roles in Latency

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