Manipulation of the cell cycle by human cytomegalovirus

Kalejta, Robert F.; Shenk, Thomas

doi:10.2741/kalejta

Cited by 77 publications

(72 citation statements)

References 79 publications

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“…Although we did not find classic transforming activity associated with IE1, sustained expression of IE1 along with multiple other HCMV gene products that can inhibit cell apoptotic pathways (24)(25)(26)(27)(28)(29) and promote neoplastic transformation (30) could greatly affect the oncogenic phenotype of tumor cells expressing such HCMV gene products. Given the fact that we and others showed expression of IE1 in human glioblastomas in vivo, these findings may have relevance to the pathogenesis of this malignancy.…”

Section: Discussionmentioning

confidence: 91%

Modulation of Oncogenic Phenotype in Human Glioma Cells by Cytomegalovirus IE1–Mediated Mitogenicity

et al. 2008

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Recent evidence indicates that human cytomegalovirus (HCMV) infection occurs in a high percentage of human malignant gliomas in vivo, as the HCMV immediate early-1 (IE1) protein is detected in >90% of these tumors. The HCMV IE1 protein is essential for viral infection and has potent transactivating and oncomodulatory properties. To investigate a potential role of HCMV in glioma biology, we stably expressed the HCMV IE1 gene product in immortalized and malignant human glial cells. Here we show that stable IE1 expression can differentially affect the growth of human glioblastoma cells, resulting in either growth proliferation or arrest. IE1 expression led to dysregulation of phosphatidylinositol 3-kinase/AKT activity, Rb phosphorylation, and expression of the p53 family of proteins. In U87 and U118 glioblastoma cells, IE1 induced cellular proliferation paralleled by reduction in steady-state expression level of Rb and p53 family proteins (including p53, p63, or p73) and simultaneous induction of the phosphatidylinositol 3-kinase/AKT signaling pathway. In contrast, IE1 expression in LN229 and U251 glioblastoma cells and immortalized human astrocytes was associated with increased expression of p53 family proteins, accompanied by growth arrest or lack of enhanced proliferation. Moreover, IE1 promoted cell cycle entry and DNA synthesis of human glioma cells on both stable expression in tumor-derived cell lines as well as transient expression in primary glioblastoma cells. These findings indicate that HCMV IE1 can significantly affect important oncogenic signaling pathways in glioblastoma cells. [Cancer Res 2008;68(3):724-30]

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Section: Discussionmentioning

confidence: 91%

Modulation of Oncogenic Phenotype in Human Glioma Cells by Cytomegalovirus IE1–Mediated Mitogenicity

et al. 2008

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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%

“…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.…”

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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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“…In common with other viral infections, HCMV is known to perturb a number of host cell functions. The majority of these perturbations presumably optimize host cell functions and conditions to support viral persistence and productive viral replication (2,4,7,28,30). These viral effects are the result of a controlled program of HCMV gene expression executed through virally activated cellular transcription factors.…”

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confidence: 99%

Perinuclear localization of Na-K-Cl-cotransporter protein after human cytomegalovirus infection

Maglova¹,

Crowe²,

Russell³

2004

American Journal of Physiology-Cell Physiology

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previously reported that Na-K-Cl-cotransporter (NKCC) function and microsomal protein expression are both dramatically reduced late in human cytomegalovirus (HCMV) infection of a human fibroblast cell line (MRC-5). We now report DNA microarray data showing that no significant HCMV-dependent NKCC gene repression can be detected 30 h postexposure (PE) to the virus. Consequently, we used plasma membrane biotinylation and subsequent subcellular fractionation in combination with semiquantitative immunoblotting and confocal microscopy to investigate the possibility that intracellular redistribution of the NKCC protein after HCMV infection could be a cause of the HCMV-induced loss of NKCC ion transport function. Our results show that the lifetime of plasmalemmal NKCC protein in quiescent, uninfected MRC-5 cells is ϳ48 h, and Ͻ20% of the total expressed NKCC protein are in the plasma membrane. The remainder (ϳ80%) was detected as diffusely distributed, small punctate structures in the cytoplasm. Following HCMV infection: 1) NKCC protein expression in the plasmalemma was sharply reduced (ϳ75%) within 24 h PE and thereafter continued to slowly decrease; 2) total cellular NKCC protein content remained unchanged or slightly increased during the course of the viral infection; and 3) HCMV infection caused NKCC protein to accumulate in the perinuclear region late in the HCMV infection (72 h PE). Thus our results imply that, in the process of productive HCMV infection, NKCC protein continues to be synthesized, but, instead of being delivered to the plasma membrane, it is clustered in a large, detergentsoluble perinuclear structure.sodium-potassium-chloride-cotransporter; human fibroblast cell line; perinuclear accumulation

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Manipulation of the cell cycle by human cytomegalovirus

Cited by 77 publications

References 79 publications

Modulation of Oncogenic Phenotype in Human Glioma Cells by Cytomegalovirus IE1–Mediated Mitogenicity

Modulation of Oncogenic Phenotype in Human Glioma Cells by Cytomegalovirus IE1–Mediated Mitogenicity

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

Perinuclear localization of Na-K-Cl-cotransporter protein after human cytomegalovirus infection

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