Human Cytomegalovirus (HCMV) IE1 Plays Role in Resistance to Apoptosis with Etoposide in Cancer Cell Line by Cdk2 Accumulation

Kim, Jinhee; Kwon, Ye Jin; Park, Eun Suk; Sung, B.N.; Kim, Jung Heon; Park, Chung Gyu; Hwang, Eung Soo; Chen, Yong

doi:10.1111/j.1348-0421.2003.tb03470.x

Cited by 13 publications

(15 citation statements)

References 47 publications

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“…IEKD induced apoptotic cell death specifically in HCMV infected GSC (Figure 4D). Taken together, these results reveal an important anti-apoptotic role for IE1 in HCMV infected GSC, as it has been reported in other cell systems (32–34). …”

Section: Resultssupporting

confidence: 89%

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma

et al. 2015

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Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with onconcogenic properties. Here, we show how HCMV IE are preferentially expressed in glioma stem-like cells (GSC), where they co-localize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSC that are endogenously infected with HCMV, attenuating IE expression by an RNA-i-based strategy, was sufficient to inhibit tumorsphere formation, Sox2 expression, cell cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSC elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSC, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and pro-inflammatory cytokines, resembling the therapeutically-resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miRNA-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSC infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared to mock-infected human GSC. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in glioblastoma cells.

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Section: Resultssupporting

confidence: 89%

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma

et al. 2015

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“…Many data have indicated that both IE1 and IE2 stimulate transcription from a variety of cellular and viral genes involved in viral replication and cell survival, alone or in concert with other transcriptional regulators, including the Rb family members, the E2F family members, p53, SP1, TAFII130/TAF4 and histone modification proteins (Bonin & McDougall, 1997;Bryant et al, 2000;Fortunato et al, 1997;Hayhurst et al, 1995;Lukac et al, 1997;Margolis et al, 1995;Nevels et al, 2004b;Pajovic et al, 1997;Poma et al, 1996;Schwartz et al, 1996). The interplay between the IE proteins of HCMV and cellular factors has been implicated in disrupting normal cell-cycle progression and impeding apoptosis (Castillo et al, 2000;Kim et al, 2003;Lukac & Alwine, 1999;Murphy et al, 2000;Song & Stinski, 2002;Tanaka et al, 1999;Yu & Alwine, 2002;Zhu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Human cytomegalovirus infection downregulates the expression of glial fibrillary acidic protein in human glioblastoma U373MG cells: identification of viral genes and protein domains involved

Koh

Lee

Ahn

et al. 2009

Journal of General Virology

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Human cytomegalovirus (HCMV) has tropism for glial cells, among many other cell types. It was reported previously that the stable expression of HCMV immediate-early protein 1 (IE1) could dramatically reduce the RNA level of glial fibrillary acidic protein (GFAP), an astroglial cell-specific intermediate filament protein, which is progressively lost with an increase in glioma malignancy. To understand this phenomenon in the context of virus infection, a human glioblastoma cell line, U373MG, was infected with HCMV (strain AD169 or Towne). The RNA level of GFAP was reduced by more than 10-fold at an m.o.i. of 3 at 48 h post-infection, whilst virus treated with neutralizing antibody C23 or with UV light had a much-reduced effect. Treatment of infected cells with ganciclovir did not prevent HCMV-mediated downregulation of GFAP. Although the expression of GFAP RNA is downregulated in IE1-expressing cells, a mutant HCMV strain lacking IE1 still suppressed GFAP, indicating that other IE proteins may be involved. IE2 is also proposed to be involved in GFAP downregulation, as an adenoviral vector expressing IE2 could also reduce the RNA level of GFAP. Data from the mutational analysis indicated that HCMV infection might affect the expression of this structural protein significantly, primarily through the C-terminal acidic region of the IE1 protein. INTRODUCTIONHuman cytomegalovirus (HCMV), a member of the subfamily Betaherpesvirinae, persistently infects the majority of the world's population. Endothelial, astroglial and neuronal cells in the human brain have been shown to be infected by HCMV in vitro (Plachter et al., 1996;Poland et al., 1990;Schmidbauer et al., 1989). Among the many different cell types that the virus infects in vivo, HCMV has tropism for brain cells and is associated with serious disorders of the central nervous system in congenitally infected infants and HCMV-infected AIDS patients (Cinque et al., 1997). Recently, the presence of the HCMV genome and gene products, including the immediate-early protein 1 (IE1), has been detected in a high percentage of human malignant glioma samples, suggesting that HCMV might contribute to the malignant phenotype of glioma (Cobbs et al., 2002; Mitchell et al., 2008;Sabatier et al., 2005;Scheurer et al., 2008).The major IE genes encode the first de novo virus-encoded proteins synthesized following infection, some of which function to regulate viral and cellular gene expression during virus replication. The 72 kDa IE1 and 86 kDa IE2 proteins are the most abundantly expressed IE gene products. RNA transcripts originating from the major IE gene region span five major exons that are alternatively spliced to produce IE1 (exons 1-4) and IE2 (exons 1-3 and 5) (Stenberg et al., 1984(Stenberg et al., , 1985. Thus, exon 5 is unique to IE2, whilst exon 4 is unique to IE1 (Mocarski, 2001). The translation of IE1 and IE2 initiates from the ATG codon in exon 2, and these two proteins share 85 identical residues at their N termini. Many data have indicated that both IE1 and IE2 stimu...

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“…We utilized cell line UMG1-2 that constitutively expresses HCMV IE1 protein in U373MG cells (ATCC HTB 17) (15). U373MG cells transfected with the empty retrovirus vector LNCX2 vector (Clontech, Palo Alto, CA, U.S.A.) was used as the control.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, we focused on the HCMV gene products from the major immediate early (IE) gene. By utilizing a U373MG cell line expressing HCMV IE1 protein (15), we investigated the function of HCMV IE1 protein in modulating HSV-1 induced syncytial formation.…”

Section: Introductionmentioning

confidence: 99%

Human Cytomegalovirus IE1 Protein Enhances Herpes Simplex Virus Type 1-induced Syncytial Formation in U373MG Cells

et al. 2008

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Co-infection of herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) is not uncommon in immunocompromised hosts. Importantly, organ transplant recipients concurrently infected with HSV-1 and HCMV have a worse clinical outcome than recipients infected with a single virus. However, factors regulating the pathologic response in HSV-1, HCMV co-infected tissues are unclear. We investigated the potential biologic role of HCMV gene product immediate early 1 (IE1) protein in HSV-1-induced syncytial formation in U373MG cells. We utilized a co-infection model by infecting HSV-1 to U373MG cells constitutively expressing HCMV IE1 protein, UMG1-2. Syncytial formation was assessed by enumerating nuclei number per syncytium and number of syncytia. HSV-1-induced syncytial formation was enhanced after 24 hr in UMG1-2 cells compared with U373MG controls. The amplified phenotype in UMG1-2 cells was effectively suppressed by roscovitine in addition to inhibitors of viral replication. This is the first study to provide histological evidence of the contribution of HCMV IE1 protein to enhanced cytopathogenic responses in active HSV-1 infection.

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Human Cytomegalovirus (HCMV) IE1 Plays Role in Resistance to Apoptosis with Etoposide in Cancer Cell Line by Cdk2 Accumulation

Cited by 13 publications

References 47 publications

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma

Human cytomegalovirus infection downregulates the expression of glial fibrillary acidic protein in human glioblastoma U373MG cells: identification of viral genes and protein domains involved

Human Cytomegalovirus IE1 Protein Enhances Herpes Simplex Virus Type 1-induced Syncytial Formation in U373MG Cells

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