Deregulation of eIF4E: 4E-BP1 in Differentiated Human Papillomavirus-Containing Cells Leads to High Levels of Expression of the E7 Oncoprotein

Oh, Kwang Jin; Kalinina, Anna; Park, No Hee; Bagchi, Srilata

doi:10.1128/jvi.02380-05

Cited by 45 publications

(31 citation statements)

References 42 publications

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“…These authors also observed sustained phosphorylation of 4E-BP1 upon differentiation of CaSki cells but not with HPV-negative HaCaT cells or primary HFKs. Moreover, mTORC1 inhibition by rapamycin treatment reduced 4E-BP1 phosphorylation and HPV16 E7 oncoprotein expression in these cells (48). Increased mTOR S2448 and S6K T389 phosphorylation was also observed in HPV-positive high-grade cervical squamous intraepithelial lesions (13), and there is also evidence for increased AKT phosphorylation in HPV-positive high-grade cervical squamous intraepithelial lesions (44).…”

Section: Discussionmentioning

confidence: 95%

The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis

Spangle

Münger

2010

J Virol

189

172

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Human papillomaviruses (HPVs) are small DNA viruses with a pronounced tropism for epithelial cells. Of the greater than 200 HPV types that have been identified, a subgroup specifically infects mucosal epithelia. These mucosal HPVs are classified as "low-risk" and "high-risk," depending on the propensity for malignant progression of the lesions that they cause. Low-risk HPVs, such as HPV type 6 (HPV6) and HPV11, cause genital warts, whereas high-risk HPVs, such as HPV16 and HPV18, cause squamous intraepithelial lesions, which can undergo malignant progression. High-risk HPVs are associated with greater than 99% of cervical carcinomas and are also associated with other anogenital tumors and approximately 25% of oral cancers (reviewed in references 43 and 58). During carcinogenic progression the HPV genome frequently integrates into a host cell chromosome, resulting in persistent and dysregulated expression of the HPV E6 and E7 proteins. High-risk HPV E6 and E7 proteins have oncogenic activities and are necessary for the induction and maintenance of the transformed phenotype of cervical cancer cells (reviewed in reference 43). The best described cellular targets of the HPV E6 and E7 oncoproteins are the tumor suppressors p53 and retinoblastoma (pRB), respectively (reviewed in references 25 and 42). High-risk HPV E6 proteins cause proteasomal degradation of p53 through association with the cellular ubiquitin ligase E6AP (57). In addition to p53, other high-risk HPV E6-associated cellular proteins, including PDZ proteins, such as hDlg, hScribble, MUPP1, and MAGI 1 that bind to E6 through a carboxyl-terminal PDZ binding domain, may also be degraded by the E6/E6AP complex (19,21,29,32,33,47,61). High-risk HPV E6 proteins also transcriptionally activate hTERT, the catalytic protein subunit of human telomerase (30).HPVs initially infect basal epithelial cells, where the viral episome is maintained extrachromosomally at a low copy number. High-level viral genome replication and production of progeny virus, however, is confined to the outer, terminally differentiated layers of the infected squamous epithelium, where metabolic activity of the host cells and nutrient availability are presumably more limited. Moreover, HPV16 E7 expression may induce metabolic stress by inducing the "Warburg effect," a switch from an oxidative phosphorylation-based mode to a glycolytic mode of glucose metabolism (67). Consistent with this notion, we reported that HPV16 E7 expression in human keratinocytes triggers an autophagy-like process (65), which may serve to generate metabolites that can be used for energy-consuming processes, including viral replication.The mammalian target of the rapamycin complex 1 (mTORC1) signaling cascade serves as a metabolic sensor, integrating a diverse array of signals, including nutrient and growth factor availability. mTORC1 signaling regulates a variety of cellular processes, including cell growth, viability, and proliferation, at

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Section: Discussionmentioning

confidence: 95%

The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis

Spangle

Münger

2010

J Virol

189

172

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“…E6 interacts with and degrades the tuberous sclerosis complex 2 (TSC2), which would lead to enhanced mTOR activity [63]. The constitutive activation and overexpression of the mTOR pathway in pre-invasive and invasive squamous cell carcinoma results in the phosphorylative inactivation of mTOR target 4E-BP1, leading to translational synthesis of proteins, including the viral oncoprotein E7 [64]. E7 oncoprotein has been linked to the growth and survival of the HPV-associated cancer cells and inhibition of its expression induces cell senescence [65].…”

Section: Mammalian Target Of Rapamycin (Mtor) Inhibitorsmentioning

confidence: 99%

Treatment of metastatic cervical cancer: Future directions involving targeted agents

Díaz-Padilla

Monk

Mackay

et al. 2013

Critical Reviews in Oncology/Hematology

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“…Consequently, KSHV lytic replication is studied through reactivation, which requires one or more chem- (25). It is not fully transformed, maintains some features of primary cells, and has been used for studying pathogen-host interaction, innate immune response, differentiation, apoptosis, and tumorigenesis (41)(42)(43)(44)(45)(46)(47)(48)(49). As saliva is the major source of transmission for KSHV and epithelial cells may play an important role in producing infectious virions, we sought to identify an oral epithelial cell line that can support robust lytic replication of KSHV.…”

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus ORF18 and ORF30 Are Essential for Late Gene Expression during Lytic Replication

Gong

Xie

et al. 2014

J Virol

Self Cite

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Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several human malignances. As saliva is likely the major vehicle for KSHV transmission, we studied in vitro KSHV infection of oral epithelial cells. Through infection of two types of oral epithelial cells, normal human oral keratinocytes (NHOKs) and papilloma-immortalized human oral keratinocyte (HOK16B) cells, we found that KSHV can undergo robust lytic replication in oral epithelial cells. By employing de novo lytic infection of HOK16B cells, we studied the functions of two previously uncharacterized genes, ORF18 and ORF30, during the KSHV lytic cycle. For this purpose, an ORF18-deficient virus and an ORF30-deficient virus were generated using a mutagenesis strategy based on bacterial artificial chromosome (BAC) technology. We found that neither ORF18 nor ORF30 is required for immediately early or early gene expression or viral DNA replication, but each is essential for late gene expression during both de novo lytic replication and reactivation. This critical role of ORF18 and ORF30 in late gene expression was also observed during KSHV reactivation. In addition, global analysis of viral transcripts by RNA sequencing indicated that ORF18 and ORF30 control the same set of viral genes. Therefore, we suggest that these two viral ORFs are involved in the same mechanism or pathway that coregulates the viral late genes as a group. IMPORTANCEWhile KSHV can infect multiple cell types in vitro, only a few can support a full lytic replication cycle with progeny virions produced. Consequently, KSHV lytic replication is mostly studied through reactivation, which requires chemicals to induce the lytic cycle or overexpression of the viral transcriptional activator, RTA. In this study, we present a robust de novo lytic infection system based on oral epithelial cells. Using this system, we demonstrate the role of two viral ORFs, ORF18 and ORF30, in regulating viral gene expression during KSHV lytic replication. As the major route of KSHV transmission is thought to be via saliva, this new KSHV lytic replication system will have important utility in the field.

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Deregulation of eIF4E: 4E-BP1 in Differentiated Human Papillomavirus-Containing Cells Leads to High Levels of Expression of the E7 Oncoprotein

Cited by 45 publications

References 42 publications

The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis

The Human Papillomavirus Type 16 E6 Oncoprotein Activates mTORC1 Signaling and Increases Protein Synthesis

Treatment of metastatic cervical cancer: Future directions involving targeted agents

Kaposi's Sarcoma-Associated Herpesvirus ORF18 and ORF30 Are Essential for Late Gene Expression during Lytic Replication

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