Differential Requirements for Conserved E2 Binding Sites in the Life Cycle of Oncogenic Human Papillomavirus Type 31

Stubenrauch, Frank; Lim, Hock B.; Laimins, Laimonis A.

doi:10.1128/jvi.72.2.1071-1077.1998

Cited by 83 publications

(42 citation statements)

References 54 publications

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“…However, HPV-31 late gene expression was down by 80% and the E2 transactivation mutant expressed only a fifth of the quantities of L1 and L2 mRNA expressed by the wild-type HPV-31 genome (Stubenrauch et al, 1998). In our HPV-16based experimental system, E2 induced late gene expression three-to five-fold, which fits well with the five-fold reduction E2 induces HPV-16 late gene expression C Johansson et al in late gene expression reported for HPV-31 (Stubenrauch et al, 1998). Premature activation of HPV late gene expression could be detrimental as it would uncover the virus-infected cells for the immune system of the host that would eliminate the infection prior to efficient virus production.…”

Section: Discussionmentioning

confidence: 98%

HPV-16 E2 contributes to induction of HPV-16 late gene expression by inhibiting early polyadenylation

Johansson

Somberg

et al. 2012

The EMBO Journal

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We provide evidence that the human papillomavirus (HPV) E2 protein regulates HPV late gene expression. High levels of E2 caused a read-through at the early polyadenylation signal pAE into the late region of the HPV genome, thereby inducing expression of L1 and L2 mRNAs. This is a conserved property of E2 of both mucosal and cutaneous HPV types. Induction could be reversed by high levels of HPV-16 E1 protein, or by the polyadenylation factor CPSF30. HPV-16 E2 inhibited polyadenylation in vitro by preventing the assembly of the CPSF complex. Both the N-terminal and hinge domains of E2 were required for induction of HPV late gene expression in transfected cells as well as for inhibition of polyadenylation in vitro. Finally, overexpression of HPV-16 E2 induced late gene expression from a full-length genomic clone of HPV-16. We speculate that the accumulation of high levels of E2 during the viral life cycle, not only turns off the expression of the pro-mitotic viral E6 and E7 genes, but also induces the expression of the late HPV genes L1 and L2.

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Section: Discussionmentioning

confidence: 98%

HPV-16 E2 contributes to induction of HPV-16 late gene expression by inhibiting early polyadenylation

Johansson

Somberg

et al. 2012

The EMBO Journal

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“…With consequently rising concentrations, E2 also binds to the lowaffinity proximal E2BS3 and E2BS4. This represses transcription from the p97 promoter and thereby maintains the levels of E6 and E7 at a low and autoregulated level as shown in Figure 1A 9,10,12 and as reviewed by von Knebel Doeberitz and Vinokurova 11 (note that the numbering of E2BSs in the study by von Knebel Doeberitz and Vinokurova 11 differs from that currently used).…”

Section: Introductionmentioning

confidence: 91%

Methylation status of HPV16 E2‐binding sites classifies subtypes of HPV‐associated oropharyngeal cancers

Reuschenbach

Huebbers

Prigge

et al. 2015

Cancer

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BACKGROUND:The human papillomavirus (HPV) E2 protein is a transcriptional repressor of the oncogenes E6/E7 and loss of E2 function is considered a key step in carcinogenesis. Integration of HPV into the host genome may disrupt the E2 gene. Furthermore, methylation of CpG dinucleotides in E2-binding sites (E2BSs) in the HPV upstream regulatory region may interfere with transcriptional repression of E6 and E7 by E2. The authors hypothesized that the CpG methylation status of E2BS identifies subtypes of HPV type 16 (HPV16)-associated oropharyngeal squamous cell cancers (OPSCC) in association with E2 gene integrity and viral integration. METHODS: Methylation of 10 CpG dinucleotides within the upstream regulatory region, encompassing E2BSs 1, 2, 3, and 4, was quantitatively analyzed by bisulfite pyrosequencing in 57 HPV16-associated OPSCC cases. E2 status was analyzed by gene amplification and quantitative real-time reverse transcriptase-polymerase chain reaction. Viral integration was determined by integration-specific polymerase chain reaction methods. RESULTS: Three subgroups with differential methylation at E2BS3 and E2BS 4 were identified: 1) complete methylation (>80%) associated with the presence of integrated HPV genomes with an intact E2 gene; 2) intermediate methylation levels (20%-80%) with predominantly episomal HPV genomes with intact E2; and 3) no methylation (<20%) with a disrupted E2 gene. Patients with high methylation levels tended to have a worse 5-year overall survival compared with patients with intermediate methylation (hazard ratio, 3.23; 95% confidence interval, 1.13-9.24 [P 5.06]). CONCLUSIONS: Methylation of E2BS3 and E2BS4 in OPSCC is associated with E2 integrity and viral physical status. It might explain deregulated viral oncogene expression in the presence of E2. The prognostic significance of E2BS methylation for patients with HPV-associated OPSCC needs to be analyzed further.

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“…If the concentration of the E2 protein rises beyond a certain level, E2 binds also to the low affinity proximal E2BSs (E2BS2, 3 and 4) and represses transcription from the early promoter p97 through displacement of Sp1 and TBP from their respective binding sites, thereby keeping the levels of E6 and E7 under control. [11][12][13] Accordingly, it has been suggested that deregulated expression of E6 and E7 oncogenes and initiation of the transformation process may result from loss of the E2 repressive functions. Viral integration into the host genome usually occurs downstream of the E6 and E7 genes, often in E1 and E2 regions 14,15 and results in a loss of negative-feedback control of oncogene expression.…”

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confidence: 99%

Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions

Chaiwongkot

Vinokurova

Pientong

et al. 2012

Intl Journal of Cancer

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Enhanced expression of the HPV 16 E6-E7 oncogenes may trigger neoplastic transformation of the squamous epithelial cells at the uterine cervix. The HPV E2 protein is a key transcriptional regulator of the E6-E7 genes. It binds to four E2 binding sites (E2BSs 1-4) in the viral upstream regulatory region (URR). Modification of E2 functions, for example, by methylation of E2BSs is hypothesized to trigger enhanced expression of the viral E6-E7 oncogenes. In the majority of HPV-transformed premalignant lesions and about half of cervical carcinomas HPV genomes persist in an extra-chromosomal, episomal state, whereas they are integrated into host cells chromosomes in the remaining lesions. Here we compared the methylation profile of E2BSs 1-4 of the HPV 16 URR in a series of 18 HPV16-positive premalignant lesions and 33 invasive cervical cancers. CpGs within the E2BSs 1, 3, and 4 were higher methylated in all lesions with only episomal HPV16 genomes compared with lesions displaying single integrated copies. Samples with multiple HPV16 integrated copies displayed high methylation levels for all CpGs suggesting that the majority of multiple copies were silenced by extensive methylation. These data support the hypothesis that differential methylation of the E2BSs 1, 3 and 4 is related to the activation of viral oncogene expression in cervical lesions as long as the viral genome remains in the episomal state. Once the virus becomes integrated into host cell chromosomes these methylation patterns may be substantially altered due to complex epigenetic changes of integrated HPV genomes.Persistent infections with high-risk human papillomaviruses (HR-HPVs) are the primary cause of cancer at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus, as well as a subset of head and neck cancers. 1 The predominant HR-HPV type in cervical cancers is HPV16, accounting alone for about 50% of all cervical cancers. 2 It is commonly accepted that HPVs infect the basal cells of the squamous epithelium. Oncogenic human papillomaviruses encode two well-characterized oncoproteins, E6 and E7 that are under tight transcriptional control in early permissive, but not yet transformed genital HPV-infections. The enhanced expression of these oncogenes in basal and parabasal squamous epithelial cells of the infected epithelium is the cause of neoplastic transformation of the infected cells. 3,4 The main transforming properties of the E6 and E7 oncoproteins are related to their ability to inactivate the p53 and retinoblastoma (pRB) tumor suppressor proteins, respectively. 4-7 E7 overexpression in HPV-infected cells is accompanied by substantial overexpression of the cyclin-dependent kinase inhibitor p16 INK4a . p16 INK4a overexpression is therefore used as surrogate biomarker for HPV-transformed epithelial cells. 8 Expression of the E6 and E7 genes is regulated by the upstream regulatory region (URR). The HPV 16 URR contains sequences that regulate transcription and replication of the viral genome to which both cell...

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Differential Requirements for Conserved E2 Binding Sites in the Life Cycle of Oncogenic Human Papillomavirus Type 31

Cited by 83 publications

References 54 publications

HPV-16 E2 contributes to induction of HPV-16 late gene expression by inhibiting early polyadenylation

HPV-16 E2 contributes to induction of HPV-16 late gene expression by inhibiting early polyadenylation

Methylation status of HPV16 E2‐binding sites classifies subtypes of HPV‐associated oropharyngeal cancers

Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions

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