Journal articles: 'E7 oncoprotein'

1

DeMasi, Joseph, Michael C. Chao, Ashu S. Kumar, and Peter M. Howley. "Bovine Papillomavirus E7 Oncoprotein Inhibits Anoikis." Journal of Virology 81, no. 17 (June 27, 2007): 9419–25. http://dx.doi.org/10.1128/jvi.00422-07.

Full text

Abstract:

ABSTRACT The bovine papillomavirus type 1 (BPV-1) E7 oncoprotein is required for the full transformation activity of the virus. Although BPV-1 E7 by itself is not sufficient to induce cellular transformation, it enhances the abilities of the other BPV-1 oncogenes to induce anchorage independence. We have been exploring the mechanisms by which E7 might affect the transformation efficiency of other viral oncoproteins and in particular whether it might protect cells from apoptosis. We report here that BPV-1 E6 and E7 can each independently inhibit anoikis, a type of apoptosis that is induced upon cell detachment. Using site-directed mutagenesis, we determined regions of the E7 protein that were essential for its antiapoptotic activity. The ability of E7 to inhibit anoikis did partially correlate with an ability to enhance anchorage independence of BPV-1 E6-transformed cells. In addition, the antiapoptotic activity of E7 also only partially correlated with its ability to bind p600, a cellular protein that has previously been reported to play a role in anoikis. We conclude that the contribution of E7 to BPV-induced cellular transformation may involve its ability to inhibit anoikis but that additional functional activities must also be involved.

APA, Harvard, Vancouver, ISO, and other styles

2

Zhang, Jin-Jun, Xin-Chun Cao, Xiang-Yu Zheng, Hai-Ying Wang, and Yong-Wei Li. "Feasibility study of a human papillomavirus E6 and E7 oncoprotein test for the diagnosis of cervical precancer and cancer." Journal of International Medical Research 46, no. 3 (January 11, 2018): 1033–42. http://dx.doi.org/10.1177/0300060517736913.

Full text

Abstract:

Objective To evaluate the clinical value of human papillomavirus (HPV) E6 and E7 oncoprotein (HPV E6/E7) detection in the early screening of cervical cancer. Methods This prospective study evaluated all patients with suspected cervical intraepithelial neoplasia (CIN) as identified by the presence of at least one positive indicator from a ThinPrep cytologic test (TCT) and/or a Hybrid Capture 2 (HC2) HPV DNA test. The levels of E6/E7 oncoproteins were determined using Western blot analysis. The diagnostic value of the HPV E6/E7 protein assay was compared with the clinical diagnosis from TCT, HC2 and the gold standard of cervical biopsy histology. Results A total of 450 patients were enrolled in the study and based on histological findings, 102 patients were diagnosed with CIN1 (22.7%), 241 with CIN2 (53.6%), 96 with CIN3 (21.3%) and 11 with squamous cell carcinoma (2.4%). For a diagnosis of CIN2+, although the sensitivity of the HPV E6/E7 assay was lower than HC2 (65.5% versus 96.6%, respectively), the specificity was higher (38.2% versus 5.9%, respectively). The sensitivity of the HPV E6/E7 assay was higher than TCT (65.5% versus 36.2%, respectively). Conclusion Measuring HPV E6/E7 oncoprotein levels is a potential new biomarker for HPV type 16.

APA, Harvard, Vancouver, ISO, and other styles

3

McLaughlin-Drubin, Margaret E., and Karl Münger. "The human papillomavirus E7 oncoprotein." Virology 384, no. 2 (February 2009): 335–44. http://dx.doi.org/10.1016/j.virol.2008.10.006.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Tang, Shuang, Mingfang Tao, J. Philip McCoy, and Zhi-Ming Zheng. "The E7 Oncoprotein Is Translated from Spliced E6*I Transcripts in High-Risk Human Papillomavirus Type 16- or Type 18-Positive Cervical Cancer Cell Lines via Translation Reinitiation." Journal of Virology 80, no. 9 (May 1, 2006): 4249–63. http://dx.doi.org/10.1128/jvi.80.9.4249-4263.2006.

Full text

Abstract:

ABSTRACT High-risk human papillomaviruses (HPVs) encode two viral oncoproteins, E6 and E7, from a single bicistronic pre-mRNA containing three exons and two introns. Retention of intron 1 in the E6 coding region is essential for production of the full-length E6 oncoprotein. However, splicing of intron 1 is extremely efficient in cervical cancer cells, leading to the production of a spliced transcript, E6*I, of E6. Here, we investigated whether this splicing of intron 1 might benefit E7 production. Using RNA interference as a tool, we targeted the intron 1 region using small interfering RNAs (siRNAs) in HPV-positive cell lines. At an effective low dose, the siRNAs specifically suppressed E6 expression but not E7 expression, as demonstrated by the stabilization of p53. However, at high doses the HPV18 intron 1-specific siRNA substantially and specifically reduced the level of the 18E6*I mRNA lacking the intron region in HeLa cells, implying its nuclear silencing on the pre-mRNA before RNA splicing. Two other siRNAs targeting the exon 2 regions of HPV16 and -18, which encode the E7 oncoprotein, reduced the E6*I mRNAs to a remarkable extent and preferentially suppressed expression of E7, leading to accumulation of hypophosphorylated p105Rb and cell cycle arrest, indicating that the majority of E7 proteins are the translational products of E6*I mRNAs. This was confirmed by transient transfection in 293 cells: E7 could be translated only from the E7 open reading frame (ORF) on E6*I mRNA in a distance-dependent matter of upstream E6*I ORF by translation reinitiation. The data thus provide direct evidence that the E6*I mRNAs of high-risk HPVs are responsible for E7 production.

APA, Harvard, Vancouver, ISO, and other styles

5

Carrillo, Diego, Juan P. Muñoz, Hernán Huerta, Gabriel Leal, Alejandro Corvalán, Oscar León, Gloria M. Calaf, et al. "Upregulation of PIR gene expression induced by human papillomavirus E6 and E7 in epithelial oral and cervical cells." Open Biology 7, no. 11 (November 2017): 170111. http://dx.doi.org/10.1098/rsob.170111.

Full text

Abstract:

The hallmark of high-risk human papillomavirus (HR-HPV)-related carcinogenesis is E6 and E7 oncogene overexpression. The aim of this work was to characterize epithelial oral and cervical cancer cells that express HR-HPV E6 and E7 oncoproteins. Transcriptomic assay using DNA microarrays revealed that PIR gene expression was detected in oral cells in an HR-HPV E6/E7-dependent manner. In addition, PIR was overexpressed in HPV-positive SiHa and Ca Ski cells, whereas it was undetectable in HPV-negative C33A cells. The PIR expression was dependent on functional HR-HPV E6 and E7 oncoproteins even though the E7 oncoprotein had higher activity to induce PIR overexpression in comparison with E6. In addition, using an siRNA for PIR silencing in oral cells ectopically expressing HR-HPV E6/E7, there was a significant increase in E-cadherin transcripts and a decrease in Vimentin, Slug, Zeb and Snail transcripts, suggesting that HR-HPV-induced PIR overexpression is involved in epithelial–mesenchymal transition. Furthermore, migration of PIR-silenced cells was significantly decreased. Finally, using inhibitors of some specific pathways, it was found that EGFR/ERK and PI3 K/AKT signalling pathways are important for E7-mediated PIR overexpression. It can be concluded that PIR gene expression is highly dependent on the expression of HR-HPV oncoproteins and is important for EMT regulation.

APA, Harvard, Vancouver, ISO, and other styles

6

Carrillo-Beltrán, Diego, Juan P. Muñoz, Nahir Guerrero-Vásquez, Rancés Blanco, Oscar León, Vanesca de Souza Lino, Julio C. Tapia, et al. "Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells." Cancers 12, no. 7 (July 15, 2020): 1904. http://dx.doi.org/10.3390/cancers12071904.

Full text

Abstract:

A subset of oral carcinomas is etiologically related to high-risk human papillomavirus (HR-HPV) infection, with HPV16 being the most frequent HR-HPV type found in these carcinomas. The oncogenic role of HR-HPV is strongly dependent on the overexpression of E6 and E7 oncoproteins, which, in turn, induce p53 and pRb degradation, respectively. Additionally, it has been suggested that HR-HPV oncoproteins are involved in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducing cancer progression and metastasis. Previously, we reported that HPV16 E7 oncoprotein promotes Pirin upregulation resulting in increased epithelial–mesenchymal transition (EMT) and cell migration, with Pirin being an oxidative stress sensor and activator of NF-κB. In this study, we demonstrate the mechanism by which HPV16 E7-mediated Pirin overexpression occurs by promoting EGFR/PI3K/AKT1/NRF2 signaling, thus causing PIR/NF-κB activation in oral tumor cells. Our results demonstrate a new mechanism by which E7 contributes to oral cancer progression, proposing PIR as a potential new therapeutic target.

APA, Harvard, Vancouver, ISO, and other styles

7

Taghizadeh, Eskandar, Sepideh Jahangiri, Daryoush Rostami, Forough Taheri, Pedram Ghorbani Renani, Hassan Taghizadeh, and Seyed Mohammad Gheibi Hayat. "Roles of E6 and E7 Human Papillomavirus Proteins in Molecular Pathogenesis of Cervical Cancer." Current Protein & Peptide Science 20, no. 9 (September 17, 2019): 926–34. http://dx.doi.org/10.2174/1389203720666190618101441.

Full text

Abstract:

Human papillomavirus (HPV) cancers are expected to be major global health concerns in the upcoming decades. The growth of HPV-positive cancer cells depends on the consistent expression of oncoprotein which has been poorly taken into account in the cellular communication. Among them, E6/E7 oncoproteins are attractive therapeutic targets as their inhibition rapidly leads to the onset of aging in HPV-positive cancer cells. This cellular response is associated with the regeneration of p53, pRb anti-proliferative proteins as well as the mTOR signaling pathway; hence, the identification of involved and application of E6/E7 inhibitors can lead to new therapeutic strategies. In the present review, we focused on the pathogenicity of E6/E7 Proteins of human papillomavirus and their roles associated with the cervical cancer.

APA, Harvard, Vancouver, ISO, and other styles

8

Hu, Renjian, Zhen Dong, Kui Zhang, Guangzhao Pan, Chongyang Li, and Hongjuan Cui. "Preparation, Characterization and Diagnostic Valuation of Two Novel Anti-HPV16 E7 Oncoprotein Monoclonal Antibodies." Viruses 12, no. 3 (March 19, 2020): 333. http://dx.doi.org/10.3390/v12030333.

Full text

Abstract:

At present, the clinical detection method of human papillomavirus (HPV) is mainly based on the PCR method. However, this method can only be used to detect HPV DNA and HPV types, and cannot be used to accurately predict cervical cancer. HPV16 E7 is an oncoprotein selectively expressed in cervical cancers. In this study, we prepared an HPV16 E7-histidine (HIS) fusion oncoprotein by using a prokaryotic expression and gained several mouse anti-HPV16 E7-HIS fusion oncoprotein monoclonal antibodies (mAbs) by using hybridoma technology. Two mAbs, 69E2 (IgG2a) and 79A11 (IgM), were identified. Immunocytochemistry, immunofluorescence, immunohistochemistry, and Western blot were used to characterize the specificity of these mAbs. The sequences of the nucleotide bases and predicted amino acids of the 69E2 and 79A11 antibodies showed that they were novel antibodies. Indirect enzyme-linked immunosorbent assay (ELISA) with overlapping peptides, indirect competitive ELISA, and 3D structural modeling showed that mAbs 69E2 and 79A11 specifically bound to the three exposed peptides of the HPV16 E7 (HPV16 E749–66, HPV16 E773–85, and HPV16 E791–97). We used these two antibodies (79A11 as a capture antibody and 69E2 as a detection antibody) to establish a double-antibody sandwich ELISA based on a horseradish peroxidase (HRP)-labeled mAb and tetramethylbenzidine (TMB) detection system for quantitative detection of the HPV16 E7-HIS fusion oncoprotein, however, it was not ideal. Then we established a chemiluminescence immunoassay based on a labeled streptavidin-biotin (LSAB)-ELISA method and luminol detection system—this was sufficient for quantitative detection of the HPV16 E7-HIS fusion oncogenic protein in ng levels and was suitable for the detection of HPV16-positive cervical carcinoma tissues. Collectively, we obtained two novel mouse anti-HPV16 E7 oncoprotein mAbs and established an LSAB-lumino-dual-antibody sandwich ELISA method for the detection of the HPV16 E7-HIS fusion oncogenic protein, which might be a promising method for the diagnosis of HPV16-type cervical cancers in the early stage.

APA, Harvard, Vancouver, ISO, and other styles

9

McFarlane, Melanie, Alasdair I. MacDonald, Andrew Stevenson, and Sheila V. Graham. "Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35)." Journal of Virology 89, no. 10 (February 25, 2015): 5276–87. http://dx.doi.org/10.1128/jvi.03434-14.

Full text

Abstract:

ABSTRACTHigh-risk human papillomaviruses (HR-HPV) cause anogenital cancers, including cervical cancer, and head and neck cancers. Human papillomavirus 16 (HPV16) is the most prevalent HR-HPV. HPV oncogenesis is driven by two viral oncoproteins, E6 and E7, which are expressed through alternative splicing of a polycistronic RNA to yield four major splice isoforms (E6 full length, E6*I, E6*II, E6*X). The production of multiple mRNA isoforms from a single gene is controlled by serine/arginine-rich splicing factors (SRSFs), and HPV16 infection induces overexpression of a subset of these, SRSFs 1, 2, and 3. In this study, we examined whether these proteins could control HPV16 oncoprotein expression. Small interfering RNA (siRNA) depletion experiments revealed that SRSF1 did not affect oncoprotein RNA levels. While SRSF3 knockdown caused some reduction in E6E7 expression, depletion of SRSF2 resulted in a significant loss of E6E7 RNAs, resulting in reduced levels of the E6-regulated p53 proteins and E7 oncoprotein itself. SRSF2 contributed to the tumor phenotype of HPV16-positive cervical cancer cells, as its depletion resulted in decreased cell proliferation, reduced colony formation, and increased apoptosis. SRSF2 did not affect transcription from the P97promoter that controls viral oncoprotein expression. Rather, RNA decay experiments showed that SRSF2 is required to maintain stability of E6E7 mRNAs. These data show that SRSF2 is a key regulator of HPV16 oncoprotein expression and cervical tumor maintenance.IMPORTANCEExpression of the HPV16 oncoproteins E7 and E6 drives HPV-associated tumor formation. Although increased transcription may yield increased levels of E6E7 mRNAs, it is known that the RNAs can have increased stability upon integration into the host genome. SR splicing factors (SRSFs) control splicing but can also control other events in the RNA life cycle, including RNA stability. Previously, we demonstrated increased levels of SRSFs 1, 2, and 3 during cervical tumor progression. Now we show that SRSF2 is required for expression of E6E7 mRNAs in cervical tumor but not nontumor cells and may act by inhibiting their decay. SRSF2 depletion in W12 tumor cells resulted in increased apoptosis, decreased proliferation, and decreased colony formation, suggesting that SRSF2 has oncogenic functions in cervical tumor progression. SRSF function can be targeted by known drugs that inhibit SRSF phosphorylation, suggesting a possible new avenue in abrogating HPV oncoprotein activity.

APA, Harvard, Vancouver, ISO, and other styles

10

Bello-Rios, Ciresthel, Sarita Montaño, Olga Lilia Garibay-Cerdenares, Lilian Esmeralda Araujo-Arcos, Marco Antonio Leyva-Vázquez, and Berenice Illades-Aguiar. "Modeling and Molecular Dynamics of the 3D Structure of the HPV16 E7 Protein and Its Variants." International Journal of Molecular Sciences 22, no. 3 (January 30, 2021): 1400. http://dx.doi.org/10.3390/ijms22031400.

Full text

Abstract:

The oncogenic potential of high-risk human papillomavirus (HPV) is predicated on the production of the E6 and E7 oncoproteins, which are responsible for disrupting the control of the cell cycle. Epidemiological studies have proposed that the presence of the N29S and H51N variants of the HPV16 E7 protein is significantly associated with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains uncertain. An analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose, for the first time, a 3D structure of the E7 reference protein and two of Its variants (N29S and H51N), and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.

APA, Harvard, Vancouver, ISO, and other styles

11

Lidqvist, Maria, Olle Nilsson, Jan Holmgren, Sebastian Hölters, Eva Röijer, Matthias Dürst, and Christian Fermér. "Detection of human papillomavirus oncoprotein E7 in liquid-based cytology." Journal of General Virology 93, no. 2 (February 1, 2012): 356–63. http://dx.doi.org/10.1099/vir.0.034884-0.

Full text

Abstract:

The selection and characterization of a set of mouse mAbs against high-risk human papillomavirus (HPV) E7 oncoprotein and the development of protocols for immunocytochemistry (ICC) are described here. A large number of antibodies raised towards HPV16 and 18 E7 were tested for high-risk specificity by ELISA using a panel of HPV E7 proteins. Antibodies detecting low-risk E7 were discarded, resulting in 38 high-risk HPV E7-specific antibodies. The corresponding epitopes were mapped using overlapping HPV E7 fragments displayed on phage particles. Functionality in ICC against formalin-fixed cervical cancer cell lines was demonstrated for ten mAbs; their high-risk specificity was confirmed by Western blot analysis and ICC on transiently transformed cells expressing high- or low-risk HPV E7. These mAbs were specific for one or several of the high-risk strains HPV16, 18, 31, 35 and 45. Specific E7 staining of liquid-based cytology (LBC) samples was demonstrated for seven mAbs and optimized protocols were established. The E716-41 and E718-79 mAbs demonstrated particularly strong and specific staining of cells stored in LBC fluid for at least 6 months. It is proposed that the high-risk HPV E7 staining protocols established in this study may have the potential to be included in a complementary test for the detection and identification of malignantly transformed cells, in for example atypical squamous cells of undetermined significance samples.

APA, Harvard, Vancouver, ISO, and other styles

12

Araldi, Rodrigo Pinheiro, Jacqueline Mazzuchelli-de-Souza, Diego Grando Modolo, Edislane Barreiros de Souza, Thatiana Corrêa de Melo, Diva Denelle Spadacci-Morena, Roberta Fiusa Magnelli, et al. "Mutagenic Potential ofBos taurusPapillomavirus Type 1 E6 Recombinant Protein: First Description." BioMed Research International 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/806361.

Full text

Abstract:

Bovine papillomavirus (BPV) is considered a useful model to study HPV oncogenic process. BPV interacts with the host chromatin, resulting in DNA damage, which is attributed to E5, E6, and E7 viral oncoproteins activity. However, the oncogenic mechanisms of BPV E6 oncoproteinper seremain unknown. This study aimed to evaluate the mutagenic potential ofBos tauruspapillomavirus type 1 (BPV-1) E6 recombinant oncoprotein by the cytokinesis-block micronucleus assay (CBMNA) and comet assay (CA). Peripheral blood samples of five calves were collected. Samples were subjected to molecular diagnosis, which did not reveal presence of BPV sequences. Samples were treated with 1 μg/mL of BPV-1 E6 oncoprotein and 50 μg/mL of cyclophosphamide (positive control). Negative controls were not submitted to any treatment. The samples were submitted to the CBMNA and CA. The results showed that BPV E6 oncoprotein induces clastogenesisper se, which is indicative of genomic instability. These results allowed better understanding the mechanism of cancer promotion associated with the BPV E6 oncoprotein and revealed that this oncoprotein can induce carcinogenesisper se. E6 recombinant oncoprotein has been suggested as a possible vaccine candidate. Results pointed out that BPV E6 recombinant oncoprotein modifications are required to use it as vaccine.

APA, Harvard, Vancouver, ISO, and other styles

13

Auslander, Noam, Yuri I. Wolf, Svetlana A. Shabalina, and Eugene V. Koonin. "A unique insert in the genomes of high-risk human papillomaviruses with a predicted dual role in conferring oncogenic risk." F1000Research 8 (July 2, 2019): 1000. http://dx.doi.org/10.12688/f1000research.19590.1.

Full text

Abstract:

The differences between high risk and low risk human papillomaviruses (HR-HPV and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7. We combine genome comparison and machine learning techniques to identify a previously unnoticed insert near the 3’-end of the E6 oncoprotein gene that is unique to HR-HPV. Analysis of the insert sequence suggests that it exerts a dual effect, by creating a PDZ domain-binding motif at the C-terminus of E6 as well as eliminating the overlap between the E6 and E7 coding regions in HR-HPV. We show that as a result, the insert might enable coupled termination-reinitiation of the E6 and E7 genes, supported by motifs complementary to the human 18S rRNA. We hypothesize that the added functionality of E6 and positive regulation of E7 expression jointly account for the tumorigenic potential of HR-HPV.

APA, Harvard, Vancouver, ISO, and other styles

14

Auslander, Noam, Yuri I. Wolf, Svetlana A. Shabalina, and Eugene V. Koonin. "A unique insert in the genomes of high-risk human papillomaviruses with a predicted dual role in conferring oncogenic risk." F1000Research 8 (October 1, 2019): 1000. http://dx.doi.org/10.12688/f1000research.19590.2.

Full text

Abstract:

The differences between high risk and low risk human papillomaviruses (HR-HPV and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7. We combine genome comparison and machine learning techniques to identify a previously unnoticed insert near the 3’-end of the E6 oncoprotein gene that is unique to HR-HPV. Analysis of the insert sequence suggests that it exerts a dual effect, by creating a PDZ domain-binding motif at the C-terminus of E6, as well as eliminating the overlap between the E6 and E7 coding regions in HR-HPV. We show that, as a result, the insert might enable coupled termination-reinitiation of the E6 and E7 genes, supported by motifs complementary to the human 18S rRNA. We hypothesize that the added functionality of E6 and positive regulation of E7 expression jointly account for the tumorigenic potential of HR-HPV.

APA, Harvard, Vancouver, ISO, and other styles

15

Thomas, Jennifer T., and Laimonis A. Laimins. "Human Papillomavirus Oncoproteins E6 and E7 Independently Abrogate the Mitotic Spindle Checkpoint." Journal of Virology 72, no. 2 (February 1, 1998): 1131–37. http://dx.doi.org/10.1128/jvi.72.2.1131-1137.1998.

Full text

Abstract:

ABSTRACT The E6 and E7 genes of the high-risk human papillomavirus (HPV) types encode oncoproteins, and both act by interfering with the activity of cellular tumor suppressor proteins. E7 proteins act by associating with members of the retinoblastoma family, while E6 increases the turnover of p53. p53 has been implicated as a regulator of both the G1/S cell cycle checkpoint and the mitotic spindle checkpoint. When fibroblasts from p53 knockout mice are treated with the spindle inhibitor nocodazole, a rereplication of DNA occurs without transit through mitosis. We investigated whether E6 or E7 could induce a similar loss of mitotic checkpoint activity in human keratinocytes. Recombinant retroviruses expressing high-risk E6 alone, E7 alone, and E6 in combination with E7 were used to infect normal human foreskin keratinocytes (HFKs). Established cell lines were treated with nocodazole, stained with propidium iodide, and analyzed for DNA content by flow cytometry. Cells infected with high-risk E6 were found to continue to replicate DNA and accumulated an octaploid (8N) population. Surprisingly, expression of E7 alone was also able to bypass this checkpoint. Cells expressing E7 alone exhibited increased levels of p53, while those expressing E6 had significantly reduced levels. The p53 present in the E7 cells was active, as increased levels of p21 were observed. This suggested that E7 bypassed the mitotic checkpoint by a p53-independent mechanism. The levels of MDM2, a cellular oncoprotein also implicated in control of the mitotic checkpoint, were significantly elevated in the E7 cells compared to the normal HFKs. In E6-expressing cells, the levels of MDM2 were undetectable. It is possible that abrogation of Rb function by E7 or increased expression of MDM2 contributes to the loss of mitotic spindle checkpoint control in the E7 cells. These findings suggest mechanisms by which both HPV oncoproteins contribute to genomic instability at the mitotic checkpoint.

APA, Harvard, Vancouver, ISO, and other styles

16

Duensing, Stefan, and Karl Münger. "Human Papillomavirus Type 16 E7 Oncoprotein Can Induce Abnormal Centrosome Duplication through a Mechanism Independent of Inactivation of Retinoblastoma Protein Family Members." Journal of Virology 77, no. 22 (November 15, 2003): 12331–35. http://dx.doi.org/10.1128/jvi.77.22.12331-12335.2003.

Full text

Abstract:

ABSTRACT The human papillomavirus type 16 (HPV-16) E7 oncoprotein rapidly induces centrosome duplication errors in primary human cells, thereby increasing the propensity for multipolar mitoses, which can lead to chromosome missegregation and aneuploidy. We analyzed a series of HPV-16 E7 mutants and demonstrate that this biological activity of the E7 oncoprotein is mediated by sequences encompassing the core pRB binding site but is independent of its ability to inactivate the retinoblastoma tumor suppressor protein pRB and the related pocket proteins p107 and p130. In addition, interaction of E7 with the S4 subunit of the 26S proteasome and dysregulation of cdc25A transcription are also dispensable for the induction of centrosome duplication errors. Consistent with these results, expression of HPV-16 E7 induces abnormal centrosome duplication in a cell line that lacks functional pRB and in mouse embryo fibroblasts that are deficient for pRB, p107, and p130. These results demonstrate that the molecular mechanism whereby HPV-16 E7 induces centrosome duplication errors is independent of its ability to inactivate pRB, p107, and p130 or to interact with the S4 proteasome subunit.

APA, Harvard, Vancouver, ISO, and other styles

17

Tindle, Robert W., Karen Herd, Tracy Doan, Greg Bryson, Graham R. Leggatt, Paul Lambert, Ian H. Frazer, and Michael Street. "Nonspecific Down-Regulation of CD8+T-Cell Responses in Mice Expressing Human Papillomavirus Type 16 E7 Oncoprotein from the Keratin-14 Promoter." Journal of Virology 75, no. 13 (July 1, 2001): 5985–97. http://dx.doi.org/10.1128/jvi.75.13.5985-5997.2001.

Full text

Abstract:

ABSTRACT The E7 oncoprotein of human papillomavirus 16 (HPV16) transforms basal and suprabasal cervical epithelial cells and is a tumor-specific antigen in cervical carcinoma, to which immunotherapeutic strategies aimed at cytotoxic T-lymphocyte (CTL) induction are currently directed. By quantifying major histocompatibility complex class I tetramer-binding T cells and CTL in mice expressing an HPV16 E7 transgene from the keratin-14 (K14) promoter in basal and suprabasal keratinocytes and in thymic cortical epithelium, we show that antigen responsiveness of both E7- and non-E7-specific CD8+ cells is down-regulated compared to non-E7 transgenic control mice. We show that the effect is specific for E7, and not another transgene, expressed from the K14 promoter. Down-regulation did not involve deletion of CD8+ T cells of high affinity or high avidity, and T-cell receptor (TCR) Vβ-chain usage and TCR receptor density were similar in antigen-responsive cells from E7 transgenic and non-E7 transgenic mice. These data indicate that E7 expressed chronically from the K14 promoter nonspecifically down-regulates CD8+ T-cell responses. The in vitro data correlated with the failure of immunized E7 transgenic mice to control the growth of an E7-expressing tumor challenge. We have previously shown that E7-directed CTL down-regulation correlates with E7 expression in peripheral but not thymic epithelium (T. Doan et al., J. Virol. 73:6166–6170, 1999). The findings have implications for the immunological consequences of E7-expressing tumor development and E7-directed immunization strategies. Generically, the findings illustrate a T-cell immunomodulatory function for a virally encoded human oncoprotein.

APA, Harvard, Vancouver, ISO, and other styles

18

Oton-Gonzalez, Lucia, John Charles Rotondo, Carmen Lanzillotti, Elisa Mazzoni, Ilaria Bononi, Maria Rosa Iaquinta, Luca Cerritelli, et al. "Serum HPV16 E7 Oncoprotein Is a Recurrence Marker of Oropharyngeal Squamous Cell Carcinomas." Cancers 13, no. 13 (July 5, 2021): 3370. http://dx.doi.org/10.3390/cancers13133370.

Full text

Abstract:

Despite improved prognosis for many HPV-positive head and neck squamous cell carcinomas (HNSCCs), some cases are still marked by recurrence and metastasis. Our study aimed to identify novel biomarkers for patient stratification. Classical HPV markers: HPV-DNA, p16 and HPV mRNA expression were studied in HNSCC (n = 67) and controls (n = 58) by qPCR. Subsequently, ELISA tests were used for HPV16 L1 antibody and HPV16 E7 oncoprotein detection in serum at diagnosis and follow-up. All markers were correlated to relapse-free survival (RFS) and overall survival (OS). HPV-DNA was found in HNSCCs (29.85%), HPV16-DNA in 95% of cases, HPV16 E7 mRNA was revealed in 93.75%. p16 was overexpressed in 75% of HPV-positive HNSCC compared to negative samples and controls (p < 0.001). Classical markers correlated with improved OS (p < 0.05). Serological studies showed similar proportions of HPV16 L1 antibodies in all HNSCCs (p > 0.05). Serum E7 oncoprotein was present in 30% HPV-positive patients at diagnosis (p > 0.05) and correlated to HNSCC HPV16 E7 mRNA (p < 0.01), whereas it was associated to worse RFS and OS, especially for oropharyngeal squamous cell carcinoma (OPSCC) (p < 0.01). Detection of circulating HPV16 E7 oncoprotein at diagnosis may be useful for stratifying and monitoring HPV-positive HNSCC patients for worse prognosis, providing clinicians a tool for selecting patients for treatment de-escalation.

APA, Harvard, Vancouver, ISO, and other styles

19

Salazar-León, Jonathan, Fabiola Reyes-Román, Angélica Meneses-Acosta, Horacio Merchant, Alfredo Lagunas-Martínez, Elizabeth Meda-Monzón, María Luisa Pita-López, et al. "Silencing of hpv16 e6 and e7 oncogenic activities by small interference rna induces autophagy and apoptosis in human cervical cancer cells." Journal of Nucleic Acids Investigation 2, no. 1 (August 30, 2011): 10. http://dx.doi.org/10.4081/jnai.2011.2583.

Full text

Abstract:

Cervical cancer is the second most common form of death by cancer in women worldwide and has special attention for the development of new treatment strategies. Human Papilloma Virus (HPV) persistent infection is the main etiological agent of this neoplasia, and the main cellular transformation mechanism is by disruption of p53 and pRb function by interaction with HPV E6 and E7 oncoproteins. This generates alterations in cellular differentiation and cellular death inhibition. Thus, HPV E6 and E7 oncogenes represent suitable targets for the development of gene therapy strategies against cervical cancer. An attractive technology platform is developing for post-transcriptional selective silencing of gene expression, using small interference RNA. Therefore, in the present study, we used SiHa cells (HPV16+) transiently transfected with specific siRNA expression plasmids for HPV16 E6 and E7 oncogenes. In this model we detected repression of E6 and E7 oncogene and oncoprotein expression, an increase in p53 and hypophosphorylated pRb isoform protein expression, and autophagy and apoptosis morphology features. These findings suggest that selective silencing of HPV16 E6 and E7 oncogenes by siRNAs, has significant biological effects on the survival of human cancer cells and is a potential gene therapy strategy against cervical cancer.

APA, Harvard, Vancouver, ISO, and other styles

20

Nguyen, Christine L., Catherine Eichwald, Max L. Nibert, and Karl Münger. "Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Centrosomal Component γ-Tubulin." Journal of Virology 81, no. 24 (October 3, 2007): 13533–43. http://dx.doi.org/10.1128/jvi.01669-07.

Full text

Abstract:

ABSTRACT Expression of a high-risk human papillomavirus (HPV) E7 oncoprotein is sufficient to induce aberrant centrosome duplication in primary human cells. The resulting centrosome-associated mitotic abnormalities have been linked to the development of aneuploidy. HPV type 16 (HPV16) E7 induces supernumerary centrosomes through a mechanism that is at least in part independent of the inactivation of the retinoblastoma tumor suppressor pRb and is dependent on cyclin-dependent kinase 2 activity. Here, we show that HPV16 E7 can concentrate around mitotic spindle poles and that a small pool of HPV16 E7 is associated with centrosome fractions isolated by sucrose density gradient centrifugation. The targeting of HPV16 E7 to the centrosome, however, was not sufficient for centrosome overduplication. Nonetheless, we found that HPV16 E7 can associate with the centrosomal regulator γ-tubulin and that the recruitment of γ-tubulin to the centrosome is altered in HPV16 E7-expressing cells. Since the association of HPV16 E7 with γ-tubulin is independent of pRb, p107, and p130, our results suggest that the association with γ-tubulin contributes to the pRb/p107/p130-independent ability of HPV16 E7 to subvert centrosome homeostasis.

APA, Harvard, Vancouver, ISO, and other styles

21

Baldwin, Amy, Kyung-Won Huh, and Karl Münger. "Human Papillomavirus E7 Oncoprotein Dysregulates Steroid Receptor Coactivator 1 Localization and Function." Journal of Virology 80, no. 13 (July 1, 2006): 6669–77. http://dx.doi.org/10.1128/jvi.02497-05.

Full text

Abstract:

ABSTRACT High-risk human papillomaviruses (HPVs) are present in virtually all cervical carcinomas. However, the majority of women infected with high-risk HPVs do not develop cervical cancer. Therefore, cofactors must contribute to the development and progression of cervical cancer. Although numerous studies have implicated steroid hormones as cofactors in the initiation and progression of cervical neoplasia, the molecular mechanisms by which they contribute to cervical carcinogenesis are currently unknown. These observations led us to investigate a newly discovered association of the high-risk HPV type 16 (HPV16) E7 oncoprotein with steroid receptor coactivator 1 (SRC-1), an essential component of steroid hormone signaling. HPV16 E7 has been previously reported to interact with p300 and p300/CBP-associated factor (PCAF), members of some SRC-1 transcriptional complexes. We demonstrate here that HPV16 E7 associates in vivo and in vitro with SRC-1 independently of p300 and PCAF. Luciferase reporter constructs under the control of either the interleukin-8 promoter or a promoter containing multimerized synthetic estrogen response elements were used to determine the effect of high- and low-risk HPV E7 expression on SRC-1-mediated transcription. In addition, histone acetyltransferase (HAT) assays were performed to determine the effect of HPV E7 on SRC-1-associated HAT activity. These experiments reveal that HPV16 E7 expression down-regulates SRC-1-mediated transcription and SRC-1-associated HAT activity. SRC-1 localization experiments show that SRC-1 is relocalized to the cytoplasm in the presence of high- and low-risk HPV E7 proteins. Our data suggest that HPV E7 proteins dysregulate hormone-dependent gene expression by association with and relocalization of SRC-1. Dysregulation of SRC-1 localization and function by HPV E7 may provide insight into the molecular mechanisms by which steroid hormones act as cofactors in the induction and progression of cervical neoplasia.

APA, Harvard, Vancouver, ISO, and other styles

22

Lifsics, Andrejs, Valerija Groma, Maksims Cistjakovs, Sandra Skuja, Renars Deksnis, and Modra Murovska. "Identification of High-Risk Human Papillomavirus DNA, p16, and E6/E7 Oncoproteins in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas." Viruses 13, no. 6 (May 27, 2021): 1008. http://dx.doi.org/10.3390/v13061008.

Full text

Abstract:

Human papillomavirus (HPV) was proven to play a significant role in cancer development in the oropharynx. However, its role in the development of laryngeal (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) remains to be clarified. High-risk HPV (HR-HPV) viral proteins E6 and E7 are considered to be pertinent to HPV-related carcinogenesis. Hence, our aim was to estimate LSCC and HPSCC for HR-HPV DNA, p16, and E6/E7 oncoprotein status by using molecular virology and immunohistochemistry methods. The prevalence of HPV16 infection was 22/41 (53.7%) and 20/31 (64.5%) for LSCC and HPSCC, accordingly. The majority of HPV16+ tumor samples were stage III or IV. In most samples, the presence of either HPV16 E6 or HPV16 E7 viral protein in dysplastic or tumor cells was confirmed using immunohistochemistry. Our results suggest a high prevalence of HPV16 as a primary HR-HPV type in LSCC and HPSCC. The lack of HPV E6/E7 oncoproteins in some tumor samples may suggest either the absence of viral integration or the presence of other mechanisms of tumorigenesis. The utilization of p16 IHC as a surrogate marker of HR-HPV infection is impractical in LSCC and HPSCC.

APA, Harvard, Vancouver, ISO, and other styles

23

Oh, Kwang-Jin, Anna Kalinina, Jing Wang, Keiko Nakayama, Keiichi I. Nakayama, and Srilata Bagchi. "The Papillomavirus E7 Oncoprotein Is Ubiquitinated by UbcH7 and Cullin 1- and Skp2-Containing E3 Ligase." Journal of Virology 78, no. 10 (May 15, 2004): 5338–46. http://dx.doi.org/10.1128/jvi.78.10.5338-5346.2004.

Full text

Abstract:

ABSTRACT Recurrent infections with high-risk human papillomaviruses (HPVs) are associated with human cervical cancers. All HPV-associated cancer tissues express the viral oncoproteins E6 and E7, which stimulate cell growth. The expression of E7 is crucial for both the initiation and the maintenance of HPV-associated cancer. Recent studies showed that the level of E7 in cancer cells is regulated by ubiquitin-dependent proteolysis through the 26S proteasome. In this study, we characterized the enzymes involved in the ubiquitin-dependent proteolysis of E7. We show that UbcH7, an E2 ubiquitin-conjugating enzyme, is specifically involved in the ubiquitination of E7. Furthermore, we show that E7 interacts with the SCF (Skp-Cullin-F box) ubiquitin ligase complex containing Cullin 1 (Cul1) and Skp2 and can be ubiquitinated by the Cul1-containing ubiquitin ligase in vitro. Coimmunoprecipitation analyses revealed that E7 interacts with Skp2 and Cul1 in vivo. Finally, the half-life of E7 was found to be significantly longer in Skp2−/− mouse embryo fibroblasts (MEFs) than in wild-type MEFs. Taken together, these results suggest that the Cul1- and Skp2-containing ubiquitin ligase plays a role in the ubiquitination and proteolysis of E7. In HPV type 16-containing cervical carcinoma cell line Caski, E7 localizes to both the cytoplasm and the nucleus. Brief treatment of Caski cells with MG132 (a proteasome inhibitor) causes the accumulation of E7 in discrete nuclear bodies. These nuclear bodies are detergent insoluble and contain polyubiquitinated E7. We suggest that E7 relocates to specific nuclear bodies for proteolysis in HPV-containing epithelial cells.

APA, Harvard, Vancouver, ISO, and other styles

24

Franconi, R., S. Massa, E. Illiano, A. Muller, A. Cirilli, L. Accardd, P. DI Bonito, C. Giorgi, and A. Venuti. "Exploiting the Plant Secretory Pathway to Improve the Anticancer Activity of a Plant-Derived HPV16 E7 Vaccine." International Journal of Immunopathology and Pharmacology 19, no. 1 (January 2006): 205873920601900. http://dx.doi.org/10.1177/205873920601900119.

Full text

Abstract:

The human papillomavirus 16 (HPV16) E7 oncoprotein can be considered a ‘tumor-specific antigen’ and, therefore, it represents a promising target for a therapeutic vaccine against HPV-associated tumors. Efficient production of E7 protein with a plant-based transient expression system has been already described and it was demonstrated that E7-containing crude plant extracts confer partial protection against tumor challenge in a mouse model system. Before adopting the plant-based system as a cost-effective method for the production of an E7-based anti-cancer vaccine, some aspects, such as the oncoprotein yield, need further investigation. In the present study, we report the transient expression, mediated by a potato virus X (PVX)-derived vector, of the E7 protein targeted to the secretory system of Nicotiana benthamiana plants by using a plant-derived signal sequence. Targeting the antigen to the secretory pathway enhanced the E7 protein expression levels about five-fold. Mice immunized by s.c. administration with crude foliar extracts containing E7 showed strong stimulation of cell-mediated immune response after five boosters, as detected by ELISPOT. After challenging with the E7-expressing C3 tumor cells, tumor growth was completely inhibited in 80% of the vaccinated animals and a drastic reduction of tumor burden was observed in the remaining tumor-affected mice. These data demonstrate that, by enhancing E7 yield, it is possible to improve the anti-cancer activity of the plant-based experimental vaccine and open the way for a large-scale production of the E7 protein which could be purified or used as ‘in planta’ formulation, also suitable for oral therapeutic vaccination.

APA, Harvard, Vancouver, ISO, and other styles

25

Brehm, A., K. Ohbo, W. Zwerschke, V. Botquin, P. Jansen-Dürr, and H. R. Schöler. "Synergism with Germ Line Transcription Factor Oct-4: Viral Oncoproteins Share the Ability To Mimic a Stem Cell-Specific Activity." Molecular and Cellular Biology 19, no. 4 (April 1, 1999): 2635–43. http://dx.doi.org/10.1128/mcb.19.4.2635.

Full text

Abstract:

ABSTRACT Activation of transcription by Oct-4 from remote binding sites requires a cofactor that is restricted to embryonal stem cells. The adenovirus E1A protein can mimic the activity of this stem cell-specific factor and stimulates Oct-4 activity in differentiated cells. Here we characterize the Oct-4–E1A interaction and show that the E1A 289R protein harbors two independent Oct-4 binding sites, both of which specifically interact with the POU domain of Oct-4. Furthermore, we demonstrate that, like E1A, the human papillomavirus E7 oncoprotein also specifically binds to the Oct-4 POU domain. E7 and Oct-4 can form a complex both in vitro and in vivo. Expression of E7 in differentiated cells stimulates Oct-4-mediated transactivation from distal binding sites. Moreover, Oct-4, but not other Oct factors, is active when expressed in cells transformed by human papillomavirus. Our results suggest that different viruses have evolved oncoproteins that share the ability to target Oct-4 and to mimic a stem cell-specific activity.

APA, Harvard, Vancouver, ISO, and other styles

26

White, Elizabeth A., Rebecca E. Kramer, Justin H. Hwang, Arun T. Pores Fernando, Nana Naetar, William C. Hahn, Thomas M. Roberts, Brian S. Schaffhausen, David M. Livingston, and Peter M. Howley. "Papillomavirus E7 Oncoproteins Share Functions with Polyomavirus Small T Antigens." Journal of Virology 89, no. 5 (December 24, 2014): 2857–65. http://dx.doi.org/10.1128/jvi.03282-14.

Full text

Abstract:

ABSTRACTMany of the small DNA tumor viruses encode transforming proteins that function by targeting critical cellular pathways involved in cell proliferation and survival. In this study, we have examined whether some of the functions of the polyomavirus small T antigens (ST) are shared by the E6 and E7 oncoproteins of two oncogenic papillomaviruses. Using three different assays, we have found that E7 can provide some simian virus 40 (SV40) or murine polyomavirus (PyV) ST functions. Both human papillomavirus 16 (HPV16) and bovine papillomavirus (BPV1) E7 proteins are capable of partially substituting for SV40 ST in a transformation assay that also includes SV40 large T antigen, the catalytic subunit of cellular telomerase, and oncogenic Ras. Like SV40 ST, HPV16 E7 has the ability to override a quiescence block induced by mitogen deprivation. Like PyV ST, it also has the ability to inhibit myoblast differentiation. At least two of these activities are dependent upon the interaction of HPV16 E7 with retinoblastoma protein family members. For small T antigens, interaction with PP2A is needed for each of these functions. Even though there is no strong evidence that E6 or E7 share the ability of small T to interact with PP2A, E7 provides these functions related to cellular transformation.IMPORTANCEDNA tumor viruses have provided major insights into how cancers develop. Some viruses, like the human papillomaviruses, can cause cancer directly. Both the papillomaviruses and the polyomaviruses have served as tools for understanding pathways that are often perturbed in cancer. Here, we have compared the functions of transforming proteins from several DNA tumor viruses, including two papillomaviruses and two polyomaviruses. We tested the papillomavirus E6 and E7 oncoproteins in three functional assays and found that E7 can provide some or all of the functions of the SV40 small T antigen, another well-characterized oncoprotein, in two of these assays. In a third assay, papillomavirus E7 has the same effect as the murine polyomavirus small T protein. In summary, we report several new functions for the papillomavirus E7 proteins, which will contribute new insights into the roles of viruses in cancer and the cellular pathways they perturb in carcinogenesis.

APA, Harvard, Vancouver, ISO, and other styles

27

Alonso, Leonardo G., Clara Smal, Maria M. Garcia-Alai, Lucia Chemes, Marcelo Salame, and Gonzalo de Prat-Gay. "Chaperone Holdase Activity of Human Papillomavirus E7 Oncoprotein†." Biochemistry 45, no. 3 (January 2006): 657–67. http://dx.doi.org/10.1021/bi0522549.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Campo-Fernández, Beatriz, Dieter Morandell, Frédéric R. Santer, Werner Zwerschke, and Pidder Jansen-Dürr. "Identification of the FHL2 Transcriptional Coactivator as a New Functional Target of the E7 Oncoprotein of Human Papillomavirus Type 16." Journal of Virology 81, no. 2 (November 8, 2006): 1027–32. http://dx.doi.org/10.1128/jvi.01699-06.

Full text

Abstract:

ABSTRACT We identified the transcriptional coactivator FHL2 as a novel target of the human papillomavirus type 16 (HPV-16) E7 oncoprotein, which plays a major role in cell transformation. The interaction with FHL2 is abolished by mutations in conserved regions 1 and 2 and in the C-terminal zinc finger domain of E7, all required for its transforming potential. We found that E7 impairs the coactivator function of FHL2 on both β-catenin/LCF-dependent and AP-1-dependent promoters. Thus, the interaction with HPV-16 E7 leads to a promoter-specific impairment of FHL2 function and this may contribute to cell transformation.

APA, Harvard, Vancouver, ISO, and other styles

29

Seavey, Scott E., Marisa Holubar, Leslie J. Saucedo, and Mary Ellen Perry. "The E7 Oncoprotein of Human Papillomavirus Type 16 Stabilizes p53 through a Mechanism Independent of p19ARF." Journal of Virology 73, no. 9 (September 1, 1999): 7590–98. http://dx.doi.org/10.1128/jvi.73.9.7590-7598.1999.

Full text

Abstract:

ABSTRACT High-risk human papillomaviruses are causally associated with cervical cancer. Two viral oncogenes, E6 and E7, are expressed in most cervical cancers, and these genes cause cancer when expressed in experimental animals. The E6 protein targets the p53 tumor suppressor for degradation, while the E7 protein inactivates the retinoblastoma susceptibility protein (pRb), in part by stimulating its degradation. In contrast, expression of E7 in the absence of E6 leads to stabilization of p53. Here we show that E7 stabilizes p53 in mouse embryo fibroblasts lacking p19ARF. The stable p53 is active as a transcriptional activator, as evidenced by the increased expression of the p53-responsive mdm2 gene. Normally, MDM2 protein inhibits p53 function in an autoregulatory loop. Regulation of p53 by MDM2 is required for murine development as well as for proliferation of cultured human fibroblasts. However, E7-expressing human fibroblasts continue to divide even though E7 abrogates the ability of MDM2 and p53 to bind. Furthermore, E7-expressing cells are not more sensitive to UV light, an agent that has been reported to induce apoptosis mediated by p53. These results indicate that in addition to inhibiting the ability of MDM2 to regulate p53, E7 must block signaling steps downstream of p53 to allow cell division.

APA, Harvard, Vancouver, ISO, and other styles

30

McLaughlin-Drubin, Margaret E., Kyung-Won Huh, and Karl Münger. "Human Papillomavirus Type 16 E7 Oncoprotein Associates with E2F6." Journal of Virology 82, no. 17 (June 25, 2008): 8695–705. http://dx.doi.org/10.1128/jvi.00579-08.

Full text

Abstract:

ABSTRACT The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.

APA, Harvard, Vancouver, ISO, and other styles

31

Schulze, Almut, Boris Mannhardt, Karin Zerfass-Thome, Werner Zwerschke, and Pidder Jansen-Dürr. "Anchorage-Independent Transcription of the Cyclin A Gene Induced by the E7 Oncoprotein of Human Papillomavirus Type 16." Journal of Virology 72, no. 3 (March 1, 1998): 2323–34. http://dx.doi.org/10.1128/jvi.72.3.2323-2334.1998.

Full text

Abstract:

ABSTRACT To develop an experimental model for E7-mediated anchorage-independent growth, we studied the ability of E7-expressing NIH 3T3 subclones to enter S phase when they were cultured in suspension. We found that expression of E7 prevents the inhibition of cyclin E-associated kinase and also triggers activation of cyclin A gene expression in suspension cells. A point mutation in the amino terminus of E7 prevented E7-driven rescue of cyclin E-associated kinase activity in suspension cells; however, cells with this mutation retained some ability to activate cyclin A gene expression and promote S-phase entry. Activation of cyclin A gene expression by E7 was correlated with an increased binding of free E2F to a regulatory element in the cyclin A promoter which mediates both repression of cyclin A upon loss of adhesion and its reactivation by E7. Surprisingly, expression of E7 led to a nuclear accumulation of one species of free E2F, namely, an E2F-4–DP-1 heterodimer, that is exclusively cytoplasmic in the absence of E7. Taken together, the data reported here indicate that several different E7-dependent changes of cellular-growth-regulating pathways can cooperate to allow adhesion-independent entry into S phase.

APA, Harvard, Vancouver, ISO, and other styles

32

Kanduc, Darja. "Translational Regulation of Human Papillomavirus Type 16 E7 mRNA by the Peptide SEQIKA, Shared by Rabbit α1-Globin and Human Cytokeratin 7." Journal of Virology 76, no. 14 (July 15, 2002): 7040–48. http://dx.doi.org/10.1128/jvi.76.14.7040-7048.2002.

Full text

Abstract:

ABSTRACT The possible biochemical factors able to affect the in vitro expression of the high-risk human papillomavirus type 16 (HPV16) E7 oncoprotein have been analyzed. Evidence is provided that E7 mRNA stability is increased and, conversely, transcript translation is inhibited by binding to a 32-kDa protein from rabbit reticulocyte lysate; sequence analysis identified the 32-kDa binding protein as rabbit α1-globin protein; and interaction between rabbit α1-globin and E7 mRNA occurs through the 6-mer peptide SEQIKA present in human cytokeratin 7 protein. The in vitro data were confirmed by the occurrence of HPV16 E7 mRNA-cytokeratin 7 binding in squamous cervical cancer SiHa cells.

APA, Harvard, Vancouver, ISO, and other styles

33

Vogt, Beate, Karin Zerfaß-Thome, Almut Schulze, Jürgen W. Botz, Werner Zwerschke, and Pidder Jansen-Dürr. "Regulation of cyclin E gene expression by the human papillomavirus type 16 E7 oncoprotein." Journal of General Virology 80, no. 8 (August 1, 1999): 2103–13. http://dx.doi.org/10.1099/0022-1317-80-8-2103.

Full text

Abstract:

In this study, we characterized the 5′ regulatory region of the murine cyclin E gene and analysed activation of the gene by the E7 oncogene of human papillomavirus type 16 in transfection experiments. We found that the murine cyclin E promoter is composed of multiple regulatory elements, and we present evidence for at least two independent transcription units, designated P1 and P2. Overlapping binding sites for the cellular transcription factors Sp1 and E2F were identified in both promoters, and we found that E2F-mediated activation of transcription is inhibited by Sp1 in cotransfection experiments. The E2F/Sp1 binding sites contribute to transcriptional activation by E7, and the data suggest that the cyclin E gene is rendered E7-inducible through the combination of several cis-acting elements which display only weak intrinsic responsiveness to E7.

APA, Harvard, Vancouver, ISO, and other styles

34

Bohl, Joanna, Bruce Hull, and Scott B. Vande Pol. "Cooperative Transformation and Coexpression of Bovine Papillomavirus Type 1 E5 and E7 Proteins." Journal of Virology 75, no. 1 (January 1, 2001): 513–21. http://dx.doi.org/10.1128/jvi.75.1.513-521.2001.

Full text

Abstract:

ABSTRACT Productively infected bovine fibropapillomas were examined for bovine papillomavirus type 1 (BPV-1) E7 localization. BPV-1 E7 was observed in the cytoplasm of basal and lower spinous epithelial cells, coexpressed in the cytoplasm of basal cells with the E5 oncoprotein. E7 was also observed in nucleoli throughout the basal and spinous layers but not in the granular cell layer. Ectopic expression of E7 in cultured epithelial cells gave rise to localization similar to that seen in productive fibropapillomas, with cytoplasmic and nucleolar expression observed. Consistent with the coexpression of E7 and E5 in basal keratinocytes, BPV-1 E7 cooperated with E5 as well as E6 in an anchorage independence transformation assay. While E5 is expressed in both basal and superficial differentiating keratinocytes, BPV-1 E7 is only observed in basal and lower spinous epithelial cells. Therefore, BPV-1 E7 may serve to modulate the cellular response of basal epithelial cells to E5 expression.

APA, Harvard, Vancouver, ISO, and other styles

35

Spardy, Nicole, Anette Duensing, Domonique Charles, Nathan Haines, Tomomi Nakahara, Paul F. Lambert, and Stefan Duensing. "The Human Papillomavirus Type 16 E7 Oncoprotein Activates the Fanconi Anemia (FA) Pathway and Causes Accelerated Chromosomal Instability in FA Cells." Journal of Virology 81, no. 23 (September 26, 2007): 13265–70. http://dx.doi.org/10.1128/jvi.01121-07.

Full text

Abstract:

ABSTRACT Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. Episomal expression of HPV-16 oncoproteins was sufficient to activate the FA pathway. Importantly, the expression of HPV-16 E7 in FA-deficient cells led to accelerated chromosomal instability. Taken together, our findings establish the FA pathway as an early host cell response to high-risk HPV infection and may help to explain the greatly enhanced susceptibility of FA patients to squamous cell carcinogenesis at anatomic sites that are frequently infected by high-risk HPVs.

APA, Harvard, Vancouver, ISO, and other styles

36

Zhou, Yunying, Qishu Zhang, Ge Gao, Xiaoli Zhang, Yafei Liu, Shoudao Yuan, Xiaowei Wang, and Jason J. Chen. "Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells." Journal of Virology 90, no. 13 (April 20, 2016): 6071–84. http://dx.doi.org/10.1128/jvi.00513-16.

Full text

Abstract:

ABSTRACTThe E7 oncoprotein of the high-risk human papillomavirus (HPV) plays a major role in HPV-induced carcinogenesis. E7 abrogates the G1cell cycle checkpoint and induces genomic instability, but the mechanism is not fully understood. In this study, we performed RNA sequencing (RNA-seq) to characterize the transcriptional profile of keratinocytes expressing HPV 16 (HPV-16) E7. At the transcriptome level, 236 genes were differentially expressed between E7 and vector control cells. A subset of the differentially expressed genes, most of them novel to E7-expressing cells, was further confirmed by real-time PCR. Of interest, the activities of multiple transcription factors were altered in E7-expressing cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were investigated. The upregulated genes were enriched in cell cycle and DNA replication, as well as in the DNA metabolic process, transcription, DNA damage, DNA repair, and nucleotide metabolism. Specifically, we focused our studies on the gene encoding WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein), one of the genes that was upregulated in E7-expressing cells. WDHD1 is a component of the replisome that regulates DNA replication. Recent studies suggest that WDHD1 may also function as a DNA replication initiation factor as well as a G1checkpoint regulator. We found that in E7-expressing cells, the steady-state level of WDHD1 protein was increased along with the half-life. Moreover, downregulation of WDHD1 reduced E7-induced G1checkpoint abrogation and rereplication, demonstrating a novel function for WDHD1. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications.IMPORTANCEThe high-risk HPV types induce cervical cancer and encode an E7 oncoprotein that plays a major role in HPV-induced carcinogenesis. However, the mechanism by which E7 induces carcinogenesis is not fully understood; specific anti-HPV agents are not available. In this study, we performed RNA-seq to characterize transcriptional profiling of keratinocytes expressing HPV-16 E7 and identified more than 200 genes that were differentially expressed between E7 and vector control cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were identified. Significantly, the WDHD1 gene, one of the genes that is upregulated in E7-expressing cells, was found to play an important role in E7-induced G1checkpoint abrogation and rereplication. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications.

APA, Harvard, Vancouver, ISO, and other styles

37

Borena, Wegene, Volker H. Schartinger, Jozsef Dudas, Julia Ingruber, Maria C. Greier, Teresa B. Steinbichler, Johannes Laimer, Heribert Stoiber, Herbert Riechelmann, and Barbara Kofler. "HPV-Induced Oropharyngeal Cancer and the Role of the E7 Oncoprotein Detection via Brush Test." Cancers 12, no. 9 (August 23, 2020): 2388. http://dx.doi.org/10.3390/cancers12092388.

Full text

Abstract:

Background: High risk human papillomavirus (hr-HPV)-associated oropharyngeal cancers (OPCs) are characterized by significantly better therapy responses. In order to implement a de-escalated treatment strategy for this tumor entity, it is highly crucial to accurately distinguish HPV-associated OPCs from non-HPV-associated ones. Methods: In this prospective study, 56 patients with histologically confirmed OPC were evaluated. A commercially available sandwich ELISA test system was used for the detection of hr-HPV E7 oncoprotein targeting the genotypes 16, 18 and 45. Results were presented as optical density. Positivity for HPV DNA and p16 immunohistochemistry (IHC) was taken as the reference method. Results: E7 positivity was significantly associated with the reference method (p = 0.048). The sensitivity, specificity, positive predictive value and negative predictive value for the E7 oncoptotein was 60.9% (95% CI 38.5 to 80.3%), 66.7% (95% CI 46% to 83.5%), 64.2% (95% CI 49.4 to 77.4%) and 63.01% (95% CI 48.9–75.2%), respectively, for the cutoff provided by the manufacturer. Conclusions: We found a significant association between E7 oncoprotein detection and the currently used combination. We believe that the use of the ELISA based E7 antigen test could be a valuable addition in cases of ambiguous findings and may be used in combination with other techniques to distinguish between HPV-driven and non-HPV-driven OPCs. However, the low sensitivity of the assay coupled with the small sample size in our study may represent a limitation. We recommend that future larger studies elucidate the diagnostic value of the E7 brush test.

APA, Harvard, Vancouver, ISO, and other styles

38

Malik, Rabbiah, Sahar Fazal, and Mohammad Amjad Kamal. "Computational Analysis of Dynamical Fluctuations of Oncoprotein E7 (HPV 16) for the Hot Spot Residue Identification Using Elastic Network Model." Letters in Drug Design & Discovery 17, no. 11 (October 23, 2020): 1393–400. http://dx.doi.org/10.2174/1570180817999200606225735.

Full text

Abstract:

Aims: To find out Potential Drug targets against HPV E7. Background: Oncoprotein E7 of Human Papilloma Virus (HPV-16), after invading human body alter host protein-protein interaction networks caused by the fluctuations of amino acid residues present in E7. E7 interacts with Rb protein of human host with variable residual fluctuations, leading towards the progression of cervical cancer. Objective: Our study was focused our computational analysis of the binding and competing interactions of the E7 protein of HPV with Rb protein. Methods: Our study is based on analysis of dynamic fluctuations of E7 in host cell and correlation analysis of specific residue found in motif of LxCxE, that is the key region in stabilizing interaction between E7 and Rb. Results and Discussion: Cysteine, Leucine and Glutamic acid have been identified as hot spot residues of E7 which can provide platform for drug designing and understanding of pathogenesis of cervical cancer, in future. Our study shows validation of the vitality of linear binding motifs LxCxE of E7 of HPV in interacting with Rb as an important event in propagation of HPV in human cells and transformation of infection into cervical cancer. Conclusion: Our study shows validation of the vitality of linear binding motifs LxCxE of E7 of HPV in interacting with Rb as an important event in propagation of HPV in human cells and transformation of infection into cervical cancer. Other: E7 interacts with Rb protein of human host with variable residual fluctuations, leading towards the progression of cervical cancer.

APA, Harvard, Vancouver, ISO, and other styles

39

Oh, Kwang-Jin, Anna Kalinina, No-Hee Park, and Srilata Bagchi. "Deregulation of eIF4E: 4E-BP1 in Differentiated Human Papillomavirus-Containing Cells Leads to High Levels of Expression of the E7 Oncoprotein." Journal of Virology 80, no. 14 (July 15, 2006): 7079–88. http://dx.doi.org/10.1128/jvi.02380-05.

Full text

Abstract:

ABSTRACT Infections with high-risk human papillomaviruses (HPVs) are linked to more than 95% of cervical cancers. HPVs replicate exclusively in differentiated cells and the function of the HPV E7 oncoprotein is essential for viral replication. In this study, we investigated the mechanism that regulates E7 expression in differentiated cells. The level of E7 protein was strongly induced in HPV-containing Caski, HOK-16B, and BaP-T cells during growth in methylcellulose-containing medium, a condition that induces differentiation. Enhanced expression of E7 was observed between 4 and 8 h of culturing in methylcellulose and was maintained for up to 24 h. The increase was not due to altered stability of the E7 protein or an increase in the steady-state level of the E7 mRNA. Instead, the translation of the E7 mRNA was enhanced during differentiation. More than 70 to 80% of the E7 mRNA was found in the polysome fractions in the differentiated cells. Consistent with this observation, higher levels of the phosphorylated translator inhibitor 4E-BP1 were observed in differentiated HPV-containing cells but not in differentiated non-HPV tumor cells or primary keratinocytes. The mTOR kinase inhibitor rapamycin blocked phosphorylation of 4E-BP1 and significantly decreased the level of E7 protein in Caski cells, suggesting that phosphorylation of 4E-BP1 is linked to E7 expression. Prevailing models for the molecular mechanisms underlying E7 expression have focused largely on transcriptional regulation. The results presented in this study demonstrate a significant role of the cellular translation machinery to maintain a high level of E7 protein in differentiated cells.

APA, Harvard, Vancouver, ISO, and other styles

40

Nishimura, Akiko, Tomomi Nakahara, Takaharu Ueno, Kenta Sasaki, Satoshi Yoshida, Satoru Kyo, Peter M. Howley, and Hiroyuki Sakai. "Requirement of E7 oncoprotein for viability of HeLa cells." Microbes and Infection 8, no. 4 (April 2006): 984–93. http://dx.doi.org/10.1016/j.micinf.2005.10.015.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Li, Shufeng, Wei Zhang, Kunpeng Jiang, Haitao Shan, Minke Shi, Baojun Chen, and Zichun Hua. "Nanobody against the E7 oncoprotein of human papillomavirus 16." Molecular Immunology 109 (May 2019): 12–19. http://dx.doi.org/10.1016/j.molimm.2019.02.022.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Pan, Wei, Abhishek Datta, Guy R. Adami, Pradip Raychaudhuri, and Srilata Bagchi. "P19ARF inhibits the functions of the HPV16 E7 oncoprotein." Oncogene 22, no. 35 (August 2003): 5496–503. http://dx.doi.org/10.1038/sj.onc.1206857.

Full text

APA, Harvard, Vancouver, ISO, and other styles

43

Chemes, Lucía B., Juliana Glavina, Julián Faivovich, Gonzalo de Prat-Gay, and Ignacio E. Sánchez. "Evolution of Linear Motifs within the Papillomavirus E7 Oncoprotein." Journal of Molecular Biology 422, no. 3 (September 2012): 336–46. http://dx.doi.org/10.1016/j.jmb.2012.05.036.

Full text

APA, Harvard, Vancouver, ISO, and other styles

44

Mannhardt, Boris, Stuart A. Weinzimer, Mechthild Wagner, Marc Fiedler, Pinchas Cohen, Pidder Jansen-Dürr, and Werner Zwerschke. "Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6483–95. http://dx.doi.org/10.1128/mcb.20.17.6483-6495.2000.

Full text

Abstract:

ABSTRACT The E7 protein encoded by human papillomavirus type 16 is one of the few viral genes that can immortalize primary human cells and thereby override cellular senescence. While it is generally assumed that this property of E7 depends on its interaction with regulators of the cell cycle, we show here that E7 targets insulin-like growth factor binding protein 3 (IGFBP-3), the product of a p53-inducible gene that is overexpressed in senescent cells. IGFBP-3 can suppress cell proliferation and induce apoptosis; we show here that IGFBP-3-mediated apoptosis is inhibited by E7, which binds to IGFBP-3 and triggers its proteolytic cleavage. Two transformation-deficient mutants of E7 failed to inactivate IGFBP-3, suggesting that inactivation of IGFBP-3 may contribute to cell transformation.

APA, Harvard, Vancouver, ISO, and other styles

45

Damian-Morales, Gabriela, Nicolás Serafín-Higuera, Mario Adán Moreno-Eutimio, Enoc M. Cortés-Malagón, José Bonilla-Delgado, Genaro Rodríguez-Uribe, Rodolfo Ocadiz-Delgado, Paul F. Lambert, and Patricio Gariglio. "The HPV16 E7 Oncoprotein Disrupts Dendritic Cell Function and Induces the Systemic Expansion of CD11b+Gr1+Cells in a Transgenic Mouse Model." BioMed Research International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8091353.

Full text

Abstract:

Objective.The aim of this study was to analyze the effects of the HPV16 E7 oncoprotein on dendritic cells (DCs) and CD11b+Gr1+cells using the K14E7 transgenic mouse model.Materials and Methods.The morphology of DCs was analyzed in male mouse skin on epidermal sheets using immunofluorescence and confocal microscopy. Flow cytometry was used to determine the percentages of DCs and CD11b+Gr1+cells in different tissues and to evaluate the migration of DCs.Results.In the K14E7 mouse model, the morphology of Langerhans cells and the migratory activity of dendritic cells were abnormal. An increase in CD11b+Gr1+cells was observed in the blood and skin of K14E7 mice, and molecules related to CD11b+Gr1+chemoattraction (MCP1 and S100A9) were upregulated.Conclusions.These data suggest that the HPV16 E7 oncoprotein impairs the function and morphology of DCs and induces the systemic accumulation of CD11b+Gr1+cells.

APA, Harvard, Vancouver, ISO, and other styles

46

Sitz, Justine, Sophie Anne Blanchet, Steven F. Gameiro, Elise Biquand, Tia M. Morgan, Maxime Galloy, Julien Dessapt, et al. "Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response." Proceedings of the National Academy of Sciences 116, no. 39 (September 9, 2019): 19552–62. http://dx.doi.org/10.1073/pnas.1906102116.

Full text

Abstract:

High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.

APA, Harvard, Vancouver, ISO, and other styles

47

Strickland, Sydney Webb, and Scott Vande Pol. "The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC." Journal of Virology 90, no. 12 (March 30, 2016): 5611–21. http://dx.doi.org/10.1128/jvi.00411-16.

Full text

Abstract:

ABSTRACTWhile the role of high-risk human papillomavirus (HPV) oncoproteins E6 and E7 in targeting p53 and retinoblastoma (Rb) has been intensively studied, how E6 and E7 manipulate cellular signaling cascades to promote the viral life cycle and cancer development is less understood. Keratinocytes containing the episomal HPV-16 genome had decreased activation of AKT, which was phenocopied by HPV-16 E7 expression alone. Attenuation of phosphorylated AKT (pAKT) by E7 was independent of the Rb degradation function of E7 but could be ablated by a missense mutation in the E7 carboxy terminus, H73E, thereby defining a novel structure-function phenotype for E7. Downstream of AKT, reduced phosphorylation of p70 S6K and 4E-BP1 was also observed in E7-expressing keratinocytes, which coincided with an increase in internal ribosomal entry site (IRES)-dependent translation that enhanced the expression of several cellular proteins, including MYC, Bax, and the insulin receptor. The decrease in pAKT mediated by E7 is in contrast to the widely observed increase of pAKT in invasive cervical cancers, suggesting that the activation of AKT signaling could be acquired during the progression from initial productive infections to invasive carcinomas.IMPORTANCEHPV causes invasive cervical cancers through the dysregulation of the cell cycle regulators p53 and Rb, which are degraded by the viral oncoproteins E6 and E7, respectively. Signaling cascades contribute to cancer progression and cellular differentiation, and how E6 and E7 manipulate those pathways remains unclear. The phosphoinositol 3-kinase (PI3K)/AKT pathway regulates cellular processes, including proliferation, cell survival, and cell differentiation. Surprisingly, we found that HPV-16 decreased the phosphorylation of AKT (pAKT) and that this is a function of E7 that is independent of the Rb degradation function. This is in contrast to the observed increase in AKT signaling in nearly 80% of cervical cancers, which typically show an acquired mutation within the PI3K/AKT cascade leading to constitutive activation of the pathway. Our observations suggest that multiple changes in the activation and effects of AKT signaling occur in the progression from productive HPV infections to invasive cervical cancers.

APA, Harvard, Vancouver, ISO, and other styles

48

Rice, Sadie, Seong-man Kim, Cynthia Rodriguez, William Songock, Gaurav Raikhy, Rebecca Lopez, Lauren Henderson, Arjun Yusufji, and Jason Bodily. "Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism." Viruses 12, no. 3 (March 13, 2020): 311. http://dx.doi.org/10.3390/v12030311.

Full text

Abstract:

Persistent infection by human papillomaviruses (HPVs), small, double-stranded DNA viruses that infect keratinocytes of the squamous epithelia, can lead to the development of cervical and other cancers. The viral oncoprotein E7 contributes to viral persistence in part by regulating host gene expression through binding host transcriptional regulators, although mechanisms responsible for E7-mediated transcriptional regulation are incompletely understood. Type I IFN signaling promotes the expression of anti-viral genes, called interferon-stimulated genes (ISGs), through the phosphorylation and activation of STAT1. In this study, we have observed that the CR3 domain of E7 contributes to the episomal maintenance of viral genomes. Transcriptome analysis revealed that E7 transcriptionally suppresses a subset of ISGs but not through regulation of STAT1 activation. Instead, we discovered that E7 associates with Mediator kinase CDK8 and this is correlated with the recruitment of CDK8 to ISG promoters and reduced ISG expression. E7 fails to suppress ISGs in the absence of CDK8, indicating that CDK8 function contributes to the suppression of ISGs by E7. Altogether, E7/CDK8 association may be a novel mechanism by which E7 inhibits innate immune signaling.

APA, Harvard, Vancouver, ISO, and other styles

49

Helt, Anna-Marija, Jens Oliver Funk, and Denise A. Galloway. "Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells." Journal of Virology 76, no. 20 (October 15, 2002): 10559–68. http://dx.doi.org/10.1128/jvi.76.20.10559-10568.2002.

Full text

Abstract:

ABSTRACT The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and E7 Δ79-83 (deletion of positions 79 through 83) were further tested in several models of cell cycle arrest associated with elevated levels of p21. C-terminal mutations rendered E7 unable to induce S phase and endoreduplication in differentiated keratinocytes and rendered it less efficient in delaying senescence of human mammary epithelial cells. Interestingly, when cell cycle arrest was induced with a peptide form of p21, the E7 C-terminal mutants were deficient in overcoming arrest, whereas a mutant defective in Rb binding was competent in inhibiting G1 arrest. These results suggest that the inactivation of both p21 and Rb by E7 contributes to subversion of cell cycle control in normal human epithelia but that neither p21 nor Rb inactivation alone is sufficient.

APA, Harvard, Vancouver, ISO, and other styles

50

Lee, Seoung-Ae, Charles Ho, Madison Troxler, Chin-Yo Lin, and Sang-Hyuk Chung. "Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein." Viruses 13, no. 3 (March 8, 2021): 433. http://dx.doi.org/10.3390/v13030433.

Full text

Abstract:

Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV+ than HPV− cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV+ SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'E7 oncoprotein'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles