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Article: Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses.

James, Claire D / Lewis, Rachel L / Fakunmoju, Alexis L / Witt, Austin J / Youssef, Aya H / Wang, Xu / Rais, Nabiha M / Prabhakar, Apurva Tadimari / Otoa, Raymonde / Bristol, Molly L

bioRxiv : the preprint server for biology

2024

Abstract: Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers ( ... ...

Abstract	Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.09.588680
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Article ; Online: Interaction with TopBP1 Is Required for Human Papillomavirus 16 E2 Plasmid Segregation/Retention Function during Mitosis.

Prabhakar, Apurva T / James, Claire D / Das, Dipon / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Morgan, Iain M

Journal of virology

2022 Volume 96, Issue 16, Page(s) e0083022

Abstract: Human papillomavirus 16 (HPV16) E2 is a DNA-binding protein that regulates transcription, replication and potentially, segregation of the HPV16 genome during the viral life cycle. In the segregation model, E2 simultaneously binds to viral and host ... ...

Abstract	Human papillomavirus 16 (HPV16) E2 is a DNA-binding protein that regulates transcription, replication and potentially, segregation of the HPV16 genome during the viral life cycle. In the segregation model, E2 simultaneously binds to viral and host chromatin, acting as a bridge to ensure that viral genomes reside in daughter nuclei following cell division. The host chromatin receptor for E2 mediating this function is unknown. Recently, we demonstrated that CK2 phosphorylation of E2 on serine 23 (S23) is required for interaction with TopBP1, and that this interaction promotes E2 and TopBP1 recruitment to mitotic chromatin. Here, we demonstrate that in U2OS cells expressing wild-type E2 and a non-TopBP1-binding mutant (S23A, serine 23 mutated to alanine), interaction with TopBP1 is essential for E2 recruitment of plasmids to mitotic chromatin. Using novel quantitative segregation assays, we demonstrate that interaction with TopBP1 is required for E2 plasmid segregation function in U2OS and N/Tert-1 cells. Small interfering RNA (siRNA) knockdown of TopBP1 or CK2 enzyme components disrupts E2 segregation/retention function. The interaction of E2 with TopBP1 promotes increased levels of E2 protein during mitosis in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes (HFK) immortalized by the HPV16 genome. Overall, our results demonstrate that E2 has plasmid segregation activity, and that the E2-TopBP1 interaction is essential for this E2 function.
MeSH term(s)	Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Chromatin/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Genome, Viral ; Human papillomavirus 16/physiology ; Humans ; Mitosis ; Nuclear Proteins/metabolism ; Oncogene Proteins, Viral/metabolism ; Papillomavirus Infections/metabolism ; Papillomavirus Infections/pathology ; Papillomavirus Infections/virology ; Plasmids/genetics
Chemical Substances	Carrier Proteins ; Chromatin ; DNA-Binding Proteins ; E2 protein, Human papillomavirus type 16 ; Nuclear Proteins ; Oncogene Proteins, Viral ; TOPBP1 protein, human
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00830-22
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Article ; Online: Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation.

James, Claire D / Das, Dipon / Morgan, Ethan L / Otoa, Raymonde / Macdonald, Andrew / Morgan, Iain M

mSphere

2020 Volume 5, Issue 5

Abstract: Human papillomaviruses recruit a host of DNA damage response factors to their viral genome to facilitate homologous recombination replication in association with the viral replication factors E1 and E2. We previously demonstrated that SIRT1 deacetylation ...

Abstract	Human papillomaviruses recruit a host of DNA damage response factors to their viral genome to facilitate homologous recombination replication in association with the viral replication factors E1 and E2. We previously demonstrated that SIRT1 deacetylation of WRN promotes recruitment of WRN to E1-E2 replicating DNA and that WRN regulates both the levels and fidelity of E1-E2 replication. The deacetylation of WRN by SIRT1 results in an active protein able to complex with replicating DNA, but a protein that is less stable. Here, we demonstrate an inverse correlation between SIRT1 and WRN in CIN cervical lesions compared to normal control tissue, supporting our model of SIRT1 deacetylation destabilizing WRN protein. We CRISPR/Cas9 edited N/Tert-1 and N/Tert-1+HPV16 cells to knock out WRN protein expression and subjected the cells to organotypic raft cultures. In N/Tert-1 cells without WRN expression, there was enhanced basal cell proliferation, DNA damage, and thickening of the differentiated epithelium. In N/Tert-1+HPV16 cells, there was enhanced basal cell proliferation, increased DNA damage throughout the epithelium, and increased viral DNA replication. Overall, the results demonstrate that the expression of WRN is required to control the proliferation of N/Tert-1 cells and controls the HPV16 life cycle in these cells. This complements our previous data demonstrating that WRN controls the levels and fidelity of HPV16 E1-E2 DNA replication. The results describe a new role for WRN, a tumor suppressor, in controlling keratinocyte differentiation and the HPV16 life cycle.
MeSH term(s)	Cell Differentiation ; Cell Line, Transformed ; Cell Proliferation ; Cervix Uteri/cytology ; DNA Replication ; DNA, Viral/metabolism ; Epithelial Cells/physiology ; Epithelial Cells/virology ; Female ; Gene Editing ; Genome, Viral ; Host-Pathogen Interactions/genetics ; Human papillomavirus 16/genetics ; Human papillomavirus 16/physiology ; Humans ; Keratinocytes/virology ; Papillomavirus Infections/genetics ; Papillomavirus Infections/pathology ; Virus Replication ; Werner Syndrome Helicase/genetics
Chemical Substances	DNA, Viral ; WRN protein, human (EC 3.6.4.12) ; Werner Syndrome Helicase (EC 3.6.4.12)
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/mSphere.00858-20
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Article: Human papillomavirus 16 E2 interaction with TopBP1 is required for E2 and viral genome stability during the viral life cycle.

Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Hill, Ronald D / Dubey, Aanchal / Morgan, Iain M

bioRxiv : the preprint server for biology

2023

Abstract: CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during ... ...

Abstract	CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during the viral life cycle. Introduction of the S23A mutation into the HPV16 genome results in a loss of E2 expression and viral genome integration during organotypic rafting. Co-culture of N/Tert-1+E2-S23A cells with J2 fibroblasts results in E2-S23A degradation via the proteasome, wild-type E2 is not degraded. TopBP1 siRNA treatment of N/Tert-1+E2-WT cells results in E2 degradation only in the presence of J2 cells demonstrating the critical role for TopBP1 in maintaining E2 stability. The CK2 inhibitor CX4945 promotes E2-WT degradation in the presence of fibroblasts as it disrupts E2-TopBP1 interaction. siRNA targeting SIRT1 rescues E2-S23A stability in N/Tert-1 cells treated with J2 fibroblasts, with an increased E2-S23A acetylation. The results demonstrate that the E2-TopBP1 interaction is critical during the viral life cycle as it prevents fibroblast stimulated SIRT1 mediated deacetylation of E2 that promotes protein degradation. This means that the E2-TopBP1 complex maintains E2 and viral genome stability and that disruption of this complex can promote viral genome integration. Finally, we demonstrate that HPV11 E2 also interacts with TopBP1 and that this interaction is critical for HPV11 E2 stability in the presence of J2 cells. Treatment of N/Tert-1+11E2-WT cells with CX4945 results in 11E2 degradation. Therefore, CK2 inhibition is a therapeutic strategy for alleviating HPV11 diseases, including juvenile respiratory papillomatosis. Importance: Human papillomaviruses are pathogens that cause a host of diseases ranging from benign warts to cancers. There are no therapeutics available for combating these diseases that directly target viral proteins or processes, therefore we must enhance our understanding of HPV life cycles to assist with identifying novel treatments. In this report, we demonstrate that HPV16 and HPV11 E2 protein expression is dependent upon TopBP1 interaction in keratinocytes interacting with fibroblasts, which recapitulate stromal interactions in culture. The degradation of 16E2 promotes HPV16 genome integration, therefore the E2-TopBP1 interaction is critical during the viral life cycle. We demonstrate that the CK2 inhibitor CX4945 disrupts HPV11 interaction with TopBP1 and destabilizes HPV11 E2 protein in the presence of J2 fibroblasts; we propose that CX4945 could alleviate HPV11 disease burden.
Language	English
Publishing date	2023-01-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.11.523702
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Article: Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function.

Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Hill, Ronald D / Dubey, Aanchal / Wu, Shwu-Yuan / Chiang, Cheng-Ming / Morgan, Iain M

bioRxiv : the preprint server for biology

2023

Abstract: During the human papillomavirus 16 life cycle, the E2 protein binds simultaneously to the viral genome and host chromatin throughout mitosis, ensuring viral genomes reside in daughter cell nuclei following cell division. Previously, we demonstrated that ... ...

Abstract	During the human papillomavirus 16 life cycle, the E2 protein binds simultaneously to the viral genome and host chromatin throughout mitosis, ensuring viral genomes reside in daughter cell nuclei following cell division. Previously, we demonstrated that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1, and that this interaction is required for optimum E2 mitotic chromatin association and plasmid segregation function. Others have implicated BRD4 in mediating the plasmid segregation function of E2 and we have demonstrated that there is a TopBP1-BRD4 complex in the cell. We therefore further investigated the role of the E2-BRD4 interaction in mediating E2 association with mitotic chromatin and plasmid segregation function. Using a combination of immunofluorescence and our novel plasmid segregation assay in U2OS and N/Tert-1 cells stably expressing a variety of E2 mutants, we report that direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for E2 association with mitotic chromatin and plasmid segregation. We also identify a novel TopBP1 mediated interaction between E2 and the BRD4 extra-terminal (ET) domain Importance: HPV16 is a causative agent in around 3-4% of all human cancers and currently there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle.
Language	English
Publishing date	2023-05-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.25.542291
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Article ; Online: Human Papillomavirus 16 E2 Interaction with TopBP1 Is Required for E2 and Viral Genome Stability during the Viral Life Cycle.

Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Hill, Ronald D / Dubey, Aanchal / Morgan, Iain M

Journal of virology

2023 Volume 97, Issue 3, Page(s) e0006323

Abstract: CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here, we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during ...

Abstract	CK2 phosphorylation of HPV16 E2 at serine 23 promotes interaction with TopBP1, and this interaction is important for E2 plasmid segregation function. Here, we demonstrate that the E2-TopBP1 interaction is critical for E2 and viral genome stability during the viral life cycle. Introduction of the S23A mutation into the HPV16 genome results in a loss of E2 expression and viral genome integration during organotypic rafting. Coculture of N/Tert-1+E2-S23A cells with J2 fibroblasts results in E2-S23A degradation via the proteasome; wild-type E2 is not degraded. TopBP1 siRNA treatment of N/Tert-1+E2-WT cells results in E2 degradation only in the presence of J2 cells demonstrating the critical role for TopBP1 in maintaining E2 stability. The CK2 inhibitor CX4945 promotes E2-WT degradation in the presence of fibroblasts as it disrupts E2-TopBP1 interaction. siRNA targeting SIRT1 rescues E2-S23A stability in N/Tert-1 cells treated with J2 fibroblasts, with an increased E2-S23A acetylation. The results demonstrate that the E2-TopBP1 interaction is critical during the viral life cycle as it prevents fibroblast stimulated SIRT1 mediated deacetylation of E2 that promotes protein degradation. This means that the E2-TopBP1 complex maintains E2 and viral genome stability and that disruption of this complex can promote viral genome integration. Finally, we demonstrate that HPV11 E2 also interacts with TopBP1 and that this interaction is critical for HPV11 E2 stability in the presence of J2 cells. Treatment of N/Tert-1 + 11E2-WT cells with CX4945 results in 11E2 degradation. Therefore, CK2 inhibition is a therapeutic strategy for alleviating HPV11 diseases, including juvenile respiratory papillomatosis.
MeSH term(s)	Humans ; Carrier Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Genome, Viral ; Genomic Instability ; Human papillomavirus 16/metabolism ; Human Papillomavirus Viruses ; Nuclear Proteins/metabolism ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Sirtuin 1/metabolism
Chemical Substances	Carrier Proteins ; DNA-Binding Proteins ; Nuclear Proteins ; Oncogene Proteins, Viral ; Sirtuin 1 (EC 3.5.1.-) ; TOPBP1 protein, human ; E2 protein, Human papillomavirus type 16
Language	English
Publishing date	2023-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00063-23
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Article: Human Papillomavirus 16 replication converts SAMHD1 into a homologous recombination factor and promotes its recruitment to replicating viral DNA.

James, Claire D / Youssef, Aya / Prabhakar, Apurva T / Otoa, Raymonde / Witt, Austin / Lewis, Rachel L / Bristol, Molly L / Wang, Xu / Zhang, Kun / Li, Renfeng / Morgan, Iain M

bioRxiv : the preprint server for biology

2023

Abstract: We have demonstrated that SAMHD1 (sterile alpha motif and histidine-aspartic domain HD-containing protein 1) is a restriction factor for the HPV16 life cycle. Here we demonstrate that in HPV negative cervical cancer C33a cells and human foreskin ... ...

Abstract	We have demonstrated that SAMHD1 (sterile alpha motif and histidine-aspartic domain HD-containing protein 1) is a restriction factor for the HPV16 life cycle. Here we demonstrate that in HPV negative cervical cancer C33a cells and human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16), SAMHD1 is recruited to E1-E2 replicating DNA. Homologous recombination (HR) factors are required for HPV16 replication and viral replication promotes phosphorylation of SAMHD1, which converts it from a dNTPase to an HR factor independent from E6/E7 expression. A SAMHD1 phosphor-mimic (SAMHD1 T592D) reduces E1-E2 mediated DNA replication in C33a cells and has enhanced recruitment to the replicating DNA. In HFK+HPV16 cells SAMHD1 T592D is recruited to the viral DNA and attenuates cellular growth, but does not attenuate growth in isogenic HFK cells immortalized by E6/E7 alone. SAMHD1 T592D also attenuates the development of viral replication foci following keratinocyte differentiation. The results indicated that enhanced SAMHD1 phosphorylation could be therapeutically beneficial in cells with HPV16 replicating genomes. Protein phosphatase 2A (PP2A) can dephosphorylate SAMHD1 and PP2A function can be inhibited by endothall. We demonstrate that endothall reduces E1-E2 replication and promotes SAMHD1 recruitment to E1-E2 replicating DNA, mimicking the SAMHD1 T592D phenotypes. Finally, we demonstrate that in head and neck cancer cell lines with HPV16 episomal genomes endothall attenuates their growth and promotes recruitment of SAMHD1 to the viral genome. The results suggest that targeting cellular phosphatases has therapeutic potential for the treatment of HPV infections and cancers. Importance: Human papillomaviruses are causative agents in around 5% of all human cancers. The development of anti-viral therapeutics depends upon an increased understanding of the viral life cycle. Here we demonstrate that HPV16 replication converts SAMHD1 into an HR factor via phosphorylation. This phosphorylation promotes recruitment of SAMHD1 to viral DNA to assist with replication. A SAMHD1 mutant that mimics phosphorylation is hyper-recruited to viral DNA and attenuates viral replication. Expression of this mutant in HPV16 immortalized cells attenuates the growth of these cells, but not cells immortalized by the viral oncogenes E6/E7 alone. Finally, we demonstrate that the phosphatase inhibitor endothall promotes hyper-recruitment of endogenous SAMHD1 to HPV16 replicating DNA and can attenuate the growth of both HPV16 immortalized human foreskin keratinocytes and HPV16 positive head and neck cancer cell lines. We propose that phosphatase inhibitors represent a novel tool for combating HPV infections and disease.
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.13.566899
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Article ; Online: Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function.

Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Yeager, Calvin / Hill, Ronald D / Dubey, Aanchal / Wu, Shwu-Yuan / Chiang, Cheng-Ming / Morgan, Iain M

Journal of virology

2023 Volume 97, Issue 10, Page(s) e0078223

Abstract: Importance: Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must ...

Abstract	Importance: Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle.
MeSH term(s)	Humans ; Bromodomain Containing Proteins ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Chromatin/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Human papillomavirus 16/genetics ; Human papillomavirus 16/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Plasmids/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Bromodomain Containing Proteins ; Cell Cycle Proteins ; Chromatin ; DNA-Binding Proteins ; Nuclear Proteins ; Oncogene Proteins, Viral ; Transcription Factors ; E2 protein, Human papillomavirus type 16 ; TOPBP1 protein, human
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00782-23
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 609: Show issues

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Article ; Online: A Critical Role for p53 during the HPV16 Life Cycle.

Fontan, Christian T / James, Claire D / Prabhakar, Apurva T / Bristol, Molly L / Otoa, Raymonde / Wang, Xu / Karimi, Elmira / Rajagopalan, Pavithra / Basu, Devraj / Morgan, Iain M

Microbiology spectrum

2022 Volume 10, Issue 3, Page(s) e0068122

Abstract: Human papillomaviruses (HPV) are causative agents in ano-genital and oral cancers; HPV16 is the most prevalent type detected in human cancers. The HPV16 E6 protein targets p53 for proteasomal degradation to facilitate proliferation of the HPV16 infected ... ...

Abstract	Human papillomaviruses (HPV) are causative agents in ano-genital and oral cancers; HPV16 is the most prevalent type detected in human cancers. The HPV16 E6 protein targets p53 for proteasomal degradation to facilitate proliferation of the HPV16 infected cell. However, in HPV16 immortalized cells E6 is predominantly spliced (E6*) and unable to degrade p53. Here, we demonstrate that human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16), and HPV16 positive oropharyngeal cancers, retain significant expression of p53. In addition, p53 levels increase in HPV16+ head and neck cancer cell lines following treatment with cisplatin. Introduction of full-length E6 into HFK+HPV16 resulted in attenuation of cellular growth (in hTERT immortalized HFK, E6 expression promoted enhanced proliferation). An understudied interaction is that between E2 and p53 and we investigated whether this was important for the viral life cycle. We generated mutant genomes with E2 unable to interact with p53 resulting in profound phenotypes in primary HFK. The mutant induced hyper-proliferation, but an ultimate arrest of cell growth; β-galactosidase staining demonstrated increased senescence, and COMET assays showed increased DNA damage compared with HFK+HPV16 wild-type cells. There was failure of the viral life cycle in organotypic rafts with the mutant HFK resulting in premature differentiation and reduced proliferation. The results demonstrate that p53 expression is critical during the HPV16 life cycle, and that this may be due to a functional interaction between E2 and p53. Disruption of this interaction has antiviral potential.
MeSH term(s)	Animals ; Human papillomavirus 16/genetics ; Human papillomavirus 16/metabolism ; Humans ; Life Cycle Stages ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Papillomaviridae/genetics ; Papillomavirus Infections ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Oncogene Proteins, Viral ; Tumor Suppressor Protein p53
Language	English
Publishing date	2022-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.00681-22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription.

James, Claire D / Fontan, Christian T / Otoa, Raymonde / Das, Dipon / Prabhakar, Apurva T / Wang, Xu / Bristol, Molly L / Morgan, Iain M

mSphere

2020 Volume 5, Issue 1

Abstract: Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are ... ...

Abstract	Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently, we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells overexpressing the viral proteins, and to further investigate the role of individual viral proteins in this repression, we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually is not sufficient to repress IIG expression in the context of the entire HPV16 genome; both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in HPV16-positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies led us to the following model. Viral replication
MeSH term(s)	Cell Line, Tumor ; Female ; Genome, Viral ; Human papillomavirus 16/pathogenicity ; Humans ; Immunity, Innate/genetics ; Oncogene Proteins, Viral/immunology ; Papillomavirus E7 Proteins/immunology ; Repressor Proteins/genetics ; Repressor Proteins/immunology ; Transcription, Genetic ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/virology
Chemical Substances	E6 protein, Human papillomavirus type 16 ; Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; Repressor Proteins ; oncogene protein E7, Human papillomavirus type 16
Language	English
Publishing date	2020-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/mSphere.00828-19
Database	MEDical Literature Analysis and Retrieval System OnLINE

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