scholarly journals Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1015
Author(s):  
Wing-Hang Ip ◽  
Britta Wilkens ◽  
Anastasia Solomatina ◽  
Judith Martin ◽  
Michael Melling ◽  
...  
Keyword(s):  
Viral Replication ◽  
Defense Mechanisms ◽  
Cell Transformation ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Transcription Unit ◽  
Antiviral Immune Response ◽  
Cell Defense ◽  
Cellular Factors ◽  
Cellular Components

The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell transformation. In this context, HAdV-C5-mediated dysregulations of cellular factors such as the tumor suppressors p53 and pRB have been intensively investigated. However, cellular components of downstream events that could affect infection and viral transformation are widely unknown. We recently observed that cellular FAM111B is highly regulated in an E1A-dependent fashion. Intriguingly, previous reports suggest that FAM111B might play roles in tumorigenesis, but its exact functions are not known to date. Here, we set out to investigate the role of FAM111B in HAdV-C5 infections. We found that (i) FAM111B levels are upregulated early and downregulated late during infection, that (ii) FAM111B expression is differentially regulated, that (iii) FAM111B expression levels depend on the presence of E1B-55K and E4orf6 and that (iv) a FAM111B knockdown increases HAdV-C5 replication. Our data indicate that FAM111B acts as an anti-adenoviral host factor that is involved in host cell defense mechanisms in productive HAdV-C5 infection. Moreover, these findings suggest that FAM111B might play an important role in the host antiviral immune response that is counteracted by HAdV-C5 E1B-55K and E4orf6 oncoproteins.

scholarly journals Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6062
Author(s):  
Margarita Neganova ◽  
Junqi Liu ◽  
Yulia Aleksandrova ◽  
Sergey Klochkov ◽  
Ruitai Fan
Keyword(s):  
Oxidative Stress ◽  
Chronic Inflammation ◽  
Defense Mechanisms ◽  
Cell Transformation ◽  
Oncogenic Signaling ◽  
Predisposing Factor ◽  
Tumor Spread ◽  
Chronic Inflammatory Response ◽  
Cell Defense ◽  
And Oxidative Stress

Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.

scholarly journals Evidence That the Adenovirus Single-Stranded DNA Binding Protein Mediates the Assembly of Biomolecular Condensates to Form Viral Replication Compartments

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1778
Author(s):  
Paloma Hidalgo ◽  
Arturo Pimentel ◽  
Diana Mojica-Santamaría ◽  
Konstantin von Stromberg ◽  
Helga Hofmann-Sieber ◽  
...  
Keyword(s):  
Viral Replication ◽  
Defense Mechanisms ◽  
Binding Protein ◽  
Human Adenovirus ◽  
Time Lapse ◽  
Low Complexity ◽  
Ssdna Binding ◽  
Intrinsically Disordered ◽  
Ssdna Binding Protein ◽  
Infected Cells

A common viral replication strategy is characterized by the assembly of intracellular compartments that concentrate factors needed for viral replication and simultaneously conceal the viral genome from host-defense mechanisms. Recently, various membrane-less virus-induced compartments and cellular organelles have been shown to represent biomolecular condensates (BMCs) that assemble through liquid-liquid phase separation (LLPS). In the present work, we analyze biophysical properties of intranuclear replication compartments (RCs) induced during human adenovirus (HAdV) infection. The viral ssDNA-binding protein (DBP) is a major component of RCs that contains intrinsically disordered and low complexity proline-rich regions, features shared with proteins that drive phase transitions. Using fluorescence recovery after photobleaching (FRAP) and time-lapse studies in living HAdV-infected cells, we show that DBP-positive RCs display properties of liquid BMCs, which can fuse and divide, and eventually form an intranuclear mesh with less fluid-like features. Moreover, the transient expression of DBP recapitulates the assembly and liquid-like properties of RCs in HAdV-infected cells. These results are of relevance as they indicate that DBP may be a scaffold protein for the assembly of HAdV-RCs and should contribute to future studies on the role of BMCs in virus-host cell interactions.

scholarly journals Early Region 1 Transforming Functions Are Dispensable for Mammary Tumorigenesis by Human Adenovirus Type 9

1999 ◽  
Vol 73 (4) ◽  
pp. 3071-3079 ◽  
Author(s):  
Darby L. Thomas ◽  
Sook Shin ◽  
Bernard H. Jiang ◽  
Hannes Vogel ◽  
Margery A. Ross ◽  
...  
Keyword(s):  
Mammary Tumorigenesis ◽  
Human Adenovirus ◽  
Mammary Tumors ◽  
Adenovirus Type ◽  
Transcription Unit ◽  
Gene Organization ◽  
Female Rats ◽  
Human Adenoviruses ◽  
Early Region ◽  
E4 Region

ABSTRACT Some human adenoviruses are tumorigenic in rodents. Subgroup A and B human adenoviruses generally induce sarcomas in both male and female animals, and the gene products encoded within viral early region 1 (E1 region) are both necessary and sufficient for this tumorigenicity. In contrast, subgroup D human adenovirus type 9 (Ad9) induces estrogen-dependent mammary tumors in female rats and requires the E4 region-encoded ORF1 oncoprotein for its tumorigenicity. Considering the established importance of the viral E1 region for tumorigenesis by adenoviruses, we investigated whether this viral transcription unit is also necessary for Ad9 to generate mammary tumors. The nucleotide sequence of the Ad9 E1 region indicated that the gene organization and predicted E1A and E1B polypeptides of Ad9 are closely related to those of other human adenovirus E1 regions. In addition, an Ad9 E1 region plasmid demonstrated focus-forming activity in both low-passage-number and established rat embryo fibroblasts, whereas a large deletion within either the E1A or E1B gene of this plasmid diminished transforming activity. Surprisingly, we found that introducing the same transformation-inactivating E1A and E1B deletions into Ad9 results in mutant viruses that retain the ability to elicit mammary tumors in rats. These results are novel in showing that Ad9 represents a unique oncogenic adenovirus in which the E4 region, rather than the E1 region, encodes the major oncogenic determinant in the rat.

Synthesis and in vitro Study of Antiviral and Virucidal Activity of Novel 2-[(4-Methyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetamide Derivatives

2011 ◽  
Vol 66 (7-8) ◽  
pp. 333-339
Author(s):  
Monika Wujec ◽  
Tomasz Plech ◽  
Agata Siwek ◽  
Barbara Rajtar ◽  
Małgorzata Polz-Dacewicz
Keyword(s):  
Viral Replication ◽  
Elemental Analysis ◽  
In Vitro Study ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Virucidal Activity ◽  
Hek 293 ◽  
H Nmr ◽  
Adenovirus Type 5

2-[(4-Methyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetamide derivatives were synthesized and their structures were confirmed by 1H NMR, IR, and elemental analysis. Cytotoxicity of the compounds towards HEK-293 and GMK cells was evaluated. Moreover, the antiviral and virucidal activities of these compounds against human adenovirus type 5 and ECHO-9 virus were assessed. Some of the newly synthesized derivatives have the potential to reduce the viral replication of both tested viruses.

scholarly journals Localization and Importance of the Adenovirus E4orf4 Protein during Lytic Infection

2008 ◽  
Vol 83 (4) ◽  
pp. 1689-1699 ◽  
Author(s):  
Marie-Joëlle Miron ◽  
Paola Blanchette ◽  
Peter Groitl ◽  
Frederic Dallaire ◽  
Jose G. Teodoro ◽  
...  
Keyword(s):  
Viral Replication ◽  
Fluorescent Protein ◽  
Point Mutations ◽  
Human Tumor ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Airway Epithelial Cells ◽  
Viral Mrnas ◽  
Virus Growth ◽  
Virus Mutant

ABSTRACT The human adenovirus type 5 (Ad5) E4orf4 product has been studied extensively although in most cases as expressed from vectors in the absence of other viral products. Thus, relatively little is known about its role in the context of an adenovirus infection. Although considerable earlier work had indicated that the E4orf4 protein is not essential for replication, a recent study using dl359, an Ad5 mutant believed to produce a nonfunctional E4orf4 protein, suggested that E4orf4 is essential for virus growth in primary small-airway epithelial cells (C. O'Shea, et al., EMBO J. 24:1211-1221, 2005). Hence, to examine further the role of E4orf4 during virus infection, we generated for the first time a set of E4orf4 virus mutants in a common Ad5 genetic background. Such mutant viruses included those that express E4orf4 proteins containing various individual point mutations, those defective entirely in E4orf4 expression, and a mutant expressing wild-type E4orf4 fused to the green fluorescent protein. E4orf4 protein was found to localize primarily in nuclear structures shown to be viral replication centers, in nucleoli, and in perinuclear bodies. Importantly, E4orf4 was shown not to be essential for virus growth in either human tumor or primary cells, at least in tissue culture. Unlike E4orf4-null virus, mutant dl359 appeared to exhibit a gain-of-function phenotype that impairs virus growth. The dl359 E4orf4 protein, which contains a large in-frame internal deletion, clustered in aggregates enriched in Hsp70 and proteasome components. In addition, the late viral mRNAs produced by dl359 accumulated abnormally in a nuclear punctate pattern. Altogether, our results indicate that E4orf4 protein is not essential for virus growth in culture and that expression of the dl359 E4orf4 product interferes with viral replication, presumably through interactions with structures in the nucleus.

scholarly journals Requirement of Sur2 for Efficient Replication of Mouse Adenovirus Type 1

2004 ◽  
Vol 78 (23) ◽  
pp. 12888-12900 ◽  
Author(s):  
Lei Fang ◽  
Jennitte L. Stevens ◽  
Arnold J. Berk ◽  
Katherine R. Spindler
Keyword(s):  
Viral Replication ◽  
Virulence Gene ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Early Gene ◽  
Mediator Complex ◽  
Growth Defect ◽  
Mrna Levels ◽  
Adenovirus E1a

ABSTRACT Mouse adenovirus type 1 (MAV-1) early region 1A (E1A) encodes a virulence gene in viral infection of mice. To broaden our understanding of the functions of E1A in MAV-1 pathogenesis, an unbiased experimental approach, glutathione S-transferase (GST) pulldown, was used to screen for cellular proteins that interact with E1A protein. We identified mouse Sur2, a subunit of Mediator complex, as a protein that binds to MAV-1 E1A. The interaction between Sur2 and MAV-1 E1A was confirmed in virus-infected cells. Conserved region 3 (CR3) of MAV-1 E1A was mapped as the region required for Sur2-E1A interaction, as is the case for human adenovirus E1A. Although it has been proposed that human adenovirus E1A recruits the Mediator complex to transactivate transcription of viral early genes, Sur2 function in adenovirus replication has not been directly tested previously. Studies on the functions of Sur2 with mouse embryonic fibroblasts (MEFs) showed that there was a multiplicity-dependent growth defect of MAV-1 in Sur2−/− MEFs compared to Sur2+/+ MEFs. Comparison of the viral DNA and viral mRNA levels in Sur2+/+ and Sur2−/− MEFs confirmed that Sur2 was important for efficient viral replication. The viral replication defects in Sur2−/− MEFs appeared to be due at least in part to a defect in viral early gene transcription.

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