B Lymphocytes from Patients with a Hypomorphic Mutation in<i>STAT3</i>Resist Epstein-Barr Virus-Driven Cell Proliferation

Koganti, Siva; Paz, Amanda de la; Freeman, Alexandra F.; Bhaduri‐McIntosh, Sumita

doi:10.1128/jvi.02601-13

Cited by 30 publications

(42 citation statements)

References 47 publications

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“…1 B and C). This increase in infected, foci-positive AD-HIES nuclei relative to healthy subject-derived nuclei agreed with our earlier observation that EBV-infected AD-HIES-derived B cells accumulate in the S phase and likely do not undergo transformation (19). Of note, although an increase in RPA protein (Fig.…”

Section: Resultssupporting

confidence: 79%

“…We previously reported that an early event such as EBV-binding or internalization results in activation and increased expression of cellular STAT3 in primary B lymphocytes. STAT3 then critically contributes to cell proliferation and transformation by promoting cell survival and relaxing the intra-S phase cell-cycle checkpoint (19). We now find that STAT3 contributes to intra-S phase checkpoint relaxation by suppressing signaling downstream of the critical S phase kinase ATR despite detection of replication stress-associated DNA damage that results from EBV infection.…”

Section: Significancementioning

confidence: 62%

“…Third, in key experiments, we also used siRNA to STAT3 to control for potential STAT3-unrelated variations among patients. Because apoptosis and intra-S phase arrest of EBV-infected STAT3-deficient B cells (19) is consistent with EBV oncogene-driven replication stress (3,21), we examined the effect of EBV infection on replication protein A (RPA) and ataxia telangiectasia and Rad3 related (ATR) proteins. Typically, RPA is recruited to single-stranded stretches of DNA in response to replication stress; this results in recruitment and activation of ATR (4).…”

Section: Resultsmentioning

confidence: 99%

“…To address how EBV-mediated early activation and increase in STAT3 may contribute to relaxation of the intra-S phase checkpoint, we used three complementary approaches. First, AG490, a JAK inhibitor was included during EBV infection to impair STAT3 activation, and thereby secondarily suppress STAT3 mRNA and protein levels (19,20). Second, to safeguard against potential off-target effects of AG490, primary B cells from patients with AD-HIES were infected with EBV.…”

Section: Resultsmentioning

confidence: 99%

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STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation

Koganti

Hui-Yuen

McAllister

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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DNA damage response (DDR) is a signaling network that senses DNA damage and activates response pathways to coordinate cellcycle progression and DNA repair. Thus, DDR is critical for maintenance of genome stability, and presents a powerful defense against tumorigenesis. Therefore, to drive cell-proliferation and transformation, viral and cellular oncogenes need to circumvent DDRinduced cell-cycle checkpoints. Unlike in hereditary cancers, mechanisms that attenuate DDR and disrupt cell-cycle checkpoints in sporadic cancers are not well understood. Using Epstein-Barr virus (EBV) as a source of oncogenes, we have previously shown that EBV-driven cell proliferation requires the cellular transcription factor STAT3. EBV infection is rapidly followed by activation and increased expression of STAT3, which mediates relaxation of the intra-S phase cell-cycle checkpoint; this facilitates viral oncogene-driven cell proliferation. We now show that replication stress-associated DNA damage, which results from EBV infection, is detected by DDR. However, signaling downstream of ATR is impaired by STAT3, leading to relaxation of the intra-S phase checkpoint. We find that STAT3 interrupts ATR-to-Chk1 signaling by promoting loss of Claspin, a protein that assists ATR to phosphorylate Chk1. This loss of Claspin which ultimately facilitates cell proliferation is mediated by caspase 7, a protein that typically promotes cell death. Our findings demonstrate how STAT3, which is constitutively active in many human cancers, suppresses DDR, fundamental to tumorigenesis. This newly recognized role for STAT3 in attenuation of DDR, discovered in the context of EBV infection, is of broad interest as the biology of cell proliferation is central to both health and disease.autosomal dominant hyper-IgE syndrome | infectious mononucleosis | latent membrane protein 1 | Epstein-Barr nuclear antigen

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Section: Resultssupporting

confidence: 79%

Section: Significancementioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation

Koganti

Hui-Yuen

McAllister

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This study and our earlier studies demonstrate that, in addition to phosphorylation and dimerization of STAT3, modulation of the protein level of STAT3 also regulates its function (22,30,(37)(38)(39). Our data also indicate that STAT3 functions at least partly by repressing the immediate-early gene product RTA, the key latency-to-lytic-phase viral switch.…”

Section: Discussionsupporting

confidence: 59%

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

King

Barbachano-Guerrero

et al. 2015

J Virol

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Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phasedirected therapies for herpesviruses. IMPORTANCELytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses, however, a substantial fraction of latently infected cells are resistant to lytic-phase-inducing stimuli. Investigating the molecular basis for this refractory state is essential for understanding how the virus persists and how it causes disease and to guide efforts to improve treatment of KSHV-mediated diseases. We found that, like two other herpesviruses, EBV and HSV-1, KSHV exploits the cellular transcription factor STAT3 to regulate the susceptibility of latently infected cells to lytic triggers. These findings highlight a common STAT3-centered strategy used by herpesviruses to maintain persistence in their hosts while also revealing a key molecule to pursue while devising methods to improve herpesvirus lytic-phase-directed therapies.T he oncogenic human gammaherpesvirus human herpesvirus 8 (HHV-8), widely known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of three human malignancies: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). Like other herpesviruses, KSHV exhi...

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Viruses in colorectal cancer

Marongiu

Allgayer

2021

Molecular Oncology

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Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

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B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation

Cited by 30 publications

References 47 publications

STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation

STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

Viruses in colorectal cancer

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