scholarly journals Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors

2006 ◽  
Vol 80 (21) ◽  
pp. 10802-10812 ◽  
Author(s):  
Patrick A. Carroll ◽  
Heidi L. Kenerson ◽  
Raymond S. Yeung ◽  
Michael Lagunoff
Keyword(s):  
Endothelial Cells ◽  
Kaposi's Sarcoma ◽  
Significant Proportion ◽  
Kaposi’S Sarcoma ◽  
Model Systems ◽  
Luciferase Reporter ◽  
Kshv Infection ◽  
Alpha Subunits ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is the etiological agent of Kaposi's sarcoma, a highly vascularized, endothelial-derived tumor. A direct role for KSHV-mediated induction of angiogenesis has been proposed based upon the nature of the neoplasia and various KSHV gene overexpression and infection model systems. We have found that KSHV infection of endothelial cells induces mRNA of hypoxia-induced factor 1α (HIF1α) and HIF2α, two homologous alpha subunits of the heterodimeric transcription factor HIF. HIF is a master regulator of both developmental and pathological angiogenesis, composed of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit. HIF is classically activated posttranscriptionally with hypoxia, leading to increased protein stability of HIF1α and/or HIF2α. However, we demonstrate that both alpha subunits are up-regulated at the transcript level by KSHV infection. The transcriptional activation of HIF leads to a functional increase in HIF activity under normoxic conditions, as demonstrated by both luciferase reporter assay and the increased expression of vascular endothelial growth factor receptor 1 (VEGFR1), an HIF-responsive gene. KSHV infection synergizes with hypoxia mimics and induces higher expression levels of HIF1α and HIF2α protein, and HIF1α is increased in a significant proportion of the latently infected endothelial cells. Src family kinases are required for the activation of HIF and the downstream gene VEGFR1 by KSHV. We also show that KS lesions, in vivo, express elevated levels of HIF1α and HIF2α proteins. Thus, KSHV stimulates the HIF pathway via transcriptional up-regulation of both HIF alphas, and this activation may play a role in KS formation, localization, and progression.

scholarly journals Kaposi’s Sarcoma-Associated Herpesvirus Viral Interleukin-6 Signaling Upregulates Integrin β3 Levels and Is Dependent on STAT3

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Ricardo Rivera-Soto ◽  
Nathan J. Dissinger ◽  
Blossom Damania
Keyword(s):  
Endothelial Cells ◽  
Interleukin 6 ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Αvβ3 Integrin ◽  
Kshv Infection ◽  
Integrin Β3 ◽  
Stat3 Signaling ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of two B-cell lymphoproliferative diseases and Kaposi’s sarcoma, an endothelial-cell-driven cancer. KSHV viral interleukin-6 (vIL-6) is a viral homolog of human IL-6 (hIL-6) that is expressed in KSHV-associated malignancies. Previous studies have shown that the expression of the integrin β3 (ITGB3) subunit is induced upon KSHV infection. Here we report that KSHV vIL-6 is able to induce the expression of ITGB3 and increase surface expression of the αVβ3 integrin heterodimer. We demonstrated using small interfering RNA (siRNA) depletion and inhibitor studies that KSHV vIL-6 can increase ITGB3 by inducing STAT3 signaling. Furthermore, we found that secreted vIL-6 is capable of inducing ITGB3 in endothelial cells in a paracrine manner. Importantly, the ability to induce ITGB3 in endothelial cells seems to be specific to vIL-6, as overexpression of hIL-6 alone did not affect levels of this integrin. Our lab and others have previously shown that vIL-6 can induce angiogenesis, and we investigated whether ITGB3 was involved in this process. We found that siRNA depletion of ITGB3 in vIL-6-expressing endothelial cells resulted in a decrease in adhesion to extracellular matrix proteins. Moreover, depletion of ITGB3 hindered the ability of vIL-6 to promote angiogenesis. In conclusion, we found that vIL-6 can singularly induce ITGB3 and that this induction is dependent on vIL-6 activation of the STAT3 signaling pathway. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies: multicentric Castleman’s disease, primary effusion lymphoma, and Kaposi’s sarcoma. Kaposi’s sarcoma is a highly angiogenic tumor that arises from endothelial cells. It has been previously reported that KSHV infection of endothelial cells leads to an increase of integrin αVβ3, a molecule observed to be involved in the angiogenic process of several malignancies. Our data demonstrate that the KSHV protein viral interleukin-6 (vIL-6) can induce integrin β3 in an intracellular and paracrine manner. Furthermore, we showed that this induction is necessary for vIL-6-mediated cell adhesion and angiogenesis, suggesting a potential role of integrin β3 in KSHV pathogenesis and development of Kaposi’s sarcoma.

scholarly journals Kaposi’s Sarcoma-Associated Herpesvirus Infection Induces the Expression of Neuroendocrine Genes in Endothelial Cells

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Mohanan Valiya Veettil ◽  
Gayathri Krishna ◽  
Arunava Roy ◽  
Anandita Ghosh ◽  
Dipanjan Dutta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Neuroendocrine Tumors ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Kshv Infection ◽  
Infected Cells ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically associated with endothelial Kaposi’s sarcoma (KS) in immunocompromised individuals. KS lesion cells exhibit many similarities to neuroendocrine (NE) cancers, such as highly vascular and red/purple tumor lesions, spindle-shaped cells, an insignificant role for classic oncogenes in tumor development, the release of bioactive amines, and indolent growth of the tumors. However, the mechanistic basis for the similarity of KS lesion endothelial cells to neuroendocrine tumors remains unknown. Next-generation sequencing and bioinformatics analysis in the present study demonstrate that endothelial cells latently infected with KSHV express several neuronal and NE genes. De novo infection of primary dermal endothelial cells with live and UV-inactivated KSHV demonstrated that viral gene expression is responsible for the upregulation of five selected NE genes (adrenomedullin 2 [ADM2], histamine receptor H1 [HRH1], neuron-specific enolase [NSE] [ENO2], neuronal protein gene product 9.5 [PGP9.5], and somatostatin receptor 1 [SSTR1]). Immunofluorescence and immunohistochemistry examinations demonstrated the robust expression of the NE genes HRH1 and NSE/ENO2 in KSHV-infected KS tissue samples and KS visceral tissue microarrays. Further analysis demonstrated that KSHV latent open reading frame K12 (ORFK12) gene (kaposin A)-mediated decreased host REST/NRSF (RE1-silencing transcription factor/neuron-restrictive silencer factor) protein, a neuronal gene transcription repressor protein, is responsible for NE gene expression in infected endothelial cells. The NE gene expression observed in KSHV-infected cells was recapitulated in uninfected endothelial cells by the exogenous expression of ORFK12 and by the treatment of cells with the REST inhibitor X5050. When the neuroactive ligand-activating receptor HRH1 and inhibitory SSTR1 were knocked out by CRISPR, HRH1 knockout (KO) significantly inhibited cell proliferation, while SSTR1 KO induced cell proliferation, thus suggesting that HRH1 and SSTR1 probably counteract each other in regulating KSHV-infected endothelial cell proliferation. These results demonstrate that the similarity of KS lesion cells to neuroendocrine tumors is probably a result of KSHV infection-induced transformation of nonneuronal endothelial cells into cells with neuroendocrine features. These studies suggest a potential role of neuroendocrine pathway genes in the pathobiological characteristics of KSHV-infected endothelial cells, including a potential mechanism of escape from the host immune system by the expression of immunologically privileged neuronal-site NE genes, and NE genes could potentially serve as markers for KSHV-infected KS lesion endothelial cells as well as novel therapeutic targets to control KS lesions. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) manipulates several cellular pathways for its survival advantage during its latency in the infected human host. Here, we demonstrate that KSHV infection upregulates the expression of genes related to neuronal and neuroendocrine (NE) functions that are characteristic of NE tumors, both in vitro and in KS patient tissues and the heterogeneity of neuroendocrine receptors having opposing roles in KSHV-infected cell proliferation. Induction of NE genes by KSHV could also provide a potential survival advantage, as the expression of proteins at immunologically privileged sites such as neurons on endothelial cells may be an avenue to escape host immune surveillance functions. The NE gene products identified here could serve as markers for KSHV-infected cells and could potentially serve as therapeutic targets to combat KSHV-associated KS.

scholarly journals Persistent Activation of STAT3 by Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells

2006 ◽  
Vol 81 (5) ◽  
pp. 2449-2458 ◽  
Author(s):  
Almira S. Punjabi ◽  
Patrick A. Carroll ◽  
Lei Chen ◽  
Michael Lagunoff
Keyword(s):  
Endothelial Cells ◽  
Tumor Cell ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Receptor Expression ◽  
Kshv Infection ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma, primary effusion lymphoma, and plasmablastic multicentric Castleman's disease. STAT3 has been shown to be important for the maintenance of primary effusion lymphoma cells in culture and is chronically activated in many tumor cell lines. However, little is known about the role of KSHV in the activation of STAT3 or the role of STAT3 in KS tumors. We demonstrate that STAT3 is activated by KSHV infection of endothelial cells, the KS tumor cell type, in a biphasic fashion. Viral binding and entry activate STAT3 in the first 2 h after infection, but this activation dissipates by 4 h postinfection. By 12 h after KSHV infection, concomitant with the expression of latent genes, STAT3 is once again activated, and this activation persists for as long as latent infection is maintained. Activated STAT3 translocates to the nucleus, where it can bind to STAT3-specific DNA elements and can activate STAT3-dependent promoter activity. Conditioned medium from KSHV-infected endothelial cells is able to transiently activate STAT3, indicating the involvement of a secreted factor and that a latency-associated factor in KSHV-infected cells is necessary for sustained activation. KSHV upregulates gp130 receptor expression, and both gp130 and JAK2 are required for the activation of STAT3. However, neither human nor viral interleukin-6 is required for STAT3 activation. Persistent activation of the oncogenic signal transducer, STAT3, by KSHV may play a critical role in the viral pathogenesis of Kaposi's sarcoma, as well as in primary effusion lymphomas.

scholarly journals Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

2015 ◽  
Vol 89 (18) ◽  
pp. 9262-9280 ◽  
Author(s):  
Fan Cheng ◽  
Tanvee Vinod Sawant ◽  
Ke Lan ◽  
Chun Lu ◽  
Jae U. Jung ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Primary Infection ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Kshv Infection ◽  
Cellular Pathways ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACTViruses often hijack cellular pathways to facilitate infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus etiologically associated with Kaposi's sarcoma, a vascular tumor of endothelial cells. Despite intensive studies, cellular pathways mediating KSHV infection and replication are still not well defined. Using an antibody array approach, we examined cellular proteins phosphorylated during primary KSHV infection of primary human umbilical vein endothelial cells. Enrichment analysis identified integrin/mitogen-activated protein kinase (integrin/MAPK), insulin/epidermal growth factor receptor (insulin/EGFR), and JAK/STAT as the activated networks during primary KSHV infection. The transcriptional factor CREB1 (cyclic AMP [cAMP]-responsive element-binding protein 1) had the strongest increase in phosphorylation. While knockdown of CREB1 had no effect on KSHV entry and trafficking, it drastically reduced the expression of lytic transcripts and proteins and the production of infectious virions. Chemical activation of CREB1 significantly enhanced viral lytic replication. In contrast, CREB1 neither influenced the expression of the latent gene LANA nor affected KSHV infectivity. Mechanistically, CREB1 was not activated through the classic cAMP/protein kinase A (cAMP/PKA) pathway or via the AKT, MK2, and RSK pathways. Rather, CREB1 was activated by the mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2). Consequently, chemical inhibition or knockdown of MSKs significantly inhibited the KSHV lytic replication program; however, it had a minimal effect on LANA expression and KSHV infectivity. Together, these results identify the MSK1/2-CREB1 proteins as novel essential effectors of KSHV lytic replication during primary infection. The differential effect of the MSK1/2-CREB1 pathway on the expression of viral latent and lytic genes might control the robustness of viral lytic replication, and therefore the KSHV replication program, during primary infection.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. Through genome-wide kinase screening, we found that KSHV activates the MSK1/2-CREB1 pathway during primary infection and that it depends on this pathway for viral lytic replication. Inhibition of this pathway blocks KSHV lytic replication. These results illustrate a mechanism by which KSHV hijacks a cellular pathway for its replication, and they identify a potential therapeutic target.

scholarly journals Immortalization of Primary Endothelial Cells by the K1 Protein of Kaposi's Sarcoma–Associated Herpesvirus

2006 ◽  
Vol 66 (7) ◽  
pp. 3658-3666 ◽  
Author(s):  
Ling Wang ◽  
Dirk P. Dittmer ◽  
Christine C. Tomlinson ◽  
Farnaz D. Fakhari ◽  
Blossom Damania
Keyword(s):  
Endothelial Cells ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Novel Cellular Genes Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma–Associated Herpesvirus

2005 ◽  
Vol 65 (12) ◽  
pp. 5084-5095 ◽  
Author(s):  
Camilo Raggo ◽  
Rebecca Ruhl ◽  
Shane McAllister ◽  
Henry Koon ◽  
Bruce J. Dezube ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Cellular Genes ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

The contribution of systems biology and reverse genetics to the understanding of Kaposi’s sarcoma-associated herpesvirus pathogenesis in endothelial cells

2009 ◽  
Vol 102 (12) ◽  
pp. 1117-1134 ◽  
Author(s):  
Andreas Konrad ◽  
Khaled Alkharsah ◽  
Ramona Jochmann ◽  
Mathias Thurau ◽  
Gaby Marquardt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Systems Biology ◽  
Kaposi's Sarcoma ◽  
Reverse Genetics ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Herpesvirus 8 ◽  
Cellular Physiology ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

SummaryKaposi’s sarcoma-associated herpesvirus (KSHV) / human herpesvirus-8 is the causative agent of the endothelial cell-derived tumour Kaposi’s sarcoma. Herpesviruses possess large complex genomes which provide many options to regulate cellular physiology during the viral life cycle and in the course of tumourigenicity. Novel techniques of systems biology and reverse genetics are increasingly applied to dissect the complex interaction of KSHV with endothelial cells. This review will outline novel results and pitfalls of these technologies in the elucidation of KSHV pathogenicity.

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