scholarly journals An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus

2006 ◽  
Vol 87 (4) ◽  
pp. 795-802 ◽  
Author(s):  
Adina Cohen ◽  
Chaya Brodie ◽  
Ronit Sarid
Keyword(s):  
Protein Kinase ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Mitogen Activated Protein Kinase ◽  
Potent Inducer ◽  
Erk Phosphorylation ◽  
Gf 109203X ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV) is implicated causally in the development of several human malignancies, including primary effusion lymphoma (PEL). PEL cells serve as tools for KSHV research, as most of them are latently infected and allow lytic virus replication in response to various stimuli. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is the most potent inducer of lytic KSHV reactivation; nevertheless, the exact mechanism by which it induces reactivation remains unknown. It has previously been reported by our group that the protein kinase C (PKC) δ isoform plays a crucial role in TPA-mediated KSHV reactivation. Here, the activation pathway was dissected and it was demonstrated that TPA induces KSHV reactivation via stimulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Western blot analysis revealed a rapid phosphorylation of ERK1/2. Cells treated with MAPK/ERK inhibitors before TPA addition demonstrated repression of ERK1/2 phosphorylation, which was associated with a block of KSHV lytic-gene expression. This inhibition prevented c-Fos accumulation, yet increased c-Jun phosphorylation. Similar results were obtained in response to rottlerin, a selective PKCδ inhibitor. Notably, the PKC inhibitor GF 109203X reduced ERK1/2 phosphorylation, c-Fos accumulation, c-Jun phosphorylation and KSHV reactivation. It is proposed that TPA induces KSHV reactivation through at least two arms. The first involves PKCδ, ERK phosphorylation and c-Fos accumulation, whilst the second requires another PKC isoform that induces the phosphorylation of c-Jun. c-Fos and c-Jun jointly form an active AP-1 complex, which functions to activate the lytic cascade of KSHV.

scholarly journals The Kaposi's Sarcoma-Associated Herpesvirus LANA Protein Stabilizes and Activates c-Myc

2007 ◽  
Vol 81 (19) ◽  
pp. 10451-10459 ◽  
Author(s):  
Jianyong Liu ◽  
Heather J. Martin ◽  
Gangling Liao ◽  
S. Diane Hayward
Keyword(s):  
Cell Cycle ◽  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
Glycogen Synthase ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Erk Phosphorylation ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) protein is functionally pleiotropic. LANA contributes to KSHV-associated pathogenesis, in part, by increasing entry of cells into S phase through a process that is driven by LANA interaction with the serine-threonine kinase glycogen synthase kinase 3 (GSK-3) and stabilization of β-catenin. We now show that LANA affects the activity of another protein involved in cell cycle regulation, c-Myc. Sequencing of c-Myc coding sequences revealed that c-Myc in KSHV-positive primary effusion lymphoma (PEL) cell lines is wild type in the N-terminal region that regulates c-Myc protein stability. Despite this, c-Myc in PEL cells is stabilized. In LANA-expressing cells, inactivation of nuclear GSK-3 reduced phosphorylation of c-Myc at Thr58 and contributed to c-Myc stabilization by decreasing c-Myc ubiquitination. Phosphorylation of c-Myc on Ser62 also affects c-Myc stability and function. We now show that LANA increases the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) and increases ERK phosphorylation of c-Myc on Ser62. LANA also interacted with c-Myc, and c-Myc amino acids 147 to 220 were required for this interaction. LANA (L1006P) retained the ability to bind to c-Myc and activate ERK1, indicating that these events did not require LANA interaction with GSK-3. Thus, LANA stabilizes c-Myc; prevents the phosphorylation of c-Myc at Thr58, an event that promotes Myc-induced apoptosis; and independently stimulates phosphorylation of c-Myc at Ser62, an event that transcriptionally activates c-Myc. LANA-mediated manipulation of c-Myc function is likely to contribute to KSHV-associated tumorigenesis through the induction of c-Myc regulated cellular genes, as well as by the stimulation of cell cycle progression.

scholarly journals Signaling Cascades Triggered by Bacterial Metabolic End Products during Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

2007 ◽  
Vol 81 (11) ◽  
pp. 6032-6042 ◽  
Author(s):  
T. L. Morris ◽  
R. R. Arnold ◽  
J. Webster-Cyriaque
Keyword(s):  
Protein Kinase ◽  
Kaposi's Sarcoma ◽  
Mapk Pathway ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Viral Reactivation ◽  
Mitogen Activated Protein Kinase ◽  
End Products ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The present studies explore the role of polymicrobial infection in the reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) and analyze signaling pathways activated upon this induction. We hypothesized that activation of the cellular stress-activated mitogen-activated protein kinase (MAPK) p38 pathway would play a key role in the bacterium-mediated disruption of viral latency similar to that of previously reported results obtained with other inducers of gammaherpesvirus lytic replication. KSHV within infected BCBL-1 cells was induced to replicate following exposure to metabolic end products from gram-negative or -positive bacteria that were then simultaneously exposed to specific inhibitors of signal transduction pathways. We have determined that bacterium-mediated induction of lytic KSHV infection is significantly reduced by the inhibition of the p38 MAPK pathway. In contrast, inhibition of the phosphatidylinositol 3-kinase pathway did not impair induction of lytic replication or p38 phosphorylation. Protein kinase C, though activated, was not the major pathway used for bacterium-induced viral reactivation. Furthermore, hyperacetylation of histones 3 and 4 was detected. Collectively, our results show that metabolic end products from these pathogens induce lytic replication of KSHV in BCBL-1 cells primarily via the activation of a stress-activated MAPK pathway. Importantly, we demonstrate for the first time a mechanism by which polymicrobial bacterial infections result in KSHV reactivation and pathogenesis.

scholarly journals Role of Protein Kinase C δ in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

2004 ◽  
Vol 78 (18) ◽  
pp. 10187-10192 ◽  
Author(s):  
Einat Deutsch ◽  
Adina Cohen ◽  
Gila Kazimirsky ◽  
Sara Dovrat ◽  
Hadara Rubinfeld ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Dominant Negative ◽  
Virus Reactivation ◽  
Kinase C ◽  
Gf 109203X ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT TPA (12-O-tetradecanoylphorbol-13-acetate), a well-known activator of protein kinase C (PKC), can experimentally induce reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) in certain latently infected cells. We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA. Translocation of the PKCδ isoform was evident shortly after TPA stimulation. Overexpression of the dominant-negative PKCδ mutant supported an essential role for the PKCδ isoform in virus reactivation, yet overexpression of PKCδ alone was not sufficient to induce lytic reactivation of KSHV, suggesting that additional signaling molecules participate in this pathway.

scholarly journals Lytic Replication-Defective Kaposi's Sarcoma-Associated Herpesvirus: Potential Role in Infection and Malignant Transformation

2004 ◽  
Vol 78 (20) ◽  
pp. 11108-11120 ◽  
Author(s):  
Jian-Hong Deng ◽  
Yan-Jin Zhang ◽  
Xin-Ping Wang ◽  
Shou-Jiang Gao
Keyword(s):  
Malignant Transformation ◽  
Cell Lines ◽  
Kaposi's Sarcoma ◽  
Potential Role ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Screening Methods ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Defective viruses often have pivotal roles in virus-induced diseases. Although Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), defective KSHV has not been reported. Using differential genetic screening methods, we show that defective KSHV is present in KS tumors and PEL cell lines. To investigate the role of defective viruses in KSHV-induced pathogenesis, we isolated and characterized a lytic replication-defective KSHV, KV-1, containing an 82-kb genomic deletion of solely lytic genes. Cells harboring KV-1 escaped G0/G1 apoptosis induced by spontaneous lytic replication occurred in cells infected with regular KSHV but maintained efficient latent replication. Consequently, KV-1-infected cells had phenotypes of enhanced cell proliferation and transformation potentials. Importantly, KV-1 was packaged as infectious virions by using regular KSHV as helpers, and KV-1-like variants were detected in cultures of two of five KSHV cell lines and 1 of 18 KS tumors. These results point to a potential role for defective viruses in the regulation of KSHV infection and malignant transformation.

scholarly journals Mechanism of Angiopoietin-1 Upregulation in Kaposi's Sarcoma-Associated Herpesvirus-Infected PEL Cell Lines

2015 ◽  
Vol 89 (9) ◽  
pp. 4786-4797 ◽  
Author(s):  
Xin Zheng ◽  
Eriko Ohsaki ◽  
Keiji Ueda
Keyword(s):  
Cell Lines ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Regulatory Region ◽  
Leukemia Cell ◽  
Kaposi’S Sarcoma ◽  
Dependent Manner ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Angiopoietin 1

ABSTRACTAngiopoietin-1 (ANGPT-1) is a secreted glycoprotein that was first characterized as a ligand of the Tie2 receptor. In a previous study using microarray analysis, we found that the expression of ANGPT-1 was upregulated in Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cell lines compared with that in uninfected Burkitt and other leukemia cell lines. Other authors have also reported focal expression of ANGPT-1 mRNA in biopsy specimens of Kaposi's sarcoma (KS) tissue from patients with AIDS. Here, to confirm these findings, we examined the expression and secretion levels of ANGPT-1 in KSHV-infected PEL cell lines and address the mechanisms ofANGPT-1transcriptional regulation. We also showed that ANGPT-1 was expressed and localized in the cytoplasm and secreted into the supernatant of KSHV-infected PEL cells. Deletion studies of the regulatory region revealed that the region encompassing nucleotides −143 to −125 of theANGPT-1-regulating sequence was responsible for this upregulation. Moreover, an electrophoretic mobility shift assay and chromatin immunoprecipitation, followed by quantitative PCR, suggested that some KSHV-infected PEL cell line-specific DNA-binding factors, such as OCT-1, should be involved in the upregulation ofANGPT-1in a sequence-dependent manner.IMPORTANCEWe confirmed that ANGPT-1 was expressed in and secreted from KSHV-infected PEL cells and that the transcriptional activity ofANGPT-1was upregulated. A 19-bp fragment was identified as the region responsible forANGPT-1upregulation through binding with OCT-1 as a core factor in PEL cells. This study suggests that ANGPT-1 is overproduced in KSHV-infected PEL cells, which could affect the pathophysiology of AIDS patients with PEL.

scholarly journals Identification and Characterization of the Orf49 Protein of Kaposi's Sarcoma-Associated Herpesvirus

2006 ◽  
Vol 80 (6) ◽  
pp. 3062-3070 ◽  
Author(s):  
Carlos M. González ◽  
Emily L. Wong ◽  
Brian S. Bowser ◽  
Gregory K. Hong ◽  
Shannon Kenney ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activation ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Cycle ◽  
Transcription Activator ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Factor C ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Kaposi's sarcoma is the most common neoplasm among human immunodeficiency virus-positive individuals. Like other herpesviruses, KSHV is able to establish a predominantly latent, life-long infection in its host. The KSHV lytic cycle can be triggered by a number of stimuli that induce the expression of the key lytic switch protein, the replication and transcription activator (RTA) encoded by Orf50. The expression of Rta is necessary and sufficient to trigger the full lytic program resulting in the ordered expression of viral proteins, release of viral progeny, and host cell death. We have characterized an unknown open reading frame, Orf49, which lies adjacent and in the opposite orientation to Orf50. Orf49 is expressed during the KSHV lytic cycle and shows early transcription kinetics. We have mapped the 5′ and 3′ ends of the unspliced Orf49 transcript, which encodes a 30-kDa protein that is localized to both the nucleus and the cytoplasm. Interestingly, we found that Orf49 was able to cooperate with Rta to activate several KSHV lytic promoters containing AP-1 sites. The Orf49-encoded protein was also able to induce transcriptional activation through c-Jun but not the ATF1, ATF2, or CREB transcription factor. We found that Orf49 could induce phosphorylation and activation of the transcription factor c-Jun, the Jun N-terminal kinase (JNK), and p38. Our data suggest that Orf49 functions to activate the JNK and p38 pathways during the KSHV lytic cycle.

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