scholarly journals Latent Nuclear Antigen of Kaposi’s Sarcoma-Associated Herpesvirus Interacts with RING3, a Homolog of theDrosophila Female Sterile Homeotic (fsh) Gene

1999 ◽  
Vol 73 (12) ◽  
pp. 9789-9795 ◽  
Author(s):  
Georgina M. Platt ◽  
Guy R. Simpson ◽  
Sibylle Mittnacht ◽  
Thomas F. Schulz
Keyword(s):  
Protein Interactions ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Latently Infected ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Carboxy Terminal ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Latent Nuclear Antigen

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) is the likely infectious cause of Kaposi’s sarcoma, primary effusion lymphoma, and some cases of multicentric Castleman’s disease. Its latent nuclear antigen (LANA) is expressed in the nuclei of latently infected cells and may play a role in the persistence of episomal viral DNA in dividing cells. Here we report that LANA interacts with RING3, a nuclear protein and member of the Drosophila fsh (female sterile homeotic) family of proteins, some of which have previously been implicated in controlling gene expression. Binding of RING3 to LANA involves the ET domain, characteristic of fsh-related proteins, suggesting that this highly conserved region is involved in protein-protein interactions. The interaction between RING3 and LANA results in phosphorylation of serine and threonine residues located between amino acids 951 and 1107 in the carboxy-terminal region of LANA. However, RING3 is not itself a kinase but appears to recruit an as yet unidentified serine/threonine protein kinase into the complex which it forms with LANA.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Inhibits Interleukin-4-Mediated STAT6 Phosphorylation To Regulate Apoptosis and Maintain Latency

2010 ◽  
Vol 84 (21) ◽  
pp. 11134-11144 ◽  
Author(s):  
Qiliang Cai ◽  
Subhash C. Verma ◽  
Ji-Young Choi ◽  
Michelle Ma ◽  
Erle S. Robertson
Keyword(s):  
Immune Response ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Cellular Growth ◽  
Interleukin 4 ◽  
Nuclear Antigen ◽  
Viral Agent ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Cytokine-mediated JAK/STAT signaling controls numerous important biologic responses like immune function, cellular growth, and differentiation. Inappropriate activation of this signaling pathway is associated with a range of malignancies. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious viral agent associated with Kaposi's sarcoma and may also contribute to B-cell disorders, which include primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, regulation of cytokine-mediated lymphocytic immune response by KSHV is not fully understood. In this report, we demonstrate that KSHV suppresses the interleukin-4 (IL-4)-stimulated immune response of B-lymphocyte activation and cell proliferation. Moreover, we show that the latency-associated nuclear antigen (LANA) encoded by KSHV is essential for viral blocking of IL-4-induced signaling. LANA reduces phosphorylation of the signal transducers and activators of transcription 6 (STAT6) on Y-641 and concomitantly its DNA binding ability. Importantly, knockdown of endogenous STAT6 dramatically increases the sensitivity of PEL cells to low-serum stress or chemical-mediated cellular apoptosis and reactivation of KSHV from latent replication. Thus, these findings suggest that the IL-4/STAT6 signaling network is precisely controlled by KSHV for survival, maintenance of latency, and suppression of the host cytokine immune response of the virus-infected cells.

scholarly journals Identification of a Novel Cellular Transcriptional Repressor Interacting with the Latent Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus

2003 ◽  
Vol 77 (18) ◽  
pp. 9758-9768 ◽  
Author(s):  
Hong-Yi Pan ◽  
Yan-Jin Zhang ◽  
Xin-Ping Wang ◽  
Jian-Hong Deng ◽  
Fu-Chun Zhou ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Kaposi's Sarcoma ◽  
Promoter Activity ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Northern Blot Hybridization ◽  
Nuclear Localization Signals ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Latent Nuclear Antigen

ABSTRACT The latent nuclear antigen (LNA) of Kaposi's sarcoma-associated herpesvirus (KSHV) has an essential role in viral latent infection. LNA maintains the stability of KSHV episomes and modulates the expression of cellular genes. A novel cellular protein KLIP1 was identified to interact with LNA through yeast two-hybrid screening, and confirmed by a glutathione S-transferase pull down assay. Domain mapping showed that KLIP1 interacted with the N-terminal domain of LNA. Northern blot hybridization with a KLIP1 probe identified a major transcript of 1.8 kb and a minor transcript of 2.8 kb. cDNA library screening and 5′-RACE revealed that the major transcript encoded an open-reading-frame of 1,257 bp and had a 5′-untranslated region of 73 nucleotides. The major KLIP1 transcript was ubiquitously present in different cell types examined. A KLIP1 synthetic peptide antibody detected a doublet of 58-kDa and 63-kDa proteins in a Western blot assay. KLIP1 had two putative nuclear localization signals and showed punctate nuclear localization when expressed as a GFP-fusion protein. KLIP1 interacted with LNA in vivo, as demonstrated by coimmunoprecipitation using KSHV-infected cells and colocalization when they were expressed as GFP- and DsRed-fusion proteins, respectively. Consistent with its interaction with LNA, nuclear localization, and possession of two leucine zipper motifs, KLIP1 behaved like a transcriptional factor and repressed herpes simplex virus thymidine kinase (TK) promoter activity in a mammalian one-hybrid assay. In addition, cotransfection with LNA alleviated the transcriptional repression effect of KLIP1 on TK promoter activity. These results suggest that KLIP1 is a new member of cellular transcriptional repressors, and that LNA is involved in deregulating cellular transcription process.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus LANA2 Is a B-Cell-Specific Latent Viral Protein That Inhibits p53

2001 ◽  
Vol 75 (1) ◽  
pp. 429-438 ◽  
Author(s):  
Carmen Rivas ◽  
Ai-En Thlick ◽  
Carlo Parravicini ◽  
Patrick S. Moore ◽  
Yuan Chang
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Blot Hybridization ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
P53 Overexpression ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is associated with three proliferative diseases ranging from viral cytokine-induced hyperplasia to monoclonal neoplasia: multicentric Castleman's disease (CD), Kaposi's sarcoma (KS), and primary effusion lymphoma (PEL). Here we report a new latency-associated 1,704-bp KSHV spliced gene belonging to a cluster of KSHV sequences having homology to the interferon regulatory factor (IRF) family of transcription factors. ORFK10.5 encodes a protein, latency-associated nuclear antigen 2 (LANA2), which is expressed in KSHV-infected hematopoietic tissues, including PEL and CD but not KS lesions. LANA2 is abundantly expressed in the nuclei of cultured KSHV-infected B cells. Transcription of K10.5 in PEL cell cultures is not inhibited by DNA polymerase inhibitors nor significantly induced by phorbol ester treatment. Unlike LANA1, LANA2 does not elicit a serologic response from patients with KS, PEL, or CD as measured by Western blot hybridization. Both KSHV vIRF1 (ORFK9) and LANA2 (ORFK10.5) appear to have arisen through gene duplication of a captured cellular IRF gene. LANA2 is a potent inhibitor of p53-induced transcription in reporter assays. LANA2 antagonizes apoptosis due to p53 overexpression in p53-null SAOS-2 cells and apoptosis due to doxorubicin treatment of wild-type p53 U2OS cells. While LANA2 specifically interacts with amino acids 290 to 393 of p53 in glutathione S-transferase pull-down assays, we were unable to demonstrate LANA2-p53 interaction in vivo by immunoprecipitation. These findings show that KSHV has tissue-specific latent gene expression programs and identify a new latent protein which may contribute to KSHV tumorigenesis in hematopoietic tissues via p53 inhibition.

scholarly journals A Cluster of Latently Expressed Genes in Kaposi’s Sarcoma-Associated Herpesvirus

1998 ◽  
Vol 72 (10) ◽  
pp. 8309-8315 ◽  
Author(s):  
Dirk Dittmer ◽  
Michael Lagunoff ◽  
Rolf Renne ◽  
Katherine Staskus ◽  
Ashley Haase ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Large Fraction ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Reading Frame ◽  
Viral Genomes ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Infection with Kaposi’s sarcoma-associated herpesvirus (KSHV) is closely associated with Kaposi’s sarcoma (KS) and primary effusion lymphoma, with viral genomes present in a latent state in the majority of tumor cells. Here we describe a cluster of latently expressed viral genes whose mRNAs are generated from a common promoter. Two mRNAs in this region encode the latency-associated nuclear antigen, the product of open reading frame 73 (ORF73). The larger RNA, of 5.8 kb, is an unspliced transcript that includes ORF72 and -71 at its 3′ end; it initiates at nucleotides (nt) 127880 to 127886 from a promoter lacking recognizable TATA elements. A less abundant mRNA, of 5.4 kb, is a variant of this transcript, in which 336 nt of 5′ noncoding information has been removed by RNA splicing. A third, more abundant RNA is generated from the same promoter region via splicing from the common splice donor at nt 127813 to an acceptor 5′ to ORF72; this transcript is the presumed mRNA for ORF72, which encodes the viral cyclin D homolog. All three RNAs are 3′ coterminal. In situ hybridization analysis with probes that can detect all three transcripts shows that the RNAs are detectable in a large fraction of BCBL-1 cells prior to lytic induction and in >70% of KS spindle cells in primary KS tumors. This confirms that these transcripts are indeed latent RNAs and suggests a role for their products in viral persistence and/or KSHV-associated proliferation.

scholarly journals DNA Binding and Modulation of Gene Expression by the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus

2001 ◽  
Vol 75 (17) ◽  
pp. 7882-7892 ◽  
Author(s):  
Alexander C. Garber ◽  
Marla A. Shu ◽  
Jianhong Hu ◽  
Rolf Renne
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Viral Gene ◽  
Mobility Shift ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The latency-associated nuclear antigen (LANA) is highly expressed in these malignancies and has been shown to play an important role in episomal maintenance, presumably by binding to a putative oriP. In addition, LANA modulates cellular and viral gene expression and interacts with the cellular tumor suppressors p53 and retinoblastoma suppressor protein. Many of these features are reminiscent of Epstein-Barr virus nuclear antigens (EBNAs), a family of six proteins expressed during latency. EBNA-1 is required for episome maintenance, binds to oriP, and strongly activates transcription from two promoters, including its own. We have previously shown that LANA can transactivate its own promoter and therefore asked whether LANA, like EBNA-1, activates transcription by direct binding to DNA. By using recombinant LANA expressed from vaccinia virus vectors for electrophoretic mobility shift assays, we found that LANA does not bind to its own promoter. In contrast, LANA binds specifically to sequences containing an imperfect 20-bp palindrome in the terminal repeat (TR) of KSHV. We further show that the C-terminal domain of LANA is sufficient for site-specific DNA binding. Unlike EBNA-1, which activates transcription through binding of oriP, we found that LANA inhibits transcription from a single TR binding site. A multimerized TR as found in the viral genome results in strong transcriptional suppression when linked to a heterologous promoter. These data suggest that LANA, although fulfilling functions similar to those of EBNA-1, does so by very different mechanisms.

scholarly journals A Domain in the C-Terminal Region of Latency-Associated Nuclear Antigen 1 of Kaposi's Sarcoma-Associated Herpesvirus Affects Transcriptional Activation and Binding to Nuclear Heterochromatin

2003 ◽  
Vol 77 (12) ◽  
pp. 7093-7100 ◽  
Author(s):  
Abel Viejo-Borbolla ◽  
Emrah Kati ◽  
Julie A. Sheldon ◽  
Kavita Nathan ◽  
Karin Mattsson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Nuclear Matrix ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Terminal Region ◽  
Nuclear Antigen ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Carboxy Terminal ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Episomal Dna

ABSTRACT The latency-associated nuclear antigen 1 (LANA-1) of Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the maintenance and replication of viral episomal DNA. The binding sites for nuclear heterochromatin and transcriptional repressor complexes are located in an amino-terminal region of LANA-1, whereas those for viral episomal DNA, p53, pRB, and members of the BRD/fsh family of nuclear proteins are located in its carboxy-terminal domain. LANA-1 activates or represses several cellular and viral promoters. In this report we show that a domain of 15 amino acids (amino acids 1129 to 1143), located close to the carboxy-terminal end of LANA-1, is required for the interaction of LANA-1 with nuclear heterochromatin or nuclear matrix, and for the ability of LANA-1 to activate the Epstein-Barr virus Cp promoter. LANA-1 proteins that are tightly associated with nuclear heterochromatin or matrix differ in molecular weight from LANA-1 proteins that can be dissociated from the nuclear matrix by high-salt buffers, suggesting that posttranslational modifications may determine the association of LANA-1 with nuclear heterochromatin or matrix.

scholarly journals A Potential α-Helix Motif in the Amino Terminus of LANA Encoded by Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Nuclear Accumulation of HIF-1α in Normoxia

2007 ◽  
Vol 81 (19) ◽  
pp. 10413-10423 ◽  
Author(s):  
Qiliang Cai ◽  
Masanao Murakami ◽  
Huaxin Si ◽  
Erle S. Robertson
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Hek293 Cells ◽  
Nuclear Accumulation ◽  
Nuclear Antigen ◽  
Cytokine Signaling ◽  
Amino Terminal ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1α suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC5S ubiquitin complex. Here we further show that HIF-1α was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential α-helical amino-terminal domain of LANA was important for HIF-1α nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1α. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1α. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1α suppressor proteins but can also induce nuclear accumulation of HIF-1α during KSHV latent infection.

scholarly journals Reduction of Kaposi’s Sarcoma-Associated Herpesvirus Latency Using CRISPR-Cas9 To Edit the Latency-Associated Nuclear Antigen Gene

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
For Yue Tso ◽  
John T. West ◽  
Charles Wood
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Adenovirus Type ◽  
Nuclear Antigen ◽  
Latently Infected ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Adenovirus Type 5 ◽  
Hiv 1 ◽  
Over Time

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS), an AIDS-defining cancer in HIV-1-infected individuals or immune-suppressed transplant patients. The prevalence for both KSHV and KS are highest in sub-Saharan Africa where HIV-1 infection is also epidemic. There is no effective treatment for advanced KS; therefore, the survival rate is low. Similar to other herpesviruses, KSHV’s ability to establish latent infection in the host presents a major challenge to KS treatment or prevention. Strategies to reduce KSHV episomal persistence in latently infected cells might lead to approaches to prevent KS development. The CRISPR-Cas9 system is a gene editing technique that has been used to specifically manipulate the HIV-1 genome but also Epstein-Barr virus (EBV) which, similar to KSHV, belongs to theGammaherpesvirusfamily. Among KSHV gene products, the latency-associated nuclear antigen (LANA) is absolutely required in the maintenance, replication, and segregation of KSHV episomes during mitosis, which makes LANA an ideal target for CRISPR-Cas9 editing. In this study, we designed a replication-incompetent adenovirus type 5 to deliver a LANA-specific Cas9 system (Ad-CC9-LANA) into various KSHV latent target cells. We showed that KSHV latently infected epithelial and endothelial cells transduced with Ad-CC9-LANA underwent significant reductions in the KSHV episome burden, LANA RNA and protein expression over time, but this effect is less profound in BC3 cells due to the low infection efficiency of adenovirus type 5 for B cells. The use of an adenovirus vector might confer potentialin vivoapplications of LANA-specific Cas9 against KSHV infection and KS.IMPORTANCEThe ability for Kaposi’s sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi’s sarcoma (KS), to establish and maintain latency has been a major challenge to clearing infection and preventing KS development. This is the first study to demonstrate the feasibility of using a KSHV LANA-targeted CRISPR-Cas9 and adenoviral delivery system to disrupt KSHV latency in infected epithelial and endothelial cell lines. Our system significantly reduced the KSHV episomal burden over time. Given the safety record of adenovirus as vaccine or delivery vectors, this approach to limit KSHV latency may also represent a viable strategy against other tumorigenic viruses and may have potential benefits in developing countries where the viral cancer burden is high.

scholarly journals Induction of Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen by the Lytic Transactivator RTA: a Novel Mechanism for Establishment of Latency

2005 ◽  
Vol 79 (12) ◽  
pp. 7453-7465 ◽  
Author(s):  
Ke Lan ◽  
Daniel A. Kuppers ◽  
Subhash C. Verma ◽  
Nikhil Sharma ◽  
Masanao Murakami ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
De Novo ◽  
Signal Sequence ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
Transcription Activator ◽  
Early Stages ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent contributing to development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman desease. Following primary infection, latency is typically established. However, the mechanism by which KSHV establishes latency is not understood. We have reported that the latency-associated nuclear antigen (LANA) can repress RTA (for replication and transcription activator) expression by down-regulating its promoter. In this study, we show that RTA is associated with the virion particle. We also show that RTA can activate the LANA promoter and induce LANA expression in transient reporter assays. Additionally, the transcription of RTA correlates with LANA expression in the early stages of de novo infection of KSHV, and induction of LANA transcription is responsive to induction of RTA with an inducible system. This induction in LANA transcription was dependent on recombination signal sequence binding protein Jκ (RBP-Jκ), as a RBP-Jκ-deficient cell line was significantly delayed and inefficient in LANA transcription with expression of RTA. These studies suggest that RTA contributes to establishment of KSHV latency by activating LANA expression in the early stages of infection by utilizing the major effector of the Notch signaling pathway RBP-Jκ. This describes a feedback mechanism by which LANA and RTA can regulate each other and is likely to be a key event in the establishment of KSHV latency.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Latent Protein LANA Interacts with HIF-1α To Upregulate RTA Expression during Hypoxia: Latency Control under Low Oxygen Conditions

2006 ◽  
Vol 80 (16) ◽  
pp. 7965-7975 ◽  
Author(s):  
Qiliang Cai ◽  
Ke Lan ◽  
Subhash C. Verma ◽  
Huaxin Si ◽  
Doug Lin ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Nuclear Antigen ◽  
Regulatory Sequences ◽  
Physical Interaction ◽  
Low Oxygen ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Hypoxia can induce lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) in primary effusion lymphoma (PEL) cells. However, the molecular mechanism of lytic reactivation of KSHV by hypoxia remains unclear. Here we show that the latency-associated nuclear antigen (LANA), which plays a crucial role in modulating viral and cellular gene expression, directly associated with a low oxygen responder, hypoxia-inducible factor-1α (HIF-1α). LANA enhanced not only the transcriptional activities of HIF-1α but also its mRNA level. Coimmunoprecipitation and immunofluorescence studies documented a physical interaction between LANA and HIF-1α in transiently transfected 293T cells as well as in PEL cell lines during hypoxia. Through sequence analysis, several putative hypoxia response elements (HRE-1 to -6) were identified in the essential lytic gene Rta promoter. Reporter assays showed that HRE-2 (−1130 to −1123) and HRE-5 and HRE-6 (+234 to +241 and +812 to +820, respectively, within the intron sequence) were necessary and sufficient for the LANA-mediated HIF-1α response. Electrophoretic mobility shift assays showed HIF-1α-dependent binding of a LANA protein complex specifically to the HRE-2, -5, and -6 motifs within the promoter regulatory sequences. This study demonstrates that hypoxia-induced KSHV lytic replication is mediated at least in part through cooperation of HIF-1α with LANA bound to the HRE motifs of the Rta promoter.

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