Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Replication and Transcription Factor Activates the K9 (vIRF) Gene through Two Distinct
            <i>cis</i>
            Elements by a Non-DNA-Binding Mechanism

Ueda, Keiji; Ishikawa, Kaoru; Nishimura, Ken; Sakakibara, Shuhei; Do, Eunju; Yamanishi, Koichi

doi:10.1128/jvi.76.23.12044-12054.2002

Cited by 51 publications

(39 citation statements)

References 41 publications

(62 reference statements)

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“…A luciferase assay was carried out to test if TLE2 could really repress the transactivation of RTA downstream genes. Previous studies have shown that ORF K8, ORF57, ORF59, and PAN are early genes that are upregulated by RTA during lytic reactivation (6,16,23,40,61,65,67). In this experiment, HEK293 or DG75 cells were transfected transiently with RTA expression vector, reporter plasmids, and TLE2 in increasing amounts.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have demonstrated that the replication and transcription activator (RTA) encoded by KSHV open reading frame 50 (ORF50) plays a pivotal role in control of the virus life cycle. This is essential and sufficient to trigger lytic replication by activating the lytic gene expression cascade, including polyadenylated nuclear (PAN) RNA, ORF K8, ORF57, ORF59, viral G-proteincoupled receptor, viral interferon regulatory factor (vIRF), K1, gB, and RTA (6,16,23,40,61,65,67). It is supposed that RTA interacts with various cellular proteins to accomplish transcription regulation.…”

mentioning

confidence: 99%

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Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Liu

Liang

et al. 2010

J Virol

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Replication and transcription activator (RTA) encoded by open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or by interaction with cellular factors, such as RBP-J, Ap-1, C/EBP-␣, and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two-hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by glutathione S-transferase (GST) binding and coimmunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were colocalized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-J has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of the RTA-responsive element at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Liu

Liang

et al. 2010

J Virol

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“…The observation that Rta directly transactivates the promoters of many of the candidate pathogenic genes of KSHV, including K12/ kaposin, vIL-6, vMIP-I, vIRF-1, vGPCR, and K1 (55,97,119,126,507,525), suggests that the ability of these proteins to abrogate normal cellular growth control and physiology is es- VOL. 67,2003 KSHV MOLECULAR GENETICS 197 on May 10, 2018 by guest http://mmbr.asm.org/ sential for optimizing the cellular and anatomical milieu for viral replication.…”

Section: Lytic Reactivation Of Kshvmentioning

confidence: 99%

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

305

367

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Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection

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“…Although the molecular means by which ORF50 protein activates target genes during lytic replication are not fully understood, emerging evidence suggests that ORF50 protein controls promoters of its targets by several distinct mechanisms. One compelling piece of evidence in support of this hypothesis is that most ORF50 response elements identified in target promoters do not share conserved DNA sequences (5,28,43,47).…”

mentioning

confidence: 99%

“…Several cellular proteins have been shown to bind DNA in target promoters of ORF50 protein. These include OCT1 and C/EBP␣ in the ORF50 promoter (38,51), Sp1 in the thymidine kinase promoter (53), C/EBP␣ in the K8 promoter (50), and unknown proteins in the K9 promoter (47). Whether all these cellular proteins mediate gene activation by direct contact with ORF50 protein remains to be determined.…”

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confidence: 99%

Autoregulation of DNA Binding and Protein Stability of Kaposi's Sarcoma-Associated Herpesvirus ORF50 Protein

Chang¹,

Miller

2004

J Virol

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A transcriptional activator encoded in open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates the viral lytic cycle. ORF50 protein activates downstream KSHV target genes by at least two mechanisms: direct recognition of response elements in promoter DNA and interaction with cellular proteins bound to promoter DNA. We have identified a multifunctional regulatory region, present in amino acids (aa) 520 to 535 of ORF50 protein, that controls DNA binding and protein stability. Deletion of aa 521 to 534 or mutation of a basic motif (KKRK) in this regulatory region dramatically enhances DNA binding by ORF50 protein, as shown by electrophoretic mobility shift, DNA affinity chromatography, and chromatin immunoprecipitation assays. Deletion of the regulatory region and mutations in the KKRK motif also lead to abundant expression of an electrophoretic mobility variant, ORF50B, which appears to be a form of ORF50 protein that is decreased in posttranslational modification. Enhanced DNA binding and enhanced expression of ORF50B are independent phenomena. The regulatory region likely inhibits DNA binding through interactions with the DNA binding domain in aa 1 to 390 and destabilizes ORF50B through interactions with a domain located in aa 590 to 650. Mutants in the KKRK motif that are enhanced in DNA binding are nonetheless impaired in activating direct targets, such as polyadenylated nuclear RNA, and indirect targets, such as ORF50 itself. The identification of an autoregulatory region emphasizes that the many functions of ORF50 protein must be subject to exquisite control to achieve optimal KSHV lytic-cycle gene expression.

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Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Replication and Transcription Factor Activates the K9 (vIRF) Gene through Two Distinct cis Elements by a Non-DNA-Binding Mechanism

Cited by 51 publications

References 41 publications

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Autoregulation of DNA Binding and Protein Stability of Kaposi's Sarcoma-Associated Herpesvirus ORF50 Protein

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