Open Reading Frame 50 Protein of Kaposi's Sarcoma-Associated Herpesvirus Directly Activates the Viral PAN and K12 Genes by Binding to Related Response Elements

Chang, Pey‐Jium; Shedd, Duane; Gradoville, Lyndle; Cho, Myung-Sam; Chen, Lee-Wen; Chang, Jimmy; Miller, George

doi:10.1128/jvi.76.7.3168-3178.2002

Cited by 126 publications

(159 citation statements)

References 42 publications

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“…Lytic infection is marked by the production of infectious virus, whereas latency is characterized by the lack of infectious virus production and the expression of a limited number of viral transcripts and proteins. One of the most abundant transcripts present in KSHV-infected cells is a long noncoding RNA, referred to as polyadenylated nuclear RNA (PAN RNA) (3,4).…”

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confidence: 99%

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Rossetto

Tarrant-Elorza

Verma

et al. 2013

J Virol

121

195

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma and body cavity lymphoma. In cell culture, KSHV results in a latent infection, and lytic reactivation is usually induced with the expression of K-Rta or by treatment with phorbol 12-myristate 13-acetate (TPA) and/or n-butyrate. Lytic infection is marked by the activation of the entire viral genomic transcription cascade and the production of infectious virus. KSHV-infected cells express a highly abundant, long, noncoding transcript referred to as polyadenylated nuclear RNA (PAN RNA). PAN RNA interacts with specific demethylases and physically binds to the KSHV genome to mediate activation of viral gene expression. A recombinant BACmid lacking the PAN RNA locus fails to express K-Rta and does not produce virus. We now show that the lack of PAN RNA expression results in the failure of the initiation of the entire KSHV transcription program. In addition to previous findings of an interaction with demethylases, we show that PAN RNA binds to protein components of Polycomb repression complex 2 (PRC2). RNA-Seq analysis using cell lines that express PAN RNA shows that transcription involving the expression of proteins involved in cell cycle, immune response, and inflammation is dysregulated. Expression of PAN RNA in various cell types results in an enhanced growth phenotype, higher cell densities, and increased survival compared to control cells. Also, PAN RNA expression mediates a decrease in the production of inflammatory cytokines. These data support a role for PAN RNA as a major global regulator of viral and cellular gene expression.K aposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma herpesvirus that is the cause of Kaposi's sarcoma (1, 2). KSHV infection in cell culture manifests mainly as a latent infection; however, there is a percentage of spontaneous lytic reactivation. Lytic infection is marked by the production of infectious virus, whereas latency is characterized by the lack of infectious virus production and the expression of a limited number of viral transcripts and proteins. One of the most abundant transcripts present in KSHV-infected cells is a long noncoding RNA, referred to as polyadenylated nuclear RNA (PAN RNA) (3, 4).We previously showed that PAN RNA interacts with cell-and virus-encoded factors and mediates the regulation of immune response gene expression (5, 6). Data from our laboratory and others indicated that PAN RNA is a major regulator of viral gene expression through a mechanism that involves a direct interaction with the viral chromosome (5, 7). PAN RNA interacts with the demethylases UTX and JMJD3 to remove the suppressive H3K23me3 mark within the KSHV viral genome. In a recent study describing the transcriptome of KSHV-infected cell lines, PAN RNA was detected in the absence of lytic-phase induction, suggesting that PAN RNA is expressed during chronic latent infection in cell culture (8). This observation suggests that PAN RNA has the potential to influence viral and cellular gene expressio...

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mentioning

confidence: 99%

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Rossetto

Tarrant-Elorza

Verma

et al. 2013

J Virol

121

195

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“…Using similar methods Chang et al (2002) showed that the 490 aa RDBD was required for recognition and lytic activation of the PANp or the promoter for K12, another gene whose expression is upregulated in the lytic cycle. This activation was also evident when the RTAresponsive sequence was fused to the heterologous adenovirus E4 promoter demonstrating that RTA activation was dependent upon the RRE but independent of binding sites for cellular transcription factors that were distinct between PANp and the E4 promoter.…”

Section: Rta Interacts With Various Promoters and Factors To Mediate mentioning

confidence: 99%

“…A region of the PANp corresponding to nucleotides À70 to À46 [numbering according to Chang et al (2002)] was found to be essential to RTA activation of PAN expression. The K d of the RTA association with PANp has been reported to be in the nanomolar range (Song et al, 2001(Song et al, , 2002, suggesting that the high affinity of RTA for the PANp is likely responsible, in part, for the abundance of PAN RNA in cells expressing lytic transcripts.…”

Section: Rta Interacts With Various Promoters and Factors To Mediate mentioning

confidence: 99%

“…These findings suggest that the linear DNA sequence in the ORF57 and K8 promoter region is more critical than the palindromic nature of that sequence. In addition to the 25 bp region conferring RTA responsiveness (defined as 50RE 57 ), sequences TATA-proximal to the 50RE 57 within the promoter were also sensitive to mutation, and any (Song et al, 2001;Chang et al, 2002). The overall identity between the ORF57 and K8 RTA-responsive promoter regions is shown boxed and the sequences that contribute to the palindrome are shaded (Duan et al, 2001;Lukac et al, 2001).…”

Section: Rta Interacts With Various Promoters and Factors To Mediate mentioning

confidence: 99%

“…However, RTA does not recognize the same sequence element in all responsive promoters. This diversity of recognition suggests that on some promoters, other viral and host factors may direct or augment DNA binding and may influence the diversity of RTA transactivation (Seaman et al, 1999;Lukac et al, 2001;Sakakibara et al, 2001;Wang et al, 2001a;Chang et al, 2002;Deng et al, 2002b;Saveliev et al, 2002).…”

Section: Rta Interacts With Various Promoters and Factors To Mediate mentioning

confidence: 99%

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The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

2003

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The mechanisms that control the replication state, latency versus lytic, of human herpesviruses have been under intense investigations. Here we summarize some of the recent findings that help define such mechanisms for Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8). For HHV-8, the viral regulator of transcription activation (RTA) is a key mediator of the switch from latency to lytic gene expression in infected cells. RTA is necessary and sufficient to drive HHV-8 lytic replication and the production of viral progeny. The RTA is an immediateearly gene product, it is the initial activator of expression of a multitude of viral and cellular genes that have been implicated in the replication of HHV-8 and pathogenesis of KS. Interactions of RTA with a number of viral promoters, and with a number of transcription factors or transcriptional co-activators are highlighted. Modulation of transactivation, through alternate RTA-protein, or RTA-promoter interactions, is hypothesisized to participate in the selective tissue tropism and differential pathogenesis observed in KS.

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Application of a new human cell line, F2N78, in the transient and stable production of recombinant therapeutics

Lee

Chang

Kim

et al. 2013

Biotechnology Progress

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Host cell lines developed by genetic engineering sometimes show instabilities in maintaining their genetically acquired phenotypes. Previously, a hybrid host cell line, designated as hybrid of kidney and B cells (HKB), capable of retaining selected phenotypes originally existing in the parental cells was developed via fusion of 293 cells and HH514-16 cells. Although HKB did indeed successfully preserve several favorable phenotypes, the expression of Epstein-Barr virus (EBV) specific nuclear antigen 1 (EBNA1), which should be constitutively expressed for host cells to utilize oriP expression vector in transient production of therapeutic proteins, was observed to be unstable. Here, in an attempt to obtain stable expression of EBNA1, a cell type that contains an integrated EBV genome, rather than HH514-16 cells, which harbor an episomal EBV genome, was applied for fusion with 293 cells. Fusion of 293 cells with Namalwa cells led to the creation of a new type of hybrid, F2N, which was able to stably express EBNA1 while not producing EBV particles. One of the F2N clones, F2N78, was observed to maintain EBNA1 expression for more than 1 year under serum-free suspension culture conditions along with human specific glycosyl phenotypes observed previously in HKB. In addition, F2N78 was demonstrated to be an appropriate host cell line for both the transient and stable production of recombinant therapeutics with the features of safety expected of production cell lines for human use.

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Open Reading Frame 50 Protein of Kaposi's Sarcoma-Associated Herpesvirus Directly Activates the Viral PAN and K12 Genes by Binding to Related Response Elements

Cited by 126 publications

References 42 publications

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA

The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

Application of a new human cell line, F2N78, in the transient and stable production of recombinant therapeutics

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