Dissection of the Kaposi's Sarcoma-Associated Herpesvirus Gene Expression Program by Using the Viral DNA Replication Inhibitor Cidofovir

Lu, Michael C.; Suen, Jacqueline; Frías, Carolina; Pfeiffer, Ruth M.; Tsai, Mong-Hsun; Chuang, Eric Y.; Zeichner, Steven L.

doi:10.1128/jvi.78.24.13637-13652.2004

Cited by 69 publications

(112 citation statements)

References 84 publications

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“…This kinetics of expression was closely related to EBV BGLF4, a homolog of vPK (15). Other investigators using microarray analysis, coupled with the use of an inhibitor of viral DNA synthesis, also showed that the vPK gene was expressed early in the viral lytic cycle (31). In K-Rta-inducible BCBL-1 cells, the 4.2-kb transcript, encoding ORF34 to ORF38, was sensitive to PAA; this finding differs from an earlier report (18).…”

Section: Discussioncontrasting

confidence: 56%

“…In previous reports, the vPK gene was shown to be expressed as either an early or a late gene during lytic replication, depending on the conditions used to reactivate virus in latently infected B-lymphoid tumor cells (22,31,38,39). Because the mode of action of the inducers (e.g., phorbol ester or butyrate) is complex and the fraction of cells affected is relatively small, we chose to measure the expression kinetics of vPK by K-Rta-mediated reactivation.…”

Section: Resultsmentioning

confidence: 99%

“…Previous analysis on levels of KSHV transcripts in productive infection indicated that vPK RNA was accumulated in the late phase of viral replication (22,39). However, a recent study detected vPK RNA at early time points and in the presence of an inhibitor of viral DNA synthesis (31). Detailed analysis of KSHV RNA revealed two polycistronic transcripts encoding vPK that are initiated from promoters that are active in the early stage of the viral life cycle and inducible by hypoxic conditions (18).…”

mentioning

confidence: 99%

“…Several of these viral ORFs are implicated in modulating host immune responses, promoting angiogenesis, and dysregulating cell growth (14). A model for regulated expression of KSHV genes has been deduced from numerous genetic and biochemical studies of viral RNA patterns and activities of viral transactivators (22,31,39,49). As for other herpesviruses, KSHV genes in productive infection have been classified into the following temporally distinct classes: immediate-early, early, and late.…”

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confidence: 99%

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Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Izumiya

Geelen

et al. 2007

J Virol

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The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.Kaposi's sarcoma-associated herpesvirus (KSHV), also designated human herpesvirus 8, has been linked to several malignancies, including Kaposi's sarcoma, B-cell lymphomas, primary effusion lymphomas, and multicentric Castleman's disease in immunocompromised individuals (reviewed in reference 46). Kaposi's sarcoma is the most common malignancy associated with AIDS (45). The viral genome is doublestranded DNA, approximately 165 kbp, and encodes over 81 open reading frames (ORFs) (43). The majority of the ORFs are essential for viral replication and include genes necessary for viral DNA replication, transcription, and assembly of infectious particles (51). In addition, the KSHV genome contains a large number of ORFs with homology to known cellular genes. Several of these viral ORFs are implicated in modulating host immune responses, promoting angiogenesis, and dysregulating cell growth (14). A model for regulated expression of KSHV genes has been deduced from numerous genetic and biochemical studies of viral RNA patterns and activities of viral transactivators (22,31,39,49). As for other herpesviruses, KSHV genes in productive infection have been classified into the following temporally distinct classes: immediate-early, early, and late. This virus can also establish a latent state that is characterized by presence of a multicopy circular episome of viral DNA, which expresses a small subset of viral proteins. Productive (lytic) viral replication can be induced by treatment of latently infected cell lines with butyrate,...

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Section: Discussioncontrasting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Izumiya

Geelen

et al. 2007

J Virol

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“…Nucleoside analogs that selectively inhibit viral DNA replication are the first line anti-herpesvirus drugs. Originally developed to treat herpes simplex virus infection, they also inhibit KSHV in vitro 60,[64][65][66] and have displayed activity against KSHV-associated disease based on reductions in viral oropharyngeal shedding 67,68 and clinical relief of MCD symptoms. 34,35 At the outset, we considered three alternatives: (1) ganciclovir and the immunotoxin might display additive anti-KSHV activities; (2) they might detected on a small subpopulation of induced cells; this pattern was not observed on uninduced cells (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

Chatterjee

Chandran

Berger

2012

mAbs

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KSHV Latent Genes and Their Regulation

Dittmer

2008

DNA Tumor Viruses

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Dissection of the Kaposi's Sarcoma-Associated Herpesvirus Gene Expression Program by Using the Viral DNA Replication Inhibitor Cidofovir

Cited by 69 publications

References 84 publications

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

KSHV Latent Genes and Their Regulation

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