Modulation of Cellular and Viral Gene Expression by the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus

doi:10.1128/JVI.75.1.458-468.2001

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Journal of Virology, January 2001, p. 458-468, Vol. 75, No. 1
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.1.458-468.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Modulation of Cellular and Viral Gene Expression by the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus

Rolf Renne,¹^,^* Chris Barry,² Dirk Dittmer,³ Nicole Compitello,¹ Patrick O. Brown,² and Don Ganem⁴

Division of Hematology/Oncology, Case Western Reserve University, Cleveland, Ohio 44106¹; Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305²; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190³; and Howard Hughes Medical Institute and Departments of Microbiology and Medicine, University of California, San Francisco, California 94143-0414⁴

Received 14 June 2000/Accepted 29 September 2000

Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is the likely etiological agent ofKaposi's sarcoma and primary effusion lymphoma. Common to thesemalignancies is that tumor cells are latently infected with KSHV.Viral gene expression is limited to a few genes, one of whichis the latency-associated nuclear antigen (LANA), the productof ORF73. Examination of the primary sequence of LANA revealssome structural features reminiscent of transcription factors,leading us to hypothesize that LANA may regulate viral and cellulartranscription during latency. In reporter gene-based transienttransfection assays, we found that LANA can have either positiveor negative effects on gene expression. While expression of areporter gene from several synthetic promoters was increased inthe presence of LANA, expression from the human immunodeficiencyvirus (HIV) long terminal repeat (LTR) $---$ and from NF- $kappa$ B-dependentreporter genes $---$ was reduced by LANA expression. In addition, thepromoter of KSHV ORF73 itself is activated up to 5.5-fold by LANA.This autoregulation may be important in tumorigenesis, becausetwo other genes (v-cyclin and v-FLIP) with likely roles in cellgrowth and survival are also controlled by this element. To identifycellular genes influenced by LANA, we employed cDNA array-basedexpression profiling. Six known genes (and nine expressed sequencetags) were found to be upregulated in LANA-expressing cell lines.One of these, Staf-50, is known to inhibit expression from theHIV LTR; most of the other known genes are interferon inducible,although the interferon genes themselves were not induced by LANA.These data demonstrate that LANA expression has effects on cellularand viral gene expression. We suggest that, whether direct orindirect in origin, these effects may play important roles inthe pathobiology of KSHVinfection.

^* Corresponding author. Mailing address: Division of Hematology/Oncology, Case Western Reserve University, 10900 Euclid Ave.,Cleveland, OH 44106. Phone: (216) 368-1190. Fax: (216) 368-1166.E-mail: rfr3{at}po.cwru.edu.

Journal of Virology, January 2001, p. 458-468, Vol. 75, No. 1
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.1.458-468.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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