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Journal of Virology, March 2009, p. 2140-2153, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.01871-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gene Regulation and Functional Alterations Induced by Kaposi's Sarcoma-Associated Herpesvirus-Encoded ORFK13/vFLIP in Endothelial Cells{triangledown} ,{dagger}

Shuhei Sakakibara,* Cynthia A. Pise-Masison, John N. Brady, and Giovanna Tosato

Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Received 4 September 2008/ Accepted 9 December 2008

Kaposi's sarcoma (KS) is an angioproliferative inflammatory disorder induced by endothelial cell infection with the KS-associated herpesvirus (KSHV). ORFK13/vFLIP, one of the KSHV genes expressed in KS, encodes a 188-amino-acid protein which binds to the I{kappa}b kinase (IKK) complex to activate NF-{kappa}B. We examined ORFK13/vFLIP contribution to KS phenotype and potential for therapeutic targeting. Retroviral transduction of ORFK13/vFLIP into primary human endothelial cells induces the spindle morphology distinctive of KS cells and promotes the formation of abnormal vascular networks typical of KS vasculature; upregulates the expression of proinflammatory cytokines, chemokines, and interferon-responsive genes; and stimulates the adhesion of inflammatory cells characteristic of KS lesions. Thymidine phosphorylase, a cellular enzyme markedly induced by ORFK13/vFLIP, can metabolize the prodrug 5-fluoro-5-deoxyuridine (5-dFUrd) to 5-fluouridine (5-FU), a potent thymidine synthase inhibitor, which blocks DNA and RNA synthesis. When tested for cytotoxicity, 5-dFUrd (0.1 to 1 µM) selectively killed ORFK13/vFLIP-expressing endothelial cells while sparing control cells. These results demonstrate that ORFK13/vFLIP directly and indirectly contributes to the inflammatory and vascular phenotype of KS and identify 5-dFUrd as a potential new drug that targets KSHV latency for the treatment of KS and other KSHV-associated malignancies.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 4134, Bethesda, MD 20892. Phone: (301) 594-9597. Fax: (301) 594-9585. E-mail: sakakibs{at}mail.nih.gov

{triangledown} Published ahead of print on 17 December 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, March 2009, p. 2140-2153, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.01871-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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