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 Blood, 1 January 2006, Vol. 107, No. 1, pp. 277-284.
Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-06-2350.

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NEOPLASIA

KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2

Mark Cannon, Ethel Cesarman, and Chris Boshoff

From the Division of International Medicine and Infectious Diseases, Department of Medicine, Weill Medical College of Cornell University, New York, NY; the Department of Pathology, Weill Medical College of Cornell University, New York, NY; and the Cancer Research United Kingdom (CRUK) Viral Oncology Group, The Wolfson Institute for Biomedical Research, University College London (UCL), London, United Kingdom.

Kaposi sarcoma (KS) remains the most common AIDS-associated malignancy worldwide. In sub-Saharan Africa especially, this aggressive endothelial-cell tumor is a cause of widespread morbidity and mortality. Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is now known to be an etiologic force behind KS and primary-effusion lymphoma (PEL). Over time, KSHV has pirated many human genes whose products regulate angiogenesis, inflammation, and the cell cycle. One of these, the KSHV vGPCR, is a lytic product that is a constitutively active homolog of the IL-8 receptor. Although it is considered a viral oncogene and causes KS-like lesions in mice, vGPCR expression results in cell-cycle arrest of KSHV-infected PEL cells. In the present study, we show that this arrest is mediated by p21 in a p53-independent manner; the resulting Cdk2 inhibition decreases the efficiency of chemical induction of KSHV lytic transcripts ORF 50 and 26. Importantly, Cdk2 activity is also essential for replication in other human herpesviruses. The ability of vGPCR to delay or abort KSHV replication may explain how despite being a lytic product, this potent signaling molecule has a vital role in tumor formation via its induction of various KS-associated cytokines.


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S. A. R. Rezaee, C. Cunningham, A. J. Davison, and D. J. Blackbourn
Kaposi's sarcoma-associated herpesvirus immune modulation: an overview
J. Gen. Virol., July 1, 2006; 87(7): 1781 - 1804.
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