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J. Biol. Chem., Vol. 280, Issue 5, 3862-3874, February 4, 2005

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The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Modulates Cellular Gene Expression and Protects Lymphoid Cells from p16 INK4A-induced Cell Cycle Arrest^*

Feng-Qi An, Nicole Compitello, Edward Horwitz, Michael Sramkoski, Erik S. Knudsen¶, and Rolf Renne||

From the Division of Hematology/Oncology and the Department of Molecular Biology and Microbiology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106 and the ^¶Department of Cell Biology, University of Cincinnati, Cincinnati, Ohio 45229

Latently infected Kaposi's sarcoma-associated herpes-virus (KSHV)-associated tumor cells have both endothelial and lymphoid origins and express a limited set of latent viral genes. One such gene, ORF73, encodes the latency-associated nuclear antigen (LANA), a multifunctional protein that plays roles in viral DNA replication, episome maintenance, and transcriptional regulation. LANA interacts with cellular proteins involved in transcriptional regulation such as the tumor suppressors, retinoblastoma (Rb) and p53, and RING3 family members. Although several reports about specific LANA-regulated promoters exist, only limited data are available that address how LANA expression in KSHV-infected cells globally affects cellular gene expression, thereby potentially contributing to KSHV pathogenicity. To investigate this question, we generated an Epstein-Barr virus-negative Burkitts lymphoma line that expresses LANA from a tetracycline-inducible promoter (BJAB/Tet-On/LANA), and we performed microarray-based gene expression profiling. Expression profiling at different time points post-induction revealed that 186 genes were activated or repressed over 2-fold in the presence of LANA. Of these genes, 41 are regulated in the Rb/E2F pathway, whereas 7 are related to p53 signaling. To determine whether these gene expression changes translate into LANA-dependent changes in cell cycle regulation, we overexpressed p16 INK4a, a CDK4/6 inhibitor that efficiently induces cell cycle arrest in Rb-positive cells. Under these conditions, LANA expression protects lymphoid cells from p16 INK4a-induced cell cycle arrest and induces S-phase entry.

Received for publication, July 2, 2004 , and in revised form, October 29, 2004.

^* This work was supported by grants from the American Cancer Society and National Institutes of Health Grants CA88763 and CA097939 (to R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-3.

^|| To whom correspondence should be addressed: Dept. of Molecular Genetics and Microbiology and Shands Cancer Center, University of Florida, Gainesville, FL 32610. Tel.: 352-392-9848; Fax: 352-392-5802; E-mail: rrenne{at}ufscc.ufl.edu.

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