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Journal of Virology, October 2007, p. 10413-10423, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00611-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Potential -Helix Motif in the Amino Terminus of LANA Encoded by Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Nuclear Accumulation of HIF-1 in Normoxia

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104

Received 22 March 2007/ Accepted 5 July 2007

Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1 suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC₅S ubiquitin complex. Here we further show that HIF-1 was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential -helical amino-terminal domain of LANA was important for HIF-1 nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1 suppressor proteins but can also induce nuclear accumulation of HIF-1 during KSHV latent infection.

Published ahead of print on 18 July 2007.