A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma-associated herpesvirus latency

• Published in: Nature medicine Vol. 9; no. 3; pp. 300 - 306
• Main Authors: Hayward, S. Diane, Fujimuro, Masahiro, Wu, Frederick Y, apRhys, Colette, Kajumbula, Henry, Young, David B, Hayward, Gary S
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2003
• Subjects: Amino Acid Sequence; Antigens, Viral; beta Catenin; Binding Sites; Cell Cycle - physiology; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cycloheximide - metabolism; Cytoskeletal Proteins - metabolism; Genes, Reporter; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Herpesvirus 8, Human - physiology; Humans; Molecular Sequence Data; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Binding; Protein Synthesis Inhibitors - metabolism; RNA, Small Interfering; Sequence Alignment; Trans-Activators - metabolism; Tumor Cells, Cultured; Virus Latency
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm829

The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that beta-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated beta-catenin accumulation; LANA itself upregulated expression of beta-catenin in transfected cells. LANA stabilizes beta-catenin by binding to the negative regulator GSK-3beta, causing a cell cycle-dependent nuclear accumulation of GSK-3beta. The LANA C terminus contains sequences similar to the GSK-3beta-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3beta or stabilize beta-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3beta can therefore be a source of beta-catenin dysregulation in human cancers.