Nature Medicine9, 300 - 306 (2003)
Published online: 18 February 2003; | doi:10.1038/nm829
A novel viral mechanism for dysregulation of -catenin in Kaposi's sarcoma−associated herpesvirus latency
Masahiro Fujimuro, Frederick Y. Wu, Colette apRhys, Henry Kajumbula, David B. Young, Gary S. Hayward
& S. Diane Hayward
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Correspondence should be addressed to S. Diane Hayward dhayward@jhmi.edu
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 -catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated -catenin accumulation; LANA itself upregulated expression of -catenin in transfected cells. LANA stabilizes -catenin by binding to the negative regulator GSK-3, causing a cell cycle−dependent nuclear accumulation of GSK-3. The LANA C terminus contains sequences similar to the GSK-3-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3 or stabilize -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-3 can therefore be a source of -catenin dysregulation in human cancers.
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-catenin in Kaposi's sarcoma−associated herpesvirus latency
-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated 
