A novel viral mechanism for dysregulation of β-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

Research output: Contribution to journalArticle

Abstract

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 β-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated β-catenin accumulation; LANA itself upregulated expression of β-catenin in transfected cells. LANA stabilizes β-catenin by binding to the negative regulator GSK-3β, causing a cell cycle-dependent nuclear accumulation of GSK-3β. The LANA C terminus contains sequences similar to the GSK-3β-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3β or stabilize β-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-3β can therefore be a source of β-catenin dysregulation in human cancers.

Original languageEnglish (US)
Pages (from-to)300-306
Number of pages7
JournalNature medicine
Volume9
Issue number3
DOIs
StatePublished - Mar 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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