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

被引：252

作者：

Fujimuro, M ^{[1
]}

Wu, FY ^{[1
]}

ApRhys, C ^{[1
]}

Kajumbula, H ^{[1
]}

Young, DB ^{[1
]}

Hayward, GS ^{[1
]}

Hayward, SD ^{[1
]}

机构：

[1] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA

来源：

NATURE MEDICINE | 2003年 / 9卷 / 03期

关键词：

D O I：

10.1038/nm829

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：300 / 306

页数：7

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