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

Nature Medicine volume 9, pages 300–306 (2003)Cite this article

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.

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Figure 1: β-catenin is abundant in PEL cells and KS tissue.
Figure 2: β-catenin is stabilized in PEL cells.
Figure 3: LANA mediates β-catenin stabilization and downstream Tcf and Lef responses.
Figure 4: LANA interacts with and re-localizes GSK-3β.
Figure 5: Binding to GSK-3β is essential for LANA-mediated β-catenin dysregulation.
Figure 6: LANA stimulates S-phase entry.

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Acknowledgements

We thank K. Kinzler and B. Vogelstein for the β-catenin vectors, the GL3-OT and GL3-OF reporters and SW480 cells; F. McCormick for GSK-3β DNA; and R. Agami for pSuper. This work was supported by US National Institutes of Health grant R01 CA85151 to S.D.H. and P01 CA81400 to G.S.H.

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  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Masahiro Fujimuro, Frederick Y. Wu, Colette apRhys, Henry Kajumbula, David B. Young, Gary S. Hayward & S. Diane Hayward

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Correspondence to S. Diane Hayward.

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Fujimuro, M., Wu, F., apRhys, C. et al. A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma–associated herpesvirus latency. Nat Med 9, 300–306 (2003). https://doi.org/10.1038/nm829

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