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Molecular and Cellular Biology, November 2005, p. 9249-9258, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9249-9258.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Viral FLIP Enhances Wnt Signaling Downstream of Stabilized ß-Catenin, Leading to Control of Cell Growth{dagger}

Shiho Nakagiri,1,2 Akira Murakami,2 Shinji Takada,3 Tetsu Akiyama,4 and Shin Yonehara1,2*

Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan,1 Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,2 National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan,3 Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan4

Received 29 April 2005/ Returned for modification 27 May 2005/ Accepted 2 August 2005

Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein), which is composed of two tandemly repeated death effector domains (DEDs), through reduced activation of procaspase 8. Here, we show that equine herpesvirus 2-encoded viral FLIP E8 enhances Wnt/ß-catenin signaling in a variety of cell lines. E8 was shown to strikingly augment Wnt3a signaling, as shown both in a luciferase assay for T-cell factor/ß-catenin and through induction of endogenous cyclin D1. The effect of E8 was independent of its direct binding activity with DED-containing signaling molecules, including caspase 8 and FADD, in death receptor-mediated apoptosis. E8 enhanced Wnt signaling downstream of stabilized ß-catenin, while a long form of cellular FLIP (c-FLIPL) enhanced stabilization of ß-catenin in 293T cells. Consequently, coexpression of E8 and c-FLIPL synergistically increased Wnt signaling in 293T cells. Moreover, E8-mediated stimulation of Wnt signaling induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines. Thus, viral FLIP E8 not only inhibits death receptor-mediated apoptosis but also enhances Wnt signaling pathways that are closely related to those of both ontogenesis and oncogenesis.

* Corresponding author. Mailing address: Graduate School of Biostudies, Kyoto University, SCRB/Building G, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-9234. Fax: 81-75-753-9235. E-mail: yonehara{at}lif.kyoto-u.ac.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2005, p. 9249-9258, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9249-9258.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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