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Cellular FLIP Inhibits ß-Catenin Ubiquitylation and Enhances Wnt Signaling

Mikihiko Naito,^1,* Ryohei Katayama,^1, Toshiyasu Ishioka,¹ Akiko Suga,² Kohei Takubo,¹ Masahiro Nanjo,¹ Chizuko Hashimoto,¹ Masanori Taira,^2,3 Shinji Takada,^4,5 Ritsuko Takada,^4,5 Masatoshi Kitagawa,⁶ Shu-Ichi Matsuzawa,⁷ John C. Reed,⁷ and Takashi Tsuruo^1,8

Institute of Molecular and Cellular Biosciences,¹ School of Science, The University of Tokyo, Bunkyo-ku,² Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo,⁸ CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama,³ Center for Integrative Bioscience, Okazaki National Research Institute, Okazaki, Aichi,⁴ Kondoh Differentiation Signaling Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Sakyo-ku, Kyoto,⁵ Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan,⁶ The Burnham Institute, La Jolla, California⁷

Received 2 April 2004/ Returned for modification 28 April 2004/ Accepted 28 June 2004

Cellular FLIP (cFLIP) is a close homologue of caspase 8 without caspase activity that inhibits Fas signaling. The cFLIP protein is often expressed in human tumors and is believed to suppress antitumor immune responses involving the Fas system. Here, we report that a long form of cFLIP (cFLIP-L) inhibits ß-catenin ubiquitylation and increases endogenous cytosolic ß-catenin, which results in translocation of ß-catenin into nuclei and induction of ß-catenin-dependent gene expression in cFLIP-L-expressing cells. When cells stably expressing cFLIP-L were stimulated with Wnt3a, enhanced Wnt signaling was observed compared with the control cells. Conversely, depletion of endogenous cFLIP results in reduced Wnt signaling. Furthermore, cFLIP-L increases secondary-body axis formation when coinjected with suboptimal doses of ß-catenin into early Xenopus embryos. Down-regulation of FADD by RNA-mediated interference abolishes the ß-catenin-dependent gene expression induced by cFLIP-L. These results indicate that cFLIP-L, in cooperation with FADD, enhances canonical Wnt signaling by inhibiting proteasomal degradation of ß-catenin, thus suggesting an additional mechanism involved with tumorgenesis, in addition to inhibiting Fas signaling.

M.N. and R.K. contributed equally to this work.

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