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¹ Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
² Cancer Chemotherapy Center, Japanese foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan
³ Okazaki Institute for Integrative Biosciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan
⁴ The Burnham Institute for Biomedical Research, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA

Cellular FLIP (cFLIP) is a homologue of caspase-8 without protease activity that inhibits the apoptosis signaling initiated by death receptor ligation. We previously reported that a long form of cFLIP (cFLIP-L) inhibits ubiquitylation of ß-catenin and enhances Wnt signaling. Here we show that cFLIP-L impairs the function of the ubiquitin-proteasome system (UPS), and increases the accumulation of various short-lived proteins, such as GFP conjugated with destabilization sequence, ß-catenin and HIF1, that are subjected to rapid ubiquitylation and degradation by proteasomes. Accordingly, ß-catenin- and HIF1-mediated gene expressions are induced in the cFLIP-L-expressing cells. Exogenously expressed cFLIP-L accumulates in aggregates at the peri-nuclear region in the cells, and the cFLIP-L aggregates are refractory to solubilization. Like exogenously expressed cFLIP-L, the endogenous cFLIP in A549 lung cancer cells displays particulate distribution in the cells and more than 60% of cFLIP-L is refractory to solubilization. Down-regulation of cFLIP in A549 cells by RNA-mediated interference reduced ß-catenin- and HIF1-mediated gene expression. These results suggest that cFLIP-L is prone to aggregate and impairs UPS function, which could be involved in the pathological function of cFLIP-L expressed in certain cancer cells.

^* Correspondence: E-mail: mnaito{at}iam.u-tokyo.ac.jp

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