Impairment of the ubiquitin-proteasome system by cellular FLIP
| Autor: | Michie Nishimoto, Takashi Tsuruo, John C. Reed, Toshiyasu Ishioka, Ritsuko Takada, Shu-ichi Matsuzawa, Ryo Kikuchi, Mikihiko Naito, Ryohei Katayama, Shinji Takada |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Proteasome Endopeptidase Complex
Green Fluorescent Proteins CASP8 and FADD-Like Apoptosis Regulating Protein Down-Regulation Apoptosis Cell Line Ubiquitin Cell Line Tumor Genetics Humans beta Catenin A549 cell Regulation of gene expression biology Wnt signaling pathway Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Cell biology Gene Expression Regulation Neoplastic Proteasome Gene Expression Regulation Flip Cancer cell biology.protein RNA Interference Signal transduction Signal Transduction |
| Zdroj: | Genes to cells : devoted to molecularcellular mechanisms. 12(6) |
| ISSN: | 1356-9597 |
| Popis: | 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 beta-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, beta-catenin and HIF1 alpha, that are subjected to rapid ubiquitylation and degradation by proteasomes. Accordingly, beta-catenin- and HIF1 alpha-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 beta-catenin- and HIF1 alpha-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. |
| Databáze: | OpenAIRE |
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