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Impairment of the ubiquitin‐proteasome system by cellular FLIP
Author(s) -
Ishioka Toshiyasu,
Katayama Ryohei,
Kikuchi Ryo,
Nishimoto Michie,
Takada Shinji,
Takada Ritsuko,
Matsuzawa Shuichi,
Reed John C.,
Tsuruo Takashi,
Naito Mikihiko
Publication year - 2007
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01087.x
Subject(s) - biology , proteasome , microbiology and biotechnology , ubiquitin , apoptosis , signal transduction , gene , biochemistry
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 β‐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, β‐catenin and HIF1α, that are subjected to rapid ubiquitylation and degradation by proteasomes. Accordingly, β‐catenin‐ and HIF1α‐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 β‐catenin‐ and HIF1α‐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.