Regulation of the ubiquitin-proteasome system by cellular FLIP
| Project/Area Number |
17390017
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NAITO Mikihiko The University of Tokyo, Institute of Molecular and Cellular Biosciences, Associate Professor, 分子細胞生物学研究所, 助教授 (00198011)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2006: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2005: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | FLIP / ubiquitin / proteasome / Wnt signal / nuclear localization signal / Wnt / HIF |
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| Research Abstract |
Cellular FLIP (cFLIP) is a homologue of caspase-8 without protease activity, and 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. We showed the followings in this study.
1. 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 HIF1a, that are subjected to rapid ubiquitylation and degradation by proteasomes. Accordingly, β-catenin- and HIF1a-mediated gene expression 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. Downregulation 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.
2. cFLIP-L contains a nuclear localization signal (NLS) on its carboxy terminus, and it shuttles between cytosol and nuclei. cFLIP NLS mutants and cFLIP lacking carboxy terminal 42 as predominantly localize to cytosol, and increase the accumulation of β-catenin but not enhance Wnt signaling. cFLIP-L conjugated with authentic nuclear export signal (NES) also localizes to cytosol and has lost the activity to enhance Wnt signaling. These results suggest that cFLIP-L in nuclei plays a role in Wnt signaling.
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Report
(3 results)
Research Products
(11 results)
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[Journal Article] Impairment of the ubiquitin-proteasome system by cellular FLIP.2007
Author(s)
Ishioka, T., Katayama, R., Kikuchi, R., Nishimoto, M., Takada, S., Takada, R., Matsuzawa, S.I., Reed, J.C., Tsuruo, T., Naito, M.
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Journal Title
Genes Cells 12
Pages: 735-744
Description
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[Journal Article] HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells.2005
Author(s)
Sekine, K., Hao, Y., Suzuki, Y., Takahashi, R., Tsuruo, T., Naito, M.
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Journal Title
Biochem Biophys Res Commun 330
Pages: 279-85
Description
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[Journal Article] Functional characterization of adenosine transport across the BBB in mice.2005
Author(s)
Murakami, H., Ohkura, A., Takanaga, H., Matsuo, H., Koyabu, N., Naito, M., Tsuruo, T., Ohtani, H., Sawada, Y.
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Journal Title
Int J Pharm 290
Pages: 37-44
Description
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[Journal Article] Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production.2005
Author(s)
Dohgu, S., Takata, F., Yamauchi, A., Nakagawa, S., Egawa, T., Naito, M., Tsuruo, T., Sawada, Y., Niwa, M., Kataoka, Y.
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Journal Title
Brain Res 1038
Pages: 208-15
Description
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