| Project/Area Number |
14GS0322
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| Research Category |
Grant-in-Aid for Creative Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Institution | Osaka City University |
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Principal Investigator |
IWAI Kazuhiro Osaka City University, Graduate School of Medicine, Professor (60252459)
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| Co-Investigator(Kenkyū-buntansha) |
MORI Hiroshi Osaka City University, Graduate School of Medicine, Professor (10159189)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥345,150,000 (Direct Cost: ¥265,500,000、Indirect Cost: ¥79,650,000)
Fiscal Year 2006: ¥90,480,000 (Direct Cost: ¥69,600,000、Indirect Cost: ¥20,880,000)
Fiscal Year 2005: ¥84,890,000 (Direct Cost: ¥65,300,000、Indirect Cost: ¥19,590,000)
Fiscal Year 2004: ¥84,890,000 (Direct Cost: ¥65,300,000、Indirect Cost: ¥19,590,000)
Fiscal Year 2003: ¥84,890,000 (Direct Cost: ¥65,300,000、Indirect Cost: ¥19,590,000)
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| Keywords | protein / biological molecules / stress / cancer / neurodegenerative diseases |
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| Research Abstract |
1. Functional analyses of the HOIL-1 ubiquitin ligase
a. Mechanism of target recognition by HOIL-1 A heme-regulatory motif (HRM) in IRP2 is the heme-binding site of IRP2. Oxidative modification of IRP2, generated by heme bound to the HRM and oxygen is recognized by HOIL-1, which leads to IRP2 ubiquitination. From these analyses, we show a novel iron-sensing mechanism, in which cells are sensing changes in iron concentration through heme (Nature Cell Biology, 2003; Molecular Cell, 2005).
b. Function of the ligase complex containing HOIL-1 The LUBAC ubiquitin ligase complex, composed of HOIP and HOIL-1L, an isoform of HOIL-1, generates a novel polyubiquitin chain, in which C-terminal Gly residue of ubiquitin is conjugated to a-amino group of N-terminal Met of ubiquitin (EMBO J. 2006).
c. Physiological roles of the HOIL-1 ligase We have shown that LUBAC selectively activates the NF-kB pathway through linear ubiquitination of NEMO (In submission).
2. We showed that the SCF^<Fbs1> ligase selectively recognizes the chitobiose portion of the N-linked sugar chain, which recognition mechanism is suitable for selective recognition of denatured glycoproteins (Nature, 2002; Nat. Strut. Mol. Biol., 2004).
3. We have generated transgenic mice expressing IRP2 in neuron (IRP2 Tg) and analyzed the roles of oxidative stress generated by perturbation of iron metabolism in neurodegenerative disorders. Although massive iron accumulation was not observed, reactive Fe 2+ was accumulated in IRP2 Tg neurons, which provokes oxidative damages in those cells. Also, neuronal loss and ataxia was observed in aged IRP2 Tg mice (In submission).
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