| Project/Area Number |
15590279
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Osaka City University |
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Principal Investigator |
TOKUNAGA Fuminori Osaka City University, Graduate School of Medicine, Associated Professor, 大学院・医学研究科, 助教授 (00212069)
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| Co-Investigator(Kenkyū-buntansha) |
IWAI Kazuhiro Osaka City University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (60252459)
KIRISAKO Takayoshi Osaka City University, Graduate School of Medicine, Assistant, 大学院・医学研究科, 助手 (30347497)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | ubiquitin / hepatitis B virus / NF-κB / transactivation / henatocarcinoma |
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| Research Abstract |
In the course of studies on iron-dependent degradation of iron regulatory protein 2 (IRP2), we identified a RING-type ubiquitin ligase, HOIL-1, that specifically ubiquitinates heme-oxidized IRP2. HOIL-1 had also been characterized as a hepatitis B virus X protein (HBx)-associating protein, although its function was unrevealed. We showed that HOIL-1 associates with HBx through its ubiquitin-like domain, resulting in the partial suppression of transactivation activity. Recently, we further found that HOIL-1 forms a high molecular mass complex with another uncharacterized RING-type containing protein. To investigate the role of HOIL-1 ligase complex on the pathogenesis of hepatitis B virus, we analyzed the effect of HOIL-1 complex on the transactivation activity of HBx. In HepG2 cells, co-expression of HOIL-1 complex with HBx caused to drastic increase (>10-fold) in 6x NF-κB-luciferase (Luc) reporter activity, although Rous sarcoma virus (RSV)-Luc activity was unaffected, suggesting that HBx specifically activates NF-κB pathway through the association with HOIL-1 complex. HOIL-1 complex lacking ubiquitin ligase activity had little effect on the NF-κB-Luc activity of HBx. These results suggested that HBx associates with the HOIL-1 ubiquitin ligase complex and that induces an aberrant activation of NF-κB pathway through ubiquitination activity. The mechanism might play an important role on the hepatocarcinogenesis by hepatitis B virus.
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