2002 Fiscal Year Final Research Report Summary
Molecular pathophysiology of bone marrow hypoplasia in Fanconi anemia
| Project/Area Number |
13671082
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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 |
Hematology
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| Research Institution | Jichi Medical School |
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Principal Investigator |
OTSUKI Tetsuya Jichi Medical School, Dept.of Hematology Lecturer, 医学部, 講師 (60275691)
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| Co-Investigator(Kenkyū-buntansha) |
NAGASHIMA Takahiro Jichi Medical School, Assistant, 医学部, 助手
UWAI Masaya Jichi Medical School, Assistant, 医学部, 助手 (80326826)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Fanconi anemia / hypoplasia / IKK-2 / molecular pathophysiology / apoptosis / 分子病態 |
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| Research Abstract |
Fanconi anemia (FA), a genetic disorder predisposing to aplastic anemia and cancer, is characterized by hypersensitivity to DNA-damaging agents and oxidative stress. FA cells have been shown to be hypersensitive to apoptotic stimulus induced by tumor necrosis factor-alpha (TNF-α). TNF-α mediates apoptotic signal through the activation of caspase cascade, whereas anti-apoptotic signal is also mediated by the activation of transcriptional factor, NF-_κB at the same time. For the activation of NF-_κB, induction of 26S proteasome-mediated degradation of inhibitor _κB (I_κB) by I_κB kinase complex (IKK complex) plays an important role. Interestingly, our data showed that IKK2 physically contacted with IKK complex through the direct interaction between FANCA and IKK2, a key component of IKK complex. In vitro kinase assay suggests that components of FANC protein complex are direct substrates of IKK2, and they undergo rapid, TNF-α-induced changes in phosphorylation in vivo, which are blocked by dominant-negative IKK2. These studies suggest a functional role for the IKK complex in the biological pathway is mediated by FANC proteins. Besides TNF-α stimulation, the IKK complex is responsive to ROI signal and to DNA damage, and exerts its protective effect by the activation of NF-_κB, resulting in the transcriptional up-regulation of genes corresponding redox regulation, DNA repair and resistance to apoptosis. The functional interaction between FANC proteins and IKK complex may explain the proapoptotic state of FA cells.
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[Publications] Otsuki T., Furukawa Y., Ikeda K., Endo H., Yamashita T., Shinohara A., Iwamatsu A., Ozawa K., Liu J.M.: "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex"Hum.Mol.Genet.. 10. 2651-2660 (2001)
Description
「研究成果報告書概要(欧文)」より
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