| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
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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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