| Budget Amount *help |
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2009: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
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| Research Abstract |
The tumor suppressor p53 induces cell cycle arrest and apoptosis in response to genotoxic stress. About 50% of human tumors have TP53 gene mutations ; most are missense ones that presumably lower p53's tumor suppressor activity. In this study, we explored the effects of known tumor-derived missense mutations on the stability and oligomeric structure of p53. The results suggested that threshold for loss of tumor suppressor activity in terms of the disruption of p53's tetrameric structure could be extremely low. We developed a calixarene derivative that could increase the tetrameric stability of the mutant R337H, which is found in Li-Fraumeni syndrome, a hereditary disorder characterized by familial clusters of early-onset multiple tumors. We also showed that the tetramer stability increased through the evolution of vertebrates : fish-amphibian-bird and mammals. The results suggested that the folding of the tetramerization domain would tightly control its functional expression.
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