2011 Fiscal Year Final Research Report
Stability Change of Tetrameric Structure of Tumor Suppressor Protein p53 in Mutation and Evolution, and Threshold for Loss of Tumor Suppressor Activity in Terms of Disruption of the Tetrameric Structure.
| Project/Area Number |
21310133
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Living organism molecular science
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
TOSHIAKI Imagawa 北海道大学, 大学院・理学研究院, 准教授 (20142177)
CHUMAN Yoshiro 北海道大学, 大学院・理学研究院, 助教 (40372263)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 蛋白質 / 癌 / シグナル伝達 / 系統進化 / 生体分子 |
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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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[Journal Article] Characterization of a new cancer-associated mutant of p53 with a missense mutation(K351N) in the tetramerization domain2009
Author(s)
M. Muscolini, E. Montagni, S. Caristi, T.Nomura, R. Kamada, S. Di Agostino, M. Corazzaari, M. Piacentini, G. Blandino, A. Costanzo, K. Sakaguchi, and L. Tuosto
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Journal Title
Cell Cycle
Volume: 8
Pages: 3396-405
Peer Reviewed
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