2020 Fiscal Year Final Research Report
Studying and targeting a proto-oncogenic Internal Ribosome Entry Site (IRES) in p53 mRNA that is activated by the most frequent mutations in cancer
| Project/Area Number |
18K07229
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | cancer / p53 / Delta160p53 / Cancer mutation / mRNA translation / IRES / GOF mutation / regulatory mRNA |
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| Outline of Final Research Achievements |
Full-length (FL) p53 protein from the p53 gene is a tumor suppressor. I have shown before, however, that a shorter p53 protein, D160p53, promotes cancer cell growth and invasion and is often present in cells with mutated p53. Here we could understand how D160p53 is produced in cancer cells and the impact this has for cancer progression. D160p53 protein is fabricated through an alternative process of protein synthesis that uses a specific RNA structure called IRES. The sequence that codes for this IRES in the p53 gene is often mutated in cancer. This leads to excessive and uncontrolled synthesis of D160p53 in these cells, ultimately facilitating tumor expansion. Interestingly, the mutations that activate the IRES are the most common mutations in p53 and have been known as “gain-of-function” (GOF) mutations because they create “new” oncogenic functions, though it was never understood how. We propose that GOF mutations activate an IRES that produces the pro-oncogenic protein D160p53.
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| Free Research Field |
cancer/p53/translation/regulatory mRNA
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| Academic Significance and Societal Importance of the Research Achievements |
今回の成果により、40年来の疑問であった「なぜ、がん抑制遺伝子p53は、たった1回の変異でがん遺伝子（がんを促進する遺伝子）になるのか？私たちはこう答えました。それは、1つの変異がmRNAとタンパク質に同時に作用するからです。蛋白質のアミノ酸の変化は、完全長（FL）p53として知られる癌抑制蛋白質を不活性化し、一方、mRNAのヌクレオチドの変化は、癌化を促進する機能を持つΔ160p53と呼ばれる短いp53蛋白質の合成を活性化するのである。p53が発見されてから40年が経過した今、私たちはついにp53の発癌性の活性化を標的にして、全人類の癌の50％以上を治癒することを試みることができるのです。
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