2016 Fiscal Year Final Research Report
Dissection of p53-mediated amino acid metabolism
| Project/Area Number |
15K18397
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Tumor biology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Keywords | ASS1 / ｐ５３ / Akt / アルギニン |
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| Outline of Final Research Achievements |
Here, we show that Argininosuccinate synthase 1 (ASS1), a citrulline-aspartate ligase in de novo arginine synthesis pathway, was directly transactivated by p53 in response to genotoxic stress, resulting in the rearrangement of arginine metabolism. Analyses of ASS1-deficient cells generated using the CRISPR-Cas9 system revealed that ASS1 plays a pivotal role in limiting Akt phosphorylation. In addition, aberrant activation of Akt resulting from ASS1 loss disrupted Akt-mediated cell survival signaling activity under genotoxic stress. Building on these results, we demonstrated that p53 induced an intrinsic Akt repressor, ASS1, and the perturbation of ASS1 expression rendered cells susceptible to genotoxic stress. Our findings uncover a new function of p53 in the regulation of Akt signaling and how p53, ASS1, and Akt are interrelated to each other.
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| Free Research Field |
分子生物学
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