2021 Fiscal Year Final Research Report
Investigation of abnormal ABCG2 localization regulated by post-transcriptional modification
| Project/Area Number |
19K16408
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | ABCG2 / Ubiquitination / Hyperuricemia / Transporter |
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| Outline of Final Research Achievements |
The ABCG2 transporter (also known as breast cancer resistance protein, BCRP) has a high allele frequency of single nucleotide polymorphisms in Japanese. Among them, the Q141K mutant (c. 421C>A) shows a lower expression, resulting in decreased substrate clearance. In this study, we investigated the mechanism of reduced expression of the Q141K mutant based on post-translational modifications.
Our results showed that wild-type Gln141 might be important for protein stability and that the Q141K mutant is down-regulated due to reduced stability caused by loss of Gln141 as well as ubiquitination at the Lys141, which promotes early to late endosomal translocation.
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| Free Research Field |
薬物動態学
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| Academic Significance and Societal Importance of the Research Achievements |
ABCG2は高尿酸血症や痛風の原因遺伝子として見出されているほか，ABCG2の機能低下は生活習慣病の重要な危険因子と考えられている．他にも，臨床で基質薬物のクリアランスが低下するなど，Q141K変異体は生体ホメオスタシスや薬物治療上の問題点となっている．本検討結果はc.421C>Aによる遺伝性疾患であっても薬物によりUb化を制御することで発現を回復できる可能性を示すものである。本研究により，翻訳後修飾を調節することでトランスポーターを制御し，関連疾患症状の改善および基質薬物の動態を至適化できる新しい方法論を提唱することができるものと期待される．
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