Establishment salivary gland-targeted Flcn knockout mice
| Project/Area Number |
18K09382
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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 56050:Otorhinolaryngology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
蓮見 壽史 横浜市立大学, 医学部, 助教 (40749876)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 唾液腺特異的ノックアウトマウス / 条件特異的遺伝子破壊 / FLCN / 唾液腺特異的ノックアウトマウ / FNIP1 / 唾液腺腫瘍 / Birt-Hogg-Dube症候群 / FLCN遺伝子 / ミトコンドリア / mTOR / TFE3 |
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| Outline of Final Research Achievements |
FLCN is a tumor suppressor gene which controls energy homeostasis through regulation of a variety of metabolic pathways including mitochondrial oxidative metabolism and autophagy. Birt-Hogg-Dubé (BHD) syndrome which is driven by germline alteration of the FLCN gene, predisposes patients to develop salivary gland tumors. Here, we report metabolic roles for FLCN in the salivary gland. Salivary gland-targeted Flcn knockout mice developed cytoplasmic clear cell formation in ductal cells with increased mitochondrial biogenesis, upregulated mTOR-S6K pathway, upregulated TFE3-GPNMB axis and upregulated lipid metabolism. Proteomic and metabolite analysis using LC/MS and GC/MS revealed that Flcn inactivation in salivary gland triggers metabolic reprogramming towards the pentose phosphate pathway which consequently upregulates nucleotide synthesis and redox regulation, further supporting that Flcn controls metabolic homeostasis in salivary gland.
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| Academic Significance and Societal Importance of the Research Achievements |
唾液腺腫瘍は種類が多彩でありながら頻度は高くない。加えて、樹立された細胞株が少なく、疾患モデル動物もないため、腫瘍発生・進展メカニズムの研究に用いる材料が極めて限られ、その解明が進んでいなかった。疾患モデル動物については、例えば大腸癌研究でヒトの家族性大腸腺腫症の疾患モデル動物であるAPCノックアウトマウスが作製され、腫瘍形成メカニズムの解明に多大な貢献があったように、唾液腺腫瘍でも自然発生モデルマウスの確立が望まれていた。本研究で作製された疾患モデルマウスを用いて、唾液腺における遺伝子発現・タンパク質発現を網羅的に解析することが可能となり，腫瘍形成メカニズムを解明する端緒とすることができた。
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Report
(4 results)
Research Products
(3 results)
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[Journal Article] FLCN Alteration Drives Metabolic Reprogramming Towards Nucleotide Synthesis and Cyst Formation in Salivary Gland2020
Author(s)
Isono Y, Furuya M, Kuwahara T, Sano D, Suzuki K, Jikuya R, Mitome T, Otake S, Kawahara T, Ito Y, Muraoka K, Nakaigawa N, Kimura Y, Baba M, Nagahama K, Takahata H, Saito I, Schmidt LS, Linehan WM, Kodama T, Yao M, Oridate N, Hasumi H.
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Journal Title
Biochem Biophys Res Commun
Volume: 522
Issue: 4
Pages: 931-938
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
