エネルギー・栄養感知と細胞分化・増殖シグナルハブとしてのライソゾーム新機能の解明

阐明溶酶体作为能量/营养传感和细胞分化/增殖信号中心的新功能

• 批准号: 19J15484
• 负责人: 馬 文娟
• 金额: $ 1.34万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2019
• 资助国家: 日本
• 起止时间: 2019-04-25 至 2021-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-19J15484/
• 关键词: FLCN; TFE3; nutrient; hypoxia; HIF; lysosome

I have found that FLCN complex localizing on the lysosome regulates TFE3 transcriptional activity, which in turn upregulate metabolic genes. I have obtained a clue to support a new concept that FLCN-TFE3-HIF1a axis coordinate nutrient and hypoxia signaling as follows.1) Regulation of hypoxia response pathway by aberrantly activated TFE3 transcription factor. We have reported that FLCN-TFE3 axis regulates cell proliferation and differentiation through the metabolic reprogramming. In 2020, I clarified that aberrantly activated chimeric TFE3 directly transcribed HIF1a and HIF2a and upregulated hypoxia responsive genes.2) Essential role of HIF1a in tumorigenesis by a chimeric TFE3. I have crossed HIF1a and / or HIF2a conditional KO mice with KI mice which express oncogenic chimeric TFE3 in kidneys. HIF1a knockout significantly reduced kidney tumor development, indicating its essential role as a downstream molecule of chimeric TFE3.3) Lipid metabolism pathway as an important downstream of TFE3-HIF1a axis. I performed RNA sequencing on chimeric TFE3 expressing kidneys which were knockout with HIF1a and / or HIF2a. GO analysis demonstrated that genes involved in lipid metabolism were significantly upregulated by the expression of chimeric TFE3 and downregulated by knockingout HIF1a.4) Regulation of lipid metabolism by TFE3-mTORC1-HIF1a axis. I found that amino acid starvation and hypoxia stress could activate chimeric TFE3-HIF transcriptional axis, resulting in upregulation of lipid metabolism genes.

我发现，定位于溶酶体上的Flcn复合体调节TFE3的转录活性，进而上调代谢基因。1)异常激活的TFE3转录因子对低氧反应通路的调控。我们已经报道，Flcn-TFE3轴通过代谢重编程来调节细胞的增殖和分化。2020年，我澄清了异常激活的嵌合体TFE3直接转录HIF1a和HIF2a，并上调缺氧反应基因2)HIF1a在嵌合体TFE3的肿瘤发生中的重要作用。我将HIF1a和/或HIF2a条件性KO小鼠与在肾脏中表达致癌嵌合TFE3的KI小鼠杂交。HIF1a基因敲除显著减少了肾脏肿瘤的发生，表明其作为TFE3-HIF1a轴下游的重要分子，是嵌合TFE3.3脂代谢途径的下游分子。我对表达嵌合TFE3的肾脏进行了RNA测序，这些肾脏被HIF1a和/或HIF2a敲除。GO分析表明，TFE3嵌合基因表达显著上调，HIF1a基因敲除后显著下调。4)TFE3-mTORC1-HIF1a轴对脂质代谢的调控。我发现氨基酸饥饿和低氧应激可以激活TFE3-HIF嵌合转录轴，导致脂代谢基因上调。

项目成果

Regulation of hypoxia response pathway by chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma

Xp11.2易位肾细胞癌中发现的嵌合TFE3转录因子对缺氧反应途径的调节

• 发表时间: 2020
• 作者: Wenjuan Ma;Takanobu Motoshima;Shintaro Funasaki;Yorifumi Satou;Tan Benjy Jek Yang;Hisashi Hasumi;Mitsuko Furuya;Masahiro Yao;W. Marston Linehan;Yuichi Oike;Toshio Suda;Tomomi Kamba;Masaya Baba
• 通讯作者: Masaya Baba

NIH(米国)

美国国立卫生研究院

National University of Singapore(シンガポール)

新加坡国立大学

National Cancer Institute, NIH/University of Washington(米国)

国家癌症研究所、NIH/华盛顿大学（美国）

Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages

• DOI: 10.1038/s41420-020-00300-3
• 发表时间: 2020-07-23
• 期刊: CELL DEATH DISCOVERY
• 影响因子: 7
• 作者: Nasser, Hesham;Adhikary, Partho;Suzu, Shinya
• 通讯作者: Suzu, Shinya