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.

我发现位于溶酶体上的 FLCN 复合物调节 TFE3 转录活性，进而上调代谢基因。我获得了支持FLCN-TFE3-HIF1a轴协调营养和缺氧信号传导的新概念的线索，如下：1）异常激活的TFE3转录因子对缺氧反应途径的调节。我们报道FLCN-TFE3轴通过代谢重编程调节细胞增殖和分化。 2020年，我阐明了异常激活的嵌合TFE3直接转录HIF1a和HIF2a并上调缺氧反应基因。2）嵌合TFE3在肿瘤发生中HIF1a的重要作用。我将 HIF1a 和/或 HIF2a 条件 KO 小鼠与在肾脏中表达致癌嵌合 TFE3 的 KI 小鼠进行了杂交。 HIF1a 敲除显着减少了肾肿瘤的发展，表明其作为嵌合 TFE3 下游分子的重要作用。3）脂质代谢途径作为 TFE3-HIF1a 轴的重要下游。我对表达 TFE3 的嵌合肾脏进行了 RNA 测序，这些肾脏已被 HIF1a 和/或 HIF2a 敲除。 GO分析表明，嵌合TFE3的表达显着上调参与脂质代谢的基因，敲除HIF1a则下调脂质代谢相关基因。4）TFE3-mTORC1-HIF1a轴对脂质代谢的调节。我发现氨基酸饥饿和缺氧应激可以激活嵌合TFE3-HIF转录轴，导致脂质代谢基因上调。

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

TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease.

TFE3 Xp11.2 易位肾细胞癌小鼠模型揭示了新的治疗靶点，并将 GPNMB 确定为人类疾病的诊断标记物。

• DOI: 10.1158/1541-7786.mcr-18-1235
• 发表时间: 2019
• 影响因子: 5.2
• 作者: Baba M; Furuya M; Motoshima T; Lang M; Funasaki S; Ma W; Sun HW; Hasumi H; Huang Y; Kato I; Kadomatsu T; Satou Y; Morris N; Karim BO; Ileva L; Kalen JD; Wilan Krisna LA; Hasumi Y; Sugiyama A; Kurahashi R; Nishimoto K; Oyama M; Nagashima Y; Kuroda N; Araki
• 通讯作者: Araki

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: 2019
• 作者: Wenjuan Ma; Takanobu Motoshima; Yorifumi Satou; Paola Miyazato; Hisashi Hasumi; Tsuyoshi Kadomatsu; Mitsuko Furuya; Yoshiaki Kubota; Masahiro Yao; W. Marston Linehan; Yuichi Oike; Tomomi Kamba; Masaya Baba
• 通讯作者: Masaya Baba

National University of Singapore(シンガポール)

新加坡国立大学

NIH(米国)

美国国立卫生研究院