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

• 研究課題/領域番号: 19J15484
• 研究種目: 特別研究員奨励費
• 配分区分: 補助金
• 応募区分: 国内
• 審査区分: 小区分48040:医化学関連
• 研究機関: 熊本大学
• 研究代表者: 馬 文娟 熊本大学, 医学教育部, 特別研究員(DC2)
• 研究期間 (年度): 2019-04-25 – 2021-03-31
• 研究課題ステータス: 完了 (2020年度)
• 配分額: 2,100千円 (直接経費: 2,100千円); 2020年度: 1,000千円 (直接経費: 1,000千円); 2019年度: 1,100千円 (直接経費: 1,100千円)
• キーワード: FLCN / TFE3 / nutrient / hypoxia / HIF / lysosome

研究開始時の研究の概要

Tumor suppressor Folliculin (FLCN) is involved in metabolic pathways via amino acid sensing on lysosomes. Recently, we found that FLCN and Rab related protein co-localize on lysosomes. We hypothesize that lysosome may acts as a decision-making center in nutrient and energy sensing, regulating cell proliferation and differentiation. We aim to clarify how lysosomal signaling pathways respond to external and internal cues and how they ultimately enable metabolic homeostasis and cellular adaptation by FLCN complex.

研究実績の概要

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.

現在までの達成度 (段落)

令和2年度が最終年度であるため、記入しない。

今後の研究の推進方策

令和2年度が最終年度であるため、記入しない。

研究成果

• [国際共同研究] National Cancer Institute, NIH/University of Washington(米国)
• [国際共同研究] NIH(米国)
• [国際共同研究] National University of Singapore(シンガポール)
• [雑誌論文] Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages (2020)
  • 著者名/発表者名: Nasser H, Adhikary P, Abdel-Daim A, Noyori O, Panaampon J, Kariya R, Okada S, Ma W, Baba M, Takizawa H, Yamane M, Niwa H, Suzu S.
  • 雑誌名: Cell Death Discovery 巻: 63 号: 1 ページ: 63-63
  • DOI: 10.1038/s41420-020-00300-3
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • 著者名/発表者名: 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 K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
  • 雑誌名: Molecular Cancer Research 巻: 印刷中 号: 8 ページ: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • 査読あり / オープンアクセス / 国際共著
• [学会発表] Regulation of hypoxia response pathway by chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2020)
  • 著者名/発表者名: 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
  • 学会等名: The 79th Annual Meeting of the Japanese Cancer Association
• [学会発表] Regulation of hypoxia response pathway by chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2019)
  • 著者名/発表者名: 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
  • 学会等名: 先端モデル動物プラットフォーム 2019年度若手支援技術講習会