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

• Project/Area Number: 19J15484
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kumamoto University
• Principal Investigator: 馬 文娟 熊本大学, 医学教育部, 特別研究員(DC2)
• Project Period (FY): 2019-04-25 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,100,000 (Direct Cost: ¥2,100,000); Fiscal Year 2020: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2019: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: FLCN / TFE3 / nutrient / hypoxia / HIF / lysosome

Outline of Research at the Start

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.

Outline of Annual Research Achievements

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.

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] National Cancer Institute, NIH/University of Washington(米国)
• [Int'l Joint Research] NIH(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Journal Article] Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages (2020)
  • Author(s): 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.
  • Journal Title: Cell Death Discovery Volume: 63 Issue: 1 Pages: 63-63
  • DOI: 10.1038/s41420-020-00300-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • Author(s): 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
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 8 Pages: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Regulation of hypoxia response pathway by chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2020)
  • Author(s): 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
  • Organizer: The 79th Annual Meeting of the Japanese Cancer Association
• [Presentation] Regulation of hypoxia response pathway by chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2019)
  • Author(s): 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
  • Organizer: 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