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

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19J15484
• 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
• Keywords: FLCN / TFE3 / nutrient / hypoxia / HIF

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)
  • Country Name: U.S.A.
  • Counterpart Institution: National Cancer Institute, NIH/University of Washington
• [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 Pages: -
  • DOI: 10.1038/s41420-020-00300-3. eCollection 2020.
  • 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