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Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth

Chiara Di Malta1, Diletta Siciliano1, Alessia Calcagni1

  • 1Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.

Science (New York, N.Y.)
|June 17, 2017
PubMed

Insights

Master regulators of lysosome function, MiT/TFE transcription factors, control mTORC1 activity by regulating RagD. This pathway is crucial for nutrient adaptation and fuels cancer cell growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates anabolic pathways in response to nutrients.
  • mTORC1 is recruited to the lysosome by Rag guanosine triphosphatases (GTPases).

Purpose of the Study:

  • To investigate the role of MiT/TFE transcription factors in mTORC1 regulation.
  • To elucidate the mechanism by which MiT/TFE controls mTORC1 lysosomal recruitment and activity.

Main Methods:

  • Investigated the direct regulation of RagD expression by MiT/TFE transcription factors.
  • Utilized mouse models and human patient samples (renal cell carcinoma, pancreatic ductal adenocarcinoma, melanoma).

Main Results:

  • MiT/TFE transcription factors directly regulate RagD expression, controlling mTORC1 lysosomal recruitment and activity.
  • This mechanism mediates adaptation to nutrient availability in mice after starvation and exercise.
  • Up-regulation of MiT/TFE genes in cancers triggers RagD-mediated mTORC1 induction, promoting cell hyperproliferation and tumor growth.

Conclusions:

  • MiT/TFE transcription factors act as key regulators of the RagD-mTORC1 pathway.
  • This pathway is essential for cellular adaptation to nutrient availability.
  • The MiT/TFE-RagD-mTORC1 axis supports the metabolic demands of cancer cells, driving tumor progression.

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