期刊
SCIENCE
卷 356, 期 6343, 页码 1188-1192出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aag2553
关键词
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资金
- Italian Telethon Foundation [TGM11CB6]
- MIUR FIRB [RBAP11Z3YA]
- European Research Council [250154, 694282, 341131]
- U.S. National Institutes of Health [R01-NS078072]
- Associazione Italiana per la Ricerca sul Cancro [IG 2015 Id 17639, IG 2015 Id 17717]
- European Research Council (ERC) [341131, 694282] Funding Source: European Research Council (ERC)
The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors-master regulators of lysosomal and melanosomal biogenesis and autophagy-control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth. Up-regulation of MiT/TFE genes in cells and tissues from patients and murine models of renal cell carcinoma, pancreatic ductal adenocarcinoma, and melanoma triggered RagD-mediated mTORC1 induction, resulting in cell hyperproliferation and cancer growth. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells.
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