1. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth
- Author
-
Di Malta, Chiara, Siciliano, Diletta, Calcagni, Alessia, Monfregola, Jlenia, Punzi, Simona, Pastore, Nunzia, Eastes, Andrea N, Davis, Oliver, De Cegli, Rossella, Zampelli, Angela, Di Giovannantonio, Luca G, Nusco, Edoardo, Platt, Nick, Guida, Alessandro, Ogmundsdottir, Margret Helga, Lanfrancone, Luisa, Perera, Rushika M, Zoncu, Roberto, Pelicci, Pier Giuseppe, Settembre, Carmine, and Ballabio, Andrea
- Subjects
Digestive Diseases ,Genetics ,Nutrition ,Cancer ,Underpinning research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Animals ,Caloric Restriction ,Cell Line ,Tumor ,Cell Proliferation ,Cells ,Cultured ,Feedback ,Physiological ,Gene Expression Regulation ,Neoplastic ,HEK293 Cells ,HeLa Cells ,Hep G2 Cells ,Humans ,Liver ,Male ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Mice ,Inbred C57BL ,Neoplasms ,Signal Transduction ,Hela Cells ,General Science & Technology - Abstract
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.
- Published
- 2017