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.

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth / 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; Ballabio, Andrea. - In: SCIENCE. - ISSN 1095-9203. - 356:6343(2017), p. 1188-1192. [10.1126/science.aag2553]

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth

DI MALTA, Chiara;Calcagni, Alessia;Pastore, Nunzia;SETTEMBRE, CARMINE;BALLABIO, ANDREA
2017

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.
2017
Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth / 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; Ballabio, Andrea. - In: SCIENCE. - ISSN 1095-9203. - 356:6343(2017), p. 1188-1192. [10.1126/science.aag2553]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/678338
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 159
  • ???jsp.display-item.citation.isi??? 148
social impact