Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth

Chiara Di Malta, Diletta Siciliano, Alessia Calcagni, Jlenia Monfregola, Simona Punzi, Nunzia Pastore, Andrea N. Eastes, Oliver Davis, Rossella De Cegli, Angela Zampelli, Luca G. Di Giovannantonio, Edoardo Nusco, Nick Platt, Alessandro Guida, Margret Helga Ogmundsdottir, Luisa Lanfrancone, Rushika M. Perera, Roberto Zoncu, Pier Giuseppe Pelicci, Carmine SettembreAndrea Ballabio

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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.

Original languageEnglish
Pages (from-to)1188-1193
Number of pages6
JournalScience
Volume356
Issue number6343
DOIs
Publication statusPublished - Jun 16 2017

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Cite this

Di Malta, C., Siciliano, D., Calcagni, A., Monfregola, J., Punzi, S., Pastore, N., Eastes, A. N., Davis, O., De Cegli, R., Zampelli, A., Di Giovannantonio, L. G., Nusco, E., Platt, N., Guida, A., Ogmundsdottir, M. H., Lanfrancone, L., Perera, R. M., Zoncu, R., Pelicci, P. G., ... Ballabio, A. (2017). Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science, 356(6343), 1188-1193. https://doi.org/10.1126/science.aag2553