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Science. 2017 Jun 16;356(6343):1188-1192. doi: 10.1126/science.aag2553.

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth.

Author information

1
Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
2
Department of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy.
3
Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Anatomy and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
5
Department of Molecular and Cellular Biology and Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
6
Department of Pharmacology, University of Oxford, Oxford, UK.
7
Department of Biochemistry and Molecular Biology, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
8
Department of Oncology, University of Milan, 20139 Milan, Italy.
9
Dulbecco Telethon Institute, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
10
Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131 Naples, Italy.
11
Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy. ballabio@tigem.it.

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.

PMID:
28619945
PMCID:
PMC5730647
DOI:
10.1126/science.aag2553
[Indexed for MEDLINE]
Free PMC Article

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