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Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth

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Science  16 Jun 2017:
Vol. 356, Issue 6343, pp. 1188-1192
DOI: 10.1126/science.aag2553

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Preparing for the feast during the fast

A protein kinase complex known as mTORC1 plays a key role in cellular metabolism and nutrient sensing. Di Malta et al. elucidated a mechanism that regulates the metabolic changes that are necessary during the fast-to-feed transition. During starvation, a pair of transcription factors promotes the expression of a pair of guanosine triphosphatases that are required for mTORC1 activity and for its recruitment to the lysosome. However, mTORC1 activity also requires amino acids, which are lacking during starvation. Nevertheless, the cell becomes “primed” by this process so that on refeeding, it efficiently reactivates mTORC1, which is recruited to the lysosomal surface. This mechanism is particularly important in cancer cells.

Science, this issue p. 1188

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.

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