An mTOR-TFEB Feedback Loop Controls the Response to Starvation and Physical Exercise and Is Deregulated in Cancer

Identification: Ballabio, Andrea


Description

An mTOR-TFEB Feedback Loop Controls the Response to Starvation and Physical Exercise and is Deregulated in Cancer
 
Andrea Ballabio, M.D.
1Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy; 2Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA; 3Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy; 4Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, Texas, USA
 
The mechanistic target of rapamycin (mTOR) protein kinase plays a crucial role in the adaptation of cell metabolism to environmental cues. mTOR is assembled into two main protein complexes: the nutrient sensitive, lysosome-associated, mTOR Complex 1 (mTORC1) and the growth factor-activated mTOR Complex 2 (mTORC2). The mechanism by which nutrients promote the association of mTORC1 to the lysosomal surface is mediated by the activation of Rag GTPases (Rag A,B,C,D). We identified a lysosomal gene network and a master gene, TFEB, that regulate lysosomal biogenesis and autophagy. The function of TFEB is regulated by mTOR-mediated phosphorylation that controls its subcellular localization. In the presence of nutrients mTOR phosphorylates TFEB, promoting cytoplasmic retention, whereas during starvation de-phosphorylated TFEB translocates to the nucleus. In addition to TFEB, two other members of the MiT-TFE family of transcription factors, TFE3 and MITF, are also phosphorylated by mTOR and are regulated by similar mechanisms. Recently, we discovered that MiT-TFE transcription factors, which are substrates of mTOR, in turn control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD GTPase. 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 hyper-proliferation and cancer growth. Consistently, silencing of RagD suppressed cancer growth in melanoma xenotransplantation experiments. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells.
 
 
 
 
 
 
 

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