mTOR in aging, metabolism, and cancer.
01 Feb 2013-Current Opinion in Genetics & Development (Curr Opin Genet Dev)-Vol. 23, Iss: 1, pp 53-62
TL;DR: This review describes the most recent advances in TOR signaling with a particular focus on mammalian TOR (mTOR) in metabolic tissues vis-a-vis aging, obesity, type 2 diabetes, and cancer.
About: This article is published in Current Opinion in Genetics & Development.The article was published on 2013-02-01. It has received 414 citations till now. The article focuses on the topics: TOR signaling & mTORC1.
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TL;DR: Emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling, and this progress has expanded the list of downstream effectors and upstream regulators of m TOR signalling.
Abstract: More than 20 years after its discovery, our understanding of target of rapamycin (TOR) signalling continues to grow. Recent global 'omics' studies have revealed physiological roles of mammalian TOR (mTOR) in protein, nucleotide and lipid synthesis. Furthermore, emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling. Together, this progress has expanded the list of downstream effectors and upstream regulators of mTOR signalling.
920 citations
TL;DR: Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases and its mechanism of action is discussed and the potential utility of combination therapy with rapamycin is highlighted.
860 citations
Cites background from "mTOR in aging, metabolism, and canc..."
...Protein observedwith rictor 1/2 (protor 1/ 2) and DEPTOR are additional regulatory components (Cornu et al., 2013; Laplante and Sabatini, 2012)....
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TL;DR: SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR, and is established as an integral part of the Ragulator–RAG GTPases machinery.
Abstract: Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.
551 citations
TL;DR: The recent trends in exploiting the PI3K/Akt/mTOR pathway towards the molecular targeted therapy using small molecule inhibitors in human cancer are discussed.
508 citations
01 Feb 2009
TL;DR: It is shown that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice, and that deleting one copy of Rictor protects Pten heterozygous mice from prostate cancer.
Abstract: mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.
367 citations
References
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01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
5,553 citations
TL;DR: A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve current concepts for screening and treatment of this disease.
4,768 citations
TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.
Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.
3,684 citations