RESUMEN
Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , ADN Helicasas/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Esclerosis Tuberosa/metabolismo , Secuencia de Aminoácidos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Gránulos Citoplasmáticos/efectos de los fármacos , Gránulos Citoplasmáticos/metabolismo , ADN Helicasas/química , Evolución Molecular , Femenino , Humanos , Insulina/farmacología , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fenotipo , Proteínas de Unión a Poli-ADP-Ribosa/química , ARN Helicasas/química , Proteínas con Motivos de Reconocimiento de ARN/química , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Pez Cebra/metabolismoRESUMEN
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.
Asunto(s)
Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/metabolismo , Biosíntesis de Proteínas , Animales , Comunicación Autocrina , Cisteína/metabolismo , Glutatión/metabolismo , Humanos , Ratones , Organoides/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.
Asunto(s)
Embrión de Mamíferos/citología , Complejos Multiproteicos/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Albúminas/metabolismo , Aminoácidos/metabolismo , Animales , Proliferación Celular , Supervivencia Celular , Eucariontes/clasificación , Eucariontes/citología , Eucariontes/metabolismo , Fibroblastos/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Pinocitosis , Proteínas/química , Proteínas ras/metabolismoRESUMEN
The uptake of macromolecules and cellular debris through macropinocytosis has emerged as an important nutrient acquisition strategy of cancer cells. Genetic alterations commonly found in human cancers (e.g. mutations in KRAS or loss of PTEN) have been shown to increase macropinocytosis. To identify additional effectors that enable cell growth dependent on the uptake of extracellular proteins, pancreatic ductal adenocarcinoma (PDA) cells were selected for growth in medium where extracellular albumin was the obligate source of the essential amino acid leucine. Analysis of global changes in chromatin availability and gene expression revealed that PDA cells selected under these conditions exhibited elevated activity of the transcriptional activators Yap/Taz. Knockout of Yap/Taz prevented growth of PDA cells in leucine-deficient medium, but not in complete medium. Furthermore, constitutively active forms of Yap or Taz were sufficient to stimulate macropinocytosis of extracellular protein. In addition to promoting the uptake of plasma proteins, Yap/Taz also promoted the scavenging of apoptotic cell bodies and necrotic debris by PDA cells. The Yap/Taz transcriptional target Axl was found to be essential for cell growth dependent on the uptake of dead cells and cell debris. Together, these studies suggest that the Hippo pathway effectors Yap and Taz are important transcriptional regulators of endocytic nutrient uptake.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Nutrientes/metabolismo , Pinocitosis/fisiología , Factores de Transcripción/metabolismo , Aciltransferasas , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Espacio Extracelular/metabolismo , Humanos , Ratones , Proteínas Señalizadoras YAPRESUMEN
Glycosphingolipids are a structurally diverse class of lipids that regulate plasma membrane protein function. Rizzo et al (2021) now show that GOLPH3 promotes intra-Golgi transport of several enzymes that function at branching points of sphingolipid biosynthesis. By regulating the cellular sphingolipidome, GOLPH3 promotes growth factor signaling and cell proliferation, which may explain its oncogenic properties.
Asunto(s)
Aparato de Golgi , Proteínas de la Membrana , Proliferación Celular , Glicoesfingolípidos , Proteínas de la Membrana/genética , Transducción de SeñalRESUMEN
Lipids exert diverse functions in living organisms. They form cellular membranes, store and transport energy and play signalling roles. Some lipid species function in all of these processes, making them ideal candidates to coordinate metabolism with cellular homeostasis and animal development. This theme was central to Suzanne Eaton's research in the fruit fly, Drosophila Here, we discuss her work on membrane lipid homeostasis in changing environments and on functions for lipids in the Hedgehog signalling pathway. We further highlight lipoproteins as inter-organ carriers of lipids and lipid-linked morphogens, which communicate dietary and developmental signals throughout the organism.
Asunto(s)
Proteínas Hedgehog/genética , Metabolismo de los Lípidos/genética , Lípidos/genética , Lipoproteínas/genética , Animales , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Proteínas Hedgehog/metabolismo , Homeostasis/genética , Lipoproteínas/metabolismo , Transducción de Señal/genéticaRESUMEN
Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane transporters and endolysosomal pathways. By using different nutrient sources, cells gain metabolic flexibility to survive periods of starvation. Quiescent cells take up sufficient nutrients to sustain homeostasis. However, proliferating cells depend on growth-factor-induced increases in nutrient uptake to support biomass formation. Here, we review cellular nutrient acquisition strategies and their regulation by growth factors and cell-intrinsic nutrient sensors. We also discuss how oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells.
Asunto(s)
Células/metabolismo , Animales , Proliferación Celular , Células/citología , Endocitosis , Glucosa/metabolismo , Glutamina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lisosomas/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Pinocitosis , Proteínas/química , Proteínas/metabolismo , Microambiente TumoralRESUMEN
Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates non-selective uptake of extracellular fluid in bulk. Macropinocytosis is initiated by localized polymerization of the actin cytoskeleton, which generates plasma membrane protrusions that enclose part of the environment into large endocytic vesicles. From amoebae to mammalian cells, the actin dynamics that drive macropinosome formation are regulated by a conserved set of intracellular signaling proteins including Ras superfamily GTPases and PI3-kinases. In mammalian cells, multiple upstream signaling pathways control activity of these core regulators in response to cell-extrinsic and cell-intrinsic stimuli. Growth factor signaling pathways play a central role in macropinocytosis induction. In addition, an increasing number of functionally diverse processes has been identified as macropinocytosis regulators, including several nutrient-sensing and developmental signaling pathways. Many of these signaling pathways have proto-oncogenic properties, and their dysregulation drives the high macropinocytic activity that is commonly observed in cancer cells. These regulatory principles illustrate how macropinocytosis is controlled by complex upstream inputs to exert diverse cellular functions in physiological and pathological contexts.
Asunto(s)
Pinocitosis , Transducción de Señal , Citoesqueleto de Actina , Animales , Endosomas , Péptidos y Proteínas de Señalización Intercelular , Mamíferos , Pinocitosis/fisiología , Transducción de Señal/fisiologíaRESUMEN
Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.
Asunto(s)
Aminoácidos/metabolismo , Regulación de la Expresión Génica , Complejos Multiproteicos/metabolismo , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/genética , Células HEK293 , Humanos , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Proteínas Nucleares/metabolismoRESUMEN
Ras-transformed cells can grow in amino acid-poor environments by recovering amino acids through macropinocytosis and lysosomal catabolism of extracellular proteins. However, when studying nontransformed fibroblasts, we found that Ras GTPases are dispensable for growth-factor-stimulated macropinocytosis and lysosomal catabolism of extracellular proteins. Instead, we establish a critical role for phosphatidylinositol 3-kinase (PI3-kinase) signaling in cell proliferation that is supported by protein macropinocytosis. Downstream of PI3-kinase, distinct effectors have opposing roles in regulating uptake and catabolism of extracellular proteins. Rac1 and PLC are required for nutritional use of extracellular proteins. In contrast, Akt suppresses lysosomal catabolism of ingested proteins when free amino acids are abundant. The interplay between these pathways allows cells with oncogenic PIK3CA mutations or PTEN deletion to grow using diverse amino acid sources. Thus, the prevalence of PI3-kinase and PTEN mutations in cancer may result in part because they allow cells to cope with fluctuating nutrient availability.
Asunto(s)
Aminoácidos/metabolismo , Proliferación Celular , Fibroblastos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Pinocitosis/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Células Cultivadas , Fibroblastos/citología , Ratones , Fosforilación , Transducción de Señal , Proteínas ras/metabolismoRESUMEN
Hedgehog (Hh) proteins control animal development and tissue homeostasis. They activate gene expression by regulating processing, stability, and activation of Gli/Cubitus interruptus (Ci) transcription factors. Hh proteins are secreted and spread through tissue, despite becoming covalently linked to sterol during processing. Multiple mechanisms have been proposed to release Hh proteins in distinct forms; in Drosophila, lipoproteins facilitate long-range Hh mobilization but also contain lipids that repress the pathway. Here, we show that mammalian lipoproteins have conserved roles in Sonic Hedgehog (Shh) release and pathway repression. We demonstrate that lipoprotein-associated forms of Hh and Shh specifically block lipoprotein-mediated pathway inhibition. We also identify a second conserved release form that is not sterol-modified and can be released independently of lipoproteins (Hh-N*/Shh-N*). Lipoprotein-associated Hh/Shh and Hh-N*/Shh-N* have complementary and synergistic functions. In Drosophila wing imaginal discs, lipoprotein-associated Hh increases the amount of full-length Ci, but is insufficient for target gene activation. However, small amounts of non-sterol-modified Hh synergize with lipoprotein-associated Hh to fully activate the pathway and allow target gene expression. The existence of Hh secretion forms with distinct signaling activities suggests a novel mechanism for generating a diversity of Hh responses.
Asunto(s)
Proteínas de Drosophila/metabolismo , Proteínas Hedgehog/metabolismo , Lipoproteínas/metabolismo , Animales , Drosophila , Células HeLa , Humanos , Inmunoprecipitación , Mamíferos , Transducción de Señal/genética , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Proteína con Dedos de Zinc GLI1RESUMEN
Interorgan lipid transport occurs via lipoproteins, and altered lipoprotein levels correlate with metabolic disease. However, precisely how lipoproteins affect tissue lipid composition has not been comprehensively analyzed. Here, we identify the major lipoproteins of Drosophila melanogaster and use genetics and mass spectrometry to study their assembly, interorgan trafficking, and influence on tissue lipids. The apoB-family lipoprotein Lipophorin (Lpp) is the major hemolymph lipid carrier. It is produced as a phospholipid-rich particle by the fat body, and its secretion requires Microsomal Triglyceride Transfer Protein (MTP). Lpp acquires sterols and most diacylglycerol (DAG) at the gut via Lipid Transfer Particle (LTP), another fat body-derived apoB-family lipoprotein. The gut, like the fat body, is a lipogenic organ, incorporating both de novo-synthesized and dietary fatty acids into DAG for export. We identify distinct requirements for LTP and Lpp-dependent lipid mobilization in contributing to the neutral and polar lipid composition of the brain and wing imaginal disc. These studies define major routes of interorgan lipid transport in Drosophila and uncover surprising tissue-specific differences in lipoprotein lipid utilization.
Asunto(s)
Transporte Biológico/genética , Drosophila melanogaster , Metabolismo de los Lípidos/genética , Lipoproteínas , Animales , Apolipoproteínas B/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Diglicéridos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Cuerpo Adiposo/metabolismo , Ácidos Grasos/metabolismo , Hemolinfa/metabolismo , Discos Imaginales/metabolismo , Lipoproteínas/química , Lipoproteínas/genética , Lipoproteínas/metabolismo , Distribución TisularRESUMEN
The Drosophila tracheal system is a useful model for dissecting the molecular mechanisms controlling the assembly and expansion of tubular organs. We have identified microsomal triacylglycerol transfer protein (MTP) as a new player involved in the lumen expansion in unicellular tubes. MTP is an endoplasmic reticulum resident protein that can transfer triglycerides and phospholipids between membranes in vitro. MTP lipid transfer activity is crucial for the assembly and secretion of apoB family lipoproteins, which are carriers of lipids between different tissues. Here we describe an unexpected role of MTP in tracheal development, which we postulate to be independent of its known function in lipoprotein secretion. We propose that, in tracheal cells, MTP is involved in regulation of de novo apical membrane delivery to the existing lumen and thus promotes proper expansion of the larval tracheal system.
Asunto(s)
Proteínas Portadoras/metabolismo , Tráquea/metabolismo , Triglicéridos/metabolismo , Animales , Proteínas Portadoras/genética , Drosophila , Femenino , Masculino , Modelos AnimalesRESUMEN
Lysosomes degrade and recycle macromolecules that are delivered through the biosynthetic, endocytic, and autophagic routes. Hydrolysis of the different classes of macromolecules is catalyzed by about 70 soluble enzymes that are transported from the Golgi apparatus to lysosomes in a mannose 6-phosphate (M6P)-dependent process. The molecular machinery that generates M6P tags for receptor-mediated targeting of lysosomal enzymes was thought to be understood in detail. However, recent studies on the M6P pathway have identified a previously uncharacterized core component, yielded structural insights in known components, and uncovered functions in various human diseases. Here we review molecular mechanisms of lysosomal enzyme trafficking and discuss its relevance for rare lysosomal disorders, cancer, and viral infection.
Asunto(s)
Proteínas Portadoras , Lisosomas , Humanos , Proteínas Portadoras/metabolismo , Lisosomas/metabolismoRESUMEN
Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
Asunto(s)
Senescencia Celular , Factor 5A Eucariótico de Iniciación de Traducción , Mitocondrias , Factores de Iniciación de Péptidos , Biosíntesis de Proteínas , Proteínas de Unión al ARN , Proteína p53 Supresora de Tumor , Factores de Iniciación de Péptidos/metabolismo , Factores de Iniciación de Péptidos/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Mitocondrias/metabolismo , Animales , Ratones , Vigilancia Inmunológica , Poliaminas/metabolismo , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Lisina/metabolismo , Lisina/análogos & derivadosRESUMEN
The high sterol concentration in eukaryotic cell membranes is thought to influence membrane properties such as permeability, fluidity and microdomain formation. Drosophila cannot synthesize sterols, but do require them for development. Does this simply reflect a requirement for sterols in steroid hormone biosynthesis, or is bulk membrane sterol also essential in Drosophila? If the latter is true, how do they survive fluctuations in sterol availability and maintain membrane homeostasis? Here, we show that Drosophila require both bulk membrane sterol and steroid hormones in order to complete adult development. When sterol availability is restricted, Drosophila larvae modulate their growth to maintain membrane sterol levels within tight limits. When dietary sterol drops below a minimal threshold, larvae arrest growth and development in a reversible manner. Strikingly, membrane sterol levels in arrested larvae are dramatically reduced (dropping sixfold on average) in most tissues except the nervous system. Thus, sterols are dispensable for maintaining the basic membrane biophysical properties required for cell viability; these functions can be performed by non-sterol lipids when sterols are unavailable. However, bulk membrane sterol is likely to have essential functions in specific tissues during development. In tissues in which sterol levels drop, the overall level of sphingolipids increases and the proportion of different sphingolipid variants is altered. These changes allow survival, but not growth, when membrane sterol levels are low. This relationship between sterols and sphingolipids could be an ancient and conserved principle of membrane homeostasis.
Asunto(s)
Drosophila/crecimiento & desarrollo , Drosophila/metabolismo , Esteroles/metabolismo , Animales , Animales Modificados Genéticamente , Membrana Celular/metabolismo , Supervivencia Celular , Células Cultivadas , Drosophila/embriología , Drosophila/fisiología , Embrión no Mamífero , Hormonas/metabolismo , Larva/crecimiento & desarrollo , Larva/metabolismo , Modelos Biológicos , Esfingolípidos/metabolismo , Esteroides/metabolismo , Sobrevida/fisiologíaRESUMEN
Cells produce tens of thousands of different lipid species, but the importance of this complexity in vivo is unclear. Analysis of individual tissues and cell types has revealed differences in abundance of individual lipid species, but there has been no comprehensive study comparing tissue lipidomes within a single developing organism. Here, we used quantitative shotgun profiling by high-resolution mass spectrometry to determine the absolute (molar) content of 250 species of 14 major lipid classes in 6 tissues of animals at 27 developmental stages raised on 4 different diets. Comparing these lipidomes revealed unexpected insights into lipid metabolism. Surprisingly, the fatty acids present in dietary lipids directly influence tissue phospholipid composition throughout the animal. Furthermore, Drosophila differentially regulates uptake, mobilization and tissue accumulation of specific sterols, and undergoes unsuspected shifts in fat metabolism during larval and pupal development. Finally, we observed striking differences between tissue lipidomes that are conserved between phyla. This study provides a comprehensive, quantitative and expandable resource for further pharmacological and genetic studies of metabolic disorders and molecular mechanisms underlying dietary response.
Asunto(s)
Dieta , Drosophila/metabolismo , Metabolismo de los Lípidos/fisiología , Lípidos/química , Animales , Encéfalo , Drosophila/química , Drosophila/crecimiento & desarrollo , Cuerpo Adiposo/química , Ácidos Grasos/análisis , Ácidos Grasos/química , Intestinos/química , Lípidos/análisis , Redes y Vías Metabólicas , Modelos Biológicos , Fosfolípidos/análisis , Fosfolípidos/química , Glándulas Salivales/química , Esteroles/análisis , Esteroles/química , Espectrometría de Masas en Tándem , Distribución Tisular , Alas de Animales/químicaRESUMEN
The shelterin complex at mammalian telomeres contains the single-stranded DNA-binding protein Pot1, which regulates telomere length and protects chromosome ends. Pot1 binds Tpp1, the shelterin component that connects Pot1 to the duplex telomeric DNA-binding proteins Trf1 and Trf2. Control of telomere length requires that Pot1 binds Tpp1 as well as the single-stranded telomeric DNA, but it is not known whether the protective function of Pot1 depends on Tpp1. Alternatively, Pot1 might function similarly to the Pot1-like proteins of budding and fission yeast, which have no known Tpp1-like connection to the duplex telomeric DNA. Using mutant mouse cells with diminished Tpp1 levels, RNA interference directed to mouse Tpp1 and Pot1, and complementation of mouse Pot1 knockout cells with human and mouse Pot1 variants, we show here that Tpp1 is required for the protective function of mammalian Pot1 proteins.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Proteínas de Unión a Telómeros/metabolismo , Proteínas de Unión a Telómeros/fisiología , Telómero/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/fisiología , Interferencia de ARN , Complejo Shelterina , Proteínas Similares a la Proteína de Unión a TATA-Box/antagonistas & inhibidores , Proteínas Similares a la Proteína de Unión a TATA-Box/fisiología , Proteínas de Unión a Telómeros/genética , Proteína 2 de Unión a Repeticiones TeloméricasRESUMEN
The mTOR is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTK) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data have shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer-type-specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell-type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors. SIGNIFICANCE: This study suggests that cells need to inactivate mTOR to survive nutrient stress, which could explain the rarity of mTOR mutations and the limited clinical activity of mTOR inhibitors in cancer.