Hyperactivity of mTORC1, a key mediator of cell growth, leads to stem cell depletion, although the underlying mechanisms are poorly defined. Using spermatogonial progenitor cells (SPCs) as a model system, we show that mTORC1 impairs stem cell maintenance by a negative feedback from mTORC1 to receptors required to transduce niche-derived signals. We find that SPCs lacking Plzf, ...
PubMed
The Tuberous Sclerosis Complex component, TSC1, functions as a tumor suppressor via its regulation of diverse cellular processes, particularly cell growth. TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, although the TSC1/TSC2 complex also shows ...
PubMed Central
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain ...
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor ? (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. ...
The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. Hence, mTORC1 is implicated in a large number of human diseases--including diabetes, obesity, heart disease, and cancer--that are characterized by aberrant cell growth and proliferation. Although eukaryotic translation ...
Balanced protein synthesis and degradation are crucial for proper cellular function. Protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin complex 1 (mTORC1). Quality of newly synthesized polypeptides is maintained by the molecular chaperone and ubiquitin-proteasome systems. Little is known about how cells integrate information about the ...
Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the ...
The mammalian target of rapamycin (mTOR) is a master integrator of cell energy state, nutrient status, and growth factor stimulation. This kinase is part of two distinct complexes, mTORC1 and mTORC2, and the network that regulates these two complexes is interconnected with distinct and overlapping inputs and outputs. Research published in Science Signaling has revealed new ...
NSDL National Science Digital Library
Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM(-/-) mice, despite having fewer na�ve CD8? T cells, effectively clear the virus. ...
The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and the ...
Signaling through mammalian target of rapamycin complex 1 (mTORC1) is stimulated by amino acids and insulin. Insulin inactivates TSC1/2, the GTPase-activator complex for Rheb, and Rheb�GTP activates mTORC1. It is not clear how amino acids regulate mTORC1. FKBP38 (immunophilin FK506-binding protein, 38 kDa), was recently reported to exert a negative effect on mTORC1 ...
Chronic lymphocytic leukaemia (CLL) is the commonest haematological malignancy in the western world and is incurable by cytotoxic therapy. Considerable research effort has identified the signal transduction pathways in CLL cells that contribute to anti-apoptotic signalling. Some pathways are constitutively activated in CLL cells but upregulated in normal ...
The mammalian target of rapamycin (mTOR) is a protein kinase that plays key roles in cellular regulation. It forms complexes with additional proteins. The best-understood one is mTOR complex 1 (mTORC1). The regulation and cellular functions of mTORC1 have been the subjects of intense study; despite this, many questions remain to be answered. They include questions about the actual mechanisms by ...
Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for the regulation of protein synthesis. Most of known mTORC1 regulators have been isolated and characterized using cell culture systems, and the physiological roles of these regulators have not been fully tested in vivo. Previous...
Technology Transfer Automated Retrieval System (TEKTRAN)
SummaryThe mTORC1 signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation ...
The mammalian target of rapamycin complex 1 (mTORC1) functions as an environmental sensor to promote critical cellular processes such as protein synthesis, cell growth, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 senses and responds to these ...
The liver kinase B1 (LKB1)/adenosine mono-phosphate-activated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are ...
Aberrant activation of phosphoinositide-3-kinase (PI3K)/Akt signaling has been implicated in the development and progression of multiple human cancers. During the process of skin tumor promotion induced by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), activation of epidermal Akt occurs as well as several downstream effectors ...
PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor�positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions ...
SummaryThe mammalian target of rapamycin (mTOR) is a crucial effector in a complex signaling network commonly disrupted in cancer. mTOR exerts its multiple functions in the context of two different multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) can ...
It is becoming increasingly clear that cholesterol-independent effects of statins also contribute to the cardioprotective effects, but these mechanisms remain poorly understood. We investigated the effects of lovastatin on vascular smooth muscle phenotype. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin induces vascular smooth muscle cell ...
The mammalian target of rapamycin (mTOR) assembles into two distinct multiprotein complexes known as mTORC1 and mTORC2. Of the two complexes, mTORC1 acts to integrate a variety of positive and negative signals to downstream targets that regulate cell growth. The lipid second messenger, phosphatidic acid (PA), represents one positive input to mTORC1, and it is thought to act by ...
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that regulates numerous cellular processes including cell growth, proliferation, cell cycle, and autophagy. mTOR forms two different multi-protein complexes referred to as mTOR complex 1 (mTORC1) and mTORC2, and each complex exerts distinct functions exclusively. mTORC1 activity is sensitive to ...
Phosphatidic acid (PA) is a critical mediator of mitogenic activation of mammalian target of rapamycin complex 1 (mTORC1) signaling, a master regulator of mammalian cell growth and proliferation. The mechanism by which PA activates mTORC1 signaling has remained unknown. Here, we report that PA selectively stimulates mTORC1 but not mTORC2 kinase activity in ...
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) functions as a rapamycin-sensitive environmental sensor that promotes cellular biosynthetic processes in response to growth factors and nutrients. While diverse physiological stimuli modulate mTORC1 signaling, the direct biochemical mechanisms underlying mTORC1 regulation remain poorly defined. Indeed, while three ...
Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse ...
The mammalian target of rapamycin (mTOR) is a protein kinase that, when present in a complex referred to as mTOR complex 1 (mTORC1), acts as an important regulator of growth and metabolism. The activity of the complex is regulated through multiple upstream signaling pathways, including those involving Akt and the extracellular-regulated kinase (ERK). Previous studies have ...
Protein synthesis and autophagy work as two opposing processes to control cell growth in response to nutrient supply. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) pathway, which acts as a master regulator to control protein synthesis, has recently been shown to inhibit autophagy by phosphorylating and inactivating ULK1, an autophagy regulatory protein. ULK1 also inhibits ...
BackgroundMammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires ...
mTORC1 is a critical regulator of cell growth that integrates multiple signals and is deregulated in cancer. We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex. Here we show that Redd1 induction by hypoxia is tissue dependent and that hypoxia signals are relayed to mTORC1 through different pathways in a ...
The mammalian target of rapamycin complex 1 (mTORC1) links the control of mRNA translation, cell growth, and metabolism to diverse stimuli. Inappropriate activation of mTORC1 can lead to cancer. Phorbol esters are naturally occurring products that act as potent tumor promoters. They activate isoforms of protein kinase C (PKCs) and stimulate the oncogenic MEK/ERK signaling ...
Nutritional excess and hyperlipidemia increase the heart's susceptibility to ischemic injury. Mammalian target of rapamycin (mTOR) controls the cellular response to nutritional status and may play a role in ischemic injury. To explore the effect of hypercholesterolemia on cardiac mTOR signaling, we assessed mTOR signaling in hypercholesterolemic swine (HC) ...
BackgroundPalmitate is a potent inducer of endoplasmic reticulum (ER) stress in ?-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic ?-cells, leading to ?-cell dysfunction and death. Why glucose exacerbates ?-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the ...
Insulin activation of mTOR Complex1 is accompanied by enhanced binding of substrates. We examined the mechanism and contribution of this enhancement to insulin activation of mTORC1 signaling in 293E and HeLa cells. In 293E, insulin increased the amount of mTORC1 retrieved by the transiently expressed nonphosphorylatable 4E-BP[5A] to an extent that varied inversely with the ...
The tuberous sclerosis complex (TSC) proteins TSC1 and TSC2 regulate protein translation by inhibiting the serine/threonine kinase mTORC1 (for mammalian target of rapamycin complex 1). However, how TSC1 and TSC2 control overall protein synthesis and the translation of specific mRNAs in response to different mitogenic and nutritional stimuli is largely unknown. We show here that serum withdrawal ...
The mammalian target of rapamycin (mTOR) regulates cell growth and survival via two different multiprotein complexes, mTORC1 and mTORC2. The assembly of these serine-threonine kinase multiprotein complexes occurs via poorly understood molecular mechanisms. Here, we demonstrate that GRp58/ERp57 regulates the existence and activity of mTORC1. Endogenous mTOR interacts with GRp58/ERp57 in different ...
The mammalian target of rapamycin (mTOR) signaling exists in two complexes: mTORC1 and mTORC2. Neurotensin (NT), an intestinal hormone secreted by enteroendocrine (N) cells in the small bowel, has important physiological effects in the gastrointestinal tract. The human endocrine cell line BON abundantly expresses the NT gene and synthesizes and secretes NT in a manner ...
ULK1 (Unc51-like kinase, hATG1) is a Ser/Thr kinase that plays a key role in inducing autophagy in response to starvation. ULK1 is phosphorylated and negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that ULK1 is not only a downstream effector of mTORC1 but also a negative regulator of mTORC1 signaling. ( 1-3) Here, we ...
BackgroundOur understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), ...
mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated ...
SummaryThe mammalian Target of Rapamycin Complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled ...
The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, ...
Tuberous sclerosis complex (TSC) is a relatively rare autosomal dominant disorder characterized by widespread benign tumor formation in a variety of organs. Mutations in either TSC1 or TSC2 tumor suppressor gene are responsible for TSC. The gene products of TSC1 and TSC2, also known as hamartin and tuberin, respectively, form a physical and functional complex and inhibit the mammalian target of ...
mTORC1 is a complex of proteins that includes the mammalian target of rapamycin (mTOR) and several regulatory proteins. It is activated by a variety of hormones (e.g. insulin) and nutrients (e.g. amino acids) that act to stimulate cell growth and proliferation and repressed by hormones (e.g. glucocorticoids) that act to reduce cell growth. Curiously, mTORC1 signaling is ...
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T cell activation and responses to microbial infection. However, the importance of ...
Mutations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of diverse ventral midline structures. The MID1 protein has been shown to function as an E3 ligase targeting the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitin-mediated degradation. However, the molecular pathways downstream of the ...
Selective drugs targeting dysregulated oncogenic pathways are promising cancer therapies. Because the mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in human follicular thyroid cancer (FTC), we hypothesized that its inhibition could block cancer development and progression. We, therefore, analyzed the effect of a treatment with a specific mTORC1 inhibitor (RAD001) in a ...
The mammalian target of rapamycin complex 1 (mTORC1) is a multiprotein signaling complex regulated by oncogenes and tumor suppressors. Outputs downstream of mTORC1 include ribosomal protein S6 kinase 1 (S6K1), eukaryotic translation initiation factor 4E (eIF4E), and autophagy, and their modulation leads to changes in cell growth, proliferation, and metabolism. Rapamycin, an ...
SUMMARYThe mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR, also called DEPDC6, as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1; promotes cell growth and survival; and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by ...
Tetrahydrobiopterin (BH 4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH 4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH 4-deficient Spr (-/-) mice generated by the knockout of the gene encoding ...
The PI3K pathway and its regulation of mammalian target of rapamycin complex 1 (mTORC1) and glycogen synthase kinase 3 (GSK3) play pivotal roles in controlling inflammation. In this article, we show that mTORC1 and GSK3-? converge and that the capacity of mTORC1 to affect the inflammatory response is due to the inactivation of GSK3-?. Inhibition of mTORC1 attenuated GSK3 phosphorylation and ...
BackgroundmTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E-BP1, with the latter negatively regulating eukaryotic initiation factor 4E (eIF-4E). MNK1 ...
The mammalian target of rapamycin (mTOR) kinase is present in 2 functionally distinct complexes, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). Active mTORC1 mediates phosphorylation of eIF4E-binding protein (4E-BP) and p70 S6 kinase (S6K), which is important for maintaining translation. During human cytomegalovirus (HCMV) infection, cellular stress responses are activated that normally inhibit ...
Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we ...
Targeting mTOR complex 1 (mTORC1), which regulates general protein translation, represents one of the most attractive approaches to treating cancer, since up-regulation of this pathway is a common hallmark in many tumors. Nevertheless, the use of rapamycin and its analogs in the clinic has revealed that mTORC1 pathway is embedded in a network of signaling cross-talks and ...
The opposing actions of insulin and glucagon on hepatic carbohydrate metabolism are well documented. In contrast, relatively little is known about how the two hormones interact to regulate hepatic protein metabolism. Previously, we reported that glucagon in the absence of insulin represses signaling through the mammalian target of rapamycin complex 1 (mTORC1). In the present ...
Activation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mTOR kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners toward regulating CRC progression and ...
Type 2 diabetes (T2D) is strongly linked to obesity and an adipose tissue unresponsive to insulin. The insulin resistance is due to defective insulin signaling, but details remain largely unknown. We examined insulin signaling in adipocytes from T2D patients, and contrary to findings in animal studies, we observed attenuation of insulin activation of ...
cAMP and mTOR signalling pathways control a number of critical cellular processes including metabolism, protein synthesis, proliferation and cell survival and therefore understanding the signalling events which integrate these two signalling pathways is of particular interest. In this study, we show that the pharmacological elevation ...
Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, ...
The mammalian target of rapamycin (mTOR) has attracted substantial attention because of its involvement in a variety of diseases, such as cancer, cardiac hypertrophy, diabetes and obesity. Current knowledge indicates that mTOR functions as two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 ...
The AMP-activated serine/threonine protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes that is activated under conditions of low intracellular ATP following stresses such as nutrient deprivation or hypoxia. In the past five years, work from a large number of laboratories has revealed that one of the major downstream signaling pathways regulated ...
The Ras/mitogen-activated protein kinase (MAPK) pathway regulates a variety of cellular processes by activating specific transcriptional and translational programs. Ras/MAPK signaling promotes mRNA translation and protein synthesis, but the exact molecular mechanisms underlying this regulation remain poorly understood. Increasing evidence suggests that the mammalian target of ...
Unc-51-like kinase 1 (Ulk1) plays a central role in autophagy induction. It forms a stable complex with Atg13 and focal adhesion kinase (FAK) family interacting protein of 200 kDa (FIP 200). This complex is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) in a nutrient-dependent way. AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high ...
The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator Rheb. We show that amino acids induce the movement of ...
The mammalian target of rapamycin (mTOR) is a critical sensor of nutritional sufficiency. Although much is known about the regulation of mTOR in response to growth factors, much less is known about the regulation of mTOR in response to nutrients. Amino acids have no impact on the signals that regulate Rheb, a GTPase required for the activation of mTOR complex 1 (mTORC1). ...
Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1-JNK signaling without affecting PERK and ...
INTRODUCTION: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, ...
Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 ...
The management of neuropathic pain is unsatisfactory, and new treatments are required. Because the sensitivity of a subset of fast-conducting primary afferent nociceptors is thought to be regulated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, selectively targeting mTORC1 represents a new strategy for the control of chronic pain. Here we show that ...
Abstract Mammalian target of rapamycin (mTOR), a serine/threonine kinase and component of the mTORC1 signaling complex, acts as an energy, nutrient, growth factor, stress, and redox sensor to increase protein synthesis and decrease macroautophagy. mTORC1 plays a central role in the maintenance of homeostasis and its deterioration, seen in aging. The Food and Drug ...
In this study, we explored the coordinate regulation of mTORC1 by insulin and amino acids. Rat livers were perfused with medium containing various concentrations of insulin and/or amino acids. At fasting (1�) or 2� (2�AA) concentrations of amino acids, insulin maximally stimulated Akt phosphorylation but had no effect on global rates of protein synthesis. In the absence of insulin, 4�AA ...
The protein kinase Target of rapamycin (TOR) is a key regulator of cell growth and metabolism with significant clinical relevance. TOR signals through two distinct multi-protein complexes, mTORC1 and mTORC2, the subunits of which appear to define the operational pathways. Rapamycin selectively targets mTORC1 function and the emergence of specific ATP competitive kinase ...
BackgroundSarcopenia, the loss of skeletal muscle mass during aging, increases the risk for falls and dependency. Resistance exercise (RE) training is an effective treatment to improve muscle mass and strength in older adults, but aging is associated with a smaller amount of training-induced hypertrophy. This may be due in part to an inability to stimulate muscle-protein synthesis (MPS) after an ...
Mammalian target of rapamycin (mTOR) is a protein serine-threonine kinase that functions as a central element in signaling pathway involved in control of cell growth and proliferation. mTOR exists in at least two distinct multi-protein complexes, mTORC1 and mTORC2. mTOR kinase controls the translation machinery, in response to nutrients and growth factors, via activation of ...
Food deprivation induces a repression of protein synthesis in skeletal muscle in part due to reduced signaling through the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have identified upregulated expression of the protein Regulated in DNA Damage and Development (REDD1) as an important mechanism in the regulation of mTORC1 activity in response to a variety ...
Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between ...
Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine/paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between ...
Mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase and that forms two multiprotein complexes known as the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR regulates cell growth, proliferation and survival. mTORC1 is composed of the mTOR catalytic subunit and three associated proteins: raptor, mLST8/G?L and PRAS40. mTORC2 contains mTOR, rictor, mLST8/G?L, mSin1, and protor. ...
BackgroundAcidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is ...
Page 1. AD Award Number: W81XWH-04-1-0049 TITLE: Aberrant AR Signaling as a Function of Declining Androgen PRINCIPAL ...
DTIC Science & Technology
It is clear that mTORC1 (mammalian target of rapamycin complex 1) is regulated by the presence of ambient amino acid nutrients. However, the mechanism by which amino acids regulate mTORC1 is still open to question, despite extensive efforts. Our recent work has revealed that PR61?, a B56 family regulatory subunit of PP2A (protein phosphatase 2A), associates with and regulates the activity of ...
In this review we discuss recent research in the field of human skeletal muscle protein metabolism characterizing the acute regulation of mammalian target of rapamycin complex (mTORC) 1 signaling and muscle protein synthesis (MPS) by exercise, amino acid nutrition and aging. Resistance exercise performed in the fasted state stimulates mixed MPS within 1 h post-exercise, which ...
Purpose.Mammalian target of rapamycin (mTOR)-mediated pathways play central roles in regulating aging. The purpose of the present study was to characterize the mTOR cascade in human retinal pigment epithelial (RPE) cells and to investigate its potential roles in controlling RPE senescence.Methods.Expression of major components of the mTOR signaling networks was evaluated by ...
Here we report an oral alkylphospholipid perifosine dramatically sensitizes chemo-resistant ovarian cancer cells to paclitaxel induced cell death and apoptosis in vitro. We found that co-administration perifosine with paclitaxel in human ovarian cancer cells led to the inhibition of AKT/mTOR complex 1 (mTORC1), a marked increase in ceramide and reactive oxygen species (ROS) production, and a ...
Skeletal muscle in the neonate grows at a rapid rate due in part to an enhanced sensitivity to the postprandial rise in amino acids, particularly leucine. To elucidate the molecular mechanism by which leucine stimulates protein synthesis in neonatal muscle, overnight-fasted 7-day-old piglets were treated with rapamycin [an inhibitor of mammalian target of rapamycin (mTOR) complex (mTORC)1] for 1 h ...
Oxidants are well-recognized for their capacity to reduce the phosphorylation of the mammalian target of rapamycin (mTOR) substrates, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and p70 S6 kinase 1 (S6K1), thereby hindering mRNA translation at the level of initiation. mTOR functions to regulate mRNA translation by forming the signaling complex mTORC1 (mTOR, ...
BACKGROUND & AIMS: The mammalian target of rapamycin (mTOR) plays a pivotal role in Hepatocellular Carcinoma (HCC). Previous studies indicated that inhibition of mTORC1 enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor activity, accompanied with feedback activation of AKT.Therefore, dual targeting of mTORC1/C2 should be more efficient in suppressing AKT activity and in ...
To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), ...
The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110? isoform of class IA PI3K. ...
Nutrition and physical activity have profound effects on skeletal muscle metabolism and growth. Regulation of muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for muscle growth by mediating the anabolic response to nutrients, insulin, insulin like ...
Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic ...
Hormonal, targeted and chemotherapeutic strategies largely depend on the expression of their cognate receptors and are often accompanied by intolerable toxicities. Effective and less toxic therapies for estrogen receptor negative (ER-) breast cancers are urgently needed. Here, we present the potential molecular mechanisms mediating the selective pro-apoptotic effect induced by BN107 and its ...
Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. ...
Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of human type 2 diabetes (T2DM). Although SIRT1 has a therapeutic effect on metabolic deterioration in T2DM, the precise mechanisms by which SIRT1 improves insulin resistance remain unclear. Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low-density ...
During cell proliferation, growth must occur to maintain homeostatic cell size. Here we show that E2F1 is capable of inducing growth by regulating mTORC1 activity. The activation of cell growth and mTORC1 by E2F1 is dependent on both E2F1's ability to bind DNA and to regulate gene transcription, demonstrating that a gene induction expression program is required in this process. Unlike E2F1, E2F3 ...
The livers of insulin-resistant, diabetic mice manifest selective insulin resistance, suggesting a bifurcation in the insulin signaling pathway: Insulin loses its ability to block glucose production (i.e., it fails to suppress PEPCK and other genes of gluconeogenesis), yet it retains its ability to stimulate fatty acid synthesis (i.e., continued enhancement of genes of ...
The activity of mammalian target of rapamycin (mTOR) complexes regulates essential cellular processes, such as growth, proliferation, or survival. Nutrients such as amino acids are important regulators of mTOR complex 1 (mTORC1) activation, thus affecting cell growth, protein synthesis, and autophagy. Here, we show that amino acids may also activate mTOR complex 2 (mTORC2). This activation is ...
One of the problems that affects the practical use of holographic memory is deterioration of the reproduced images due to aberration in the optical system. The medium must be interchangeable, and hence it is necessary to clarify the influence of aberration in the optical system on the signal quality and perform ...
NASA Astrophysics Data System (ADS)
Raptor is the key scaffolding protein that recruits mTOR substrates to rapamycin-sensitive mTOR Complex 1 (mTORC1), a molecular integrator of mitogenic and nutrient/energy environmental inputs into protein translation and cell growth. Although Raptor phosphorylation on various sites is pivotal in the regulation of mTORC1 activity, it remains to be elucidated whether site-specific phosphorylation ...
BackgroundAmino-acids stimulate the mammalian target of rapamycin complex(mTORC)1; mTORC1 integrates amino-acid and energy-sensing pathways in beta-cells. Rapamycin inhibits mTORC1. We examined the mTOR pathway and cell cycle data in the exocrine pancreas in diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI).DesignTissues from two diffuse PHHI cases, one pediatric control and from ...
Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferation, a major pathological manifestation of ...
Mammalian target of rapamycyin (mTOR) is a downstream serine/threonine kinase of the PI3K/AKT pathway that integrates signals from the microenvironment such as cytokines, growth factors, and nutriments to regulate multiple cellular processes, including mRNA translation, autophagy, metabolism, growth and survival. mTOR operates in two distinct multi-protein complexes: mTORC1 ...
Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all ...
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct ...
Asparaginase depletes circulating asparagine and glutamine, activating amino acid deprivation responses (AADR) such as phosphorylation of eukaryotic initiation factor 2 (p-eIF2) leading to increased mRNA levels of asparagine synthetase and CCAAT/enhancer-binding protein ? homologous protein (CHOP) and decreased mammalian target of rapamycin complex 1 (mTORC1) signaling. The ...
Protein synthesis (PS) increases after a meal in neonates, but the time course of the changes in PS in different tissues after a meal is unknown. We aimed to evaluate the changes in tissue PS, mammalian target of rapamycin complex 1 (mTORC1) activation, and proportion of ribosomal protein (rp) mRNAs in polysomes over 4 h after a bolus meal in neonatal pigs (n = 6/group; 5- to 7-d-old). The results ...
In conditions of over-nutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu (increased insulin (INS), angiotensin II (Ang II), and adverse cytokine/adipokine profile). Herein we review the diverse compensatory/adaptive mechanisms that counter the deleterious ...
While both extrinsic and intrinsic factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, less is known about the intracellular signaling pathways that control the overall commitment to differentiate. Here, we provide evidence that activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte ...
The AMP-activated protein kinase (AMPK) represses signaling through the mammalian target of rapamycin complex 1 (mTORC1). In muscle, repression of mTORC1 leads to a reduction in global protein synthesis. In contrast, repression of mTORC1 in the liver has no immediate effect on global protein synthesis. In the present study, signaling through mTORC1 and ...
Background:? The mammalian target of rapamycin (mTOR) kinase controls cell growth, proliferation, and metabolism through 2 distinct multiprotein complexes, mTORC1 and mTORC2. We reported that alcohol (EtOH) inhibits mTORC1 activity and protein synthesis in C2C12 myoblasts. However, the role that mTORC2 plays in this process has not been elucidated. In this study, we investigated whether mTORC2 ...
BackgroundEvidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce ?-amyloid (A?) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that A? reduces leptin by inhibiting the ...
Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully ...
Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value ...
Branched-chain amino acids (BCAA) supplementation has been reported to suppress the incidence of liver cancer in obese patients with liver cirrhosis or in obese and diabetic model animals of carcinogenesis. Whether BCAA directly suppresses cell proliferation of hepatic tumor cells under hyperinsulinemic condition remain to be defined. The aim of this study was to investigate the effects of BCAA on ...
Precise regulation of ribosome biogenesis is fundamental to maintain normal cell growth and proliferation, and accelerated ribosome biogenesis is associated with malignant transformation. Here, we show that the kinase AKT regulates ribosome biogenesis at multiple levels to promote ribosomal RNA (rRNA) synthesis. Transcription elongation by RNA polymerase I, which synthesizes rRNA, required ...
Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although majority of evidence linking mTOR function to ...
,2,3 & David M. Sabatini1,2,3 The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase in phospho-S6 levels that was blocked by rapamycin, an mTORC1 inhibitor. mTORC1 activation preceded that of. 2b). Furthermore, Li-RapKO or rapamycin-treated mice do have elevated serum ketones at the short
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... The upregulation of Akt activity is seen when cancer cells are treated with rapamycin, which blocks mTORC1 and inhibits S6K- phosphorylation. ...
Cortical development depends upon tightly controlled cell fate and cell survival decisions that generate a functional neuronal population, but the coordination of these two processes is poorly understood. Here we show that conditional removal of a key apical complex protein, Pals1, causes premature withdrawal from the cell cycle, inducing excessive generation of early-born postmitotic neurons ...
Despite its potent antitumor effect, clinical use of Doxorubicin is limited because of serious side effects including myocardial toxicity. Understanding the cellular mechanism involved in this process in a better manner is beneficial for optimizing Doxorubicin treatment. In the current study, the authors focus on the AMP-activated protein kinase (AMPK) in the said process. In this study, the ...
SummaryAutophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under normal nutrient ...
Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding ...
Amino acid transporters and mammalian target of rapamycin complex 1 (mTORC1) signaling are important contributors to muscle protein anabolism. Aging is associated with reduced mTORC1 signaling following resistance exercise, but the role of amino acid transporters is unknown. Young (n = 13; 28 � 2 yr) and older (n = 13; 68 � 2 yr) subjects performed a ...
The mammalian target of rapamycin (MTOR) assembles into two distinct complexes: mTOR complex 1 (mTORC1) is predominantly cytoplasmic and highly responsive to rapamycin, whereas mTOR complex 2 (mTORC2) is both cytoplasmic and nuclear, and relatively resistant to rapamycin. mTORC1 and mTORC2 phosphorylatively regulate their respective downstream effectors p70S6K/4EBP1, and Akt. The resulting ...
The mammalian target of rapamycin (mTOR) assembles into two distinct complexes: mTOR complex 1 (mTORC1) is predominantly cytoplasmic and highly responsive to rapamycin, whereas mTOR complex 2 (mTORC2) is both cytoplasmic and nuclear, and relatively resistant to rapamycin. mTORC1 and mTORC2 phosphorylatively regulate their respective downstream effectors p70S6K/4EBP1, and Akt. The resulting ...
The phosphatidylinositol 3-kinase (PI3K)/AKT and RAS oncogenic signalling modules are frequently mutated in sporadic human cancer. Although each of these pathways has been shown to play critical roles in driving tumour growth and proliferation, their activation in normal human cells can also promote cell senescence. Although the mechanisms mediating RAS-induced senescence have ...
... on diverse posttranslational modifications of amino termini (36, 47) and the more recently implicated globular domains of histones (6). These ...
... We explored the possibility that different testosterone levels may influence prostate tumor growth. We have completed the ...
In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been ...
The marked increase in skeletal muscle mass during the neonatal period is largely due to a high rate of postprandial protein synthesis that is modulated by an enhanced sensitivity to insulin and amino acids. The amino acid signaling pathway leading to the stimulation of protein synthesis has not been fully elucidated. Among the amino acids, leucine is considered to be a ...
A characteristic of cancer cells is the generation of lactate from glucose in spite of adequate oxygen for oxidative phosphorylation. This property - known as the "Warburg effect" or aerobic glycolysis - contrasts with anaerobic glycolysis, which is triggered in hypoxic normal cells. The Warburg effect is thought to provide a means for cancer cells to survive under conditions where oxygen is ...
Metformin is considered, in conjunction with lifestyle modification, as a first-line treatment modality for type 2 diabetes mellitus (DM). Recently, several clinical studies have reported reduced incidence of neoplastic diseases in DM type 2 patients treated with metformin, as compared to diet or other antidiabetic agents. Moreover, in vitro studies have disclosed significant antiproliferative and ...
Keratin intermediate filament proteins form cytoskeletal scaffolds in epithelia, the disruption of which affects cytoarchitecture, cell growth, survival, and organelle transport. However, owing to redundancy, the global function of keratins has not been defined in full. Using a targeted gene deletion strategy, we generated transgenic mice lacking the entire keratin multiprotein family. In this ...
Autophagy is an important process which maintains cellular homeostasis under stressful conditions such as starvation and pathogenic invasion. Previous observations have indicated that several cytokines are important regulators of the autophagic process. Among the various cytokines, IL-10 has a unique property which functions to suppress overall immunity. However, the functional role of IL-10 ...
Akt signal transduction induces coordinated increases in glycolysis and apoptosis resistance in a broad spectrum of cancers. Downstream of Akt, the FoxO transcription factors regulate apoptosis via Bim, but the contributions of FoxOs in regulating Akt-induced glycolysis are not well described. We find that FoxO3a knockdown is sufficient to induce apoptosis resistance in ...
Mammalian target of rapamycin (mTOR) is a key regulator of eukaryotic cell growth. In particular, mTORC1, one of the two complexes that contain mTOR, is involved in the regulation of protein synthesis, proliferation, cell cycle and autophagy. Hyperactivation of the mTOR signaling pathway is observed in human cancer. A variety of approaches including deletion analysis, yeast ...
Understanding the mechanisms that control stem cell self-renewal and differentiation are at the core of stem cell biology. In a recent issue of Cell, Hobbs et al. report that harnessing mTORC1 activity by the transcription factor PLZF is crucial to maintain the self-renewing activity of germline progenitors. PMID:20708579
The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for therapy and drug development. Biologically, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR complex 1 (mTORC1) which is predominantly cytoplasmic in subcellular localization ...
OBJECTIVEThe mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) ...
The lipogenic phenotype is a metabolic hallmark of cancer cells. Sterol regulatory element-binding proteins (SREBP) are key transcriptional factors to regulate biosynthesis of cholesterol and fatty acids. It has been poorly understood how the lipogenic phenotype in cancer cells is regulated and how it augments their malignant properties. Here we describe roles of the melanoma antigen ganglioside ...
Chromatic aberration is a form of aberration in color optical devices that produces undesirable color fringes along borders within images. It is becoming a more critical problem these days as digital cameras are getting smaller, while the number of picture elements is increasing. We propose a novel method for detecting and eliminating chromatic ...
Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for the regulation of protein synthesis. Most of known mTORC1 regulators have been isolated and characterized using cell culture systems, and the physiological roles of these regulators have not been fully tested in vivo. Previously we demonstrated that the insulin (INS) and amino acid (AA)-induced ...
In a previous study we demonstrated a requirement for activation of mTORC1 in the stimulation of eIF2B? mRNA translation in skeletal muscle in response to resistance exercise. Although that study established the necessity of mTORC1 activation, the experimental model used did not lend itself readily to address the question of whether or not mTORC1 activation was sufficient to produce the response. ...
Cell growth is influenced by environmental stress. Mammalian target of rapamycin (mTOR), the central regulator of cell growth, can be positively or negatively regulated by various stresses through different mechanisms. The p38 MAP kinase pathway is essential in cellular stress responses. Activation of MK2, a downstream kinase of p38?, enhances mTOR complex 1 (mTORC1) activity by preventing TSC2 ...
mTOR complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by hypoxia-inducible factor (HIF)-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is ...
We present a new method to generate a spherical aberration error (SAE) signal for an optical pickup unit. The SAE signal is derived from two push-pull signals that are generated by a special diffractive optical element. First experiments provided a proof of principle.
The present invention relates to methods and compositions concerning resistance to a drug for cancer comprising aberrant KIT signal, such as aberrant KIT sequence or expression. In a specific embodiment, the cancer is also initially responsive to imatinib...
National Technical Information Service (NTIS)
Aberration in ultrasound medical imaging is usually modeled by time-delay and amplitude variations concentrated on the transmitting/receiving array. This filter process is here denoted a TDA filter. The TDA filter is an approximation to the physical aberration process, which occurs over an extended part of the human body wall. Estimation of the TDA filter, ...
Insulin-like growth factor (IGF) I and bone morphogenetic proteins (BMP) are critical regulators of prostate tumor cell growth. In this report, we offer evidence that a critical support of IGF-I in prostate cancer is mediated by its ability to suppress BMP4-induced apoptosis and Smad-mediated gene expression. Suppression of BMP4 signaling by IGF-I was reversed by chemical ...
Suckling "F/A2" mice, which overexpress arginase-I in their enterocytes, develop a syndrome (hypoargininemia, reduced hair and muscle growth, impaired B-cell maturation) that resembles IGF1 deficiency. The syndrome may result from an impaired function of the GH-IGF1 axis, activation of the stress-kinase GCN2, and/or blocking of the mTORC1-signaling pathway. Arginine deficiency ...
BackgroundProtein aggregation is a hallmark of many neurodegenerative diseases and has been linked to the failure to degrade misfolded and damaged proteins. In the cell, aberrant proteins are degraded by the ubiquitin proteasome system that mainly targets short-lived proteins, or by the lysosomes that mostly clear long-lived and poorly soluble proteins. Both systems are ...
SummaryThe mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and the founding member of a signaling pathway that regulates many fundamental features of cell growth and division. In cells, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Together, ...
Phosphinositide 3-kinase (PI3K), Akt and their downstream kinase, mammalian target of rapamycin (mTOR) are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. In the present work we identified the following characteristics of this cascade. i) Local ...
Rheb is a homolog of Ras GTPase that regulates cell growth, proliferation, and regeneration via mammalian target of rapamycin (mTOR). Because of the well established potential of activated Ras to promote survival, we sought to investigate the ability of Rheb signaling to phenocopy Ras. We found that overexpression of lipid-anchored Rheb enhanced the apoptotic effects induced ...
... Abstract : The mammalian target of rapamycin complex 1 (mTORC1) formed by mTOR, Raptor, mLST8 and PRAS40 is a principal regulator of cell ...
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 Morris E of America The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integratingTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin
The mammalian target of rapamycin, best known as mTOR, is a phylogenetically conserved serine/threonine kinase that controls life-defining cellular processes such as growth, metabolism, survival, and migration under the influence of multiple interacting proteins. Historically, the cellular activities blocked by rapamycin in mammalian cells were considered the only events controlled by mTOR. ...
Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce ...
An acute bout of exercise induces repression of protein synthesis in skeletal muscle due in part to reduced signaling through the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that upregulated expression of regulated in DNA damage and development (REDD) 1 and 2 is an important mechanism in the regulation of mTORC1 activity in response to a ...
The mTOR pathway is the central regulator of cell size. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), ...
Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the ...
OBJECTIVEIn metazoans, target of rapamycin complex 1 (TORC1) plays the key role in nutrient- and hormone-dependent control of metabolism. However, the role of TORC1 in regulation of triglyceride storage and metabolism remains largely unknown.RESEARCH DESIGN AND METHODSIn this study, we analyzed the effect of activation and inhibition of the mammalian TORC1 (mTORC1) signaling ...
The target of rapamycin (TOR) complex 1 (TORC1) is a central cell growth regulator in response to a wide array of signals. The Rag GTPases play an essential role in relaying amino acid signals to TORC1 activation through direct interaction with raptor and recruitment of the TORC1 complex to lysosomes. Here we present the crystal structure of the ...
Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR ...
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a multicomponent, nutrient-sensitive protein that is implicated in a wide range of major human diseases. mTORC1 responds to both growth factors and changes in local amino acid levels. Until recently, the intracellular amino acid-sensing mechanism that regulates mTORC1 had remained unexplored. However, studies in human cells in culture have ...
... TW Glover, FS Collins, and J. Downward (1992) Aberrant regulation of ras ... 2. C. Borner and C. Fabbro (1992) Protein Kinase C: current ...
In Vivo Induction of Chromosome Instability and Aberrant Patterns of DNA Methylation in Hemapoietic Stem/Progenitor Cells by Heavy Ions ...
NASA Website
... Figure 1. Geometric relationship of the SAR system In the figure 1, the radar moves along the Y-axis ... channel and the aberration of signal channel. ...
Methods for correction of phase aberrations induced by near-field variations in the index of refraction are explored. Using signals obtained from a sampled aperture (i.e. transducer array), phase aberrations can be accurately measured with a correlation approach similar to methods used in adaptive optics and radar. However, the method ...
... Title : Development of a Novel Prognostic Marker to Link a Potential Tumor Suppressor Gene at Chromosome 6q to Aberrant Signal Transduction ...
Dr. Giubellino research has focused on cancer biomarkers and on pre-clinical drug development, specifically targeting aberrant protein signaling networks associated with cancer as a new therapeutic strategy.
Cancer.gov
Our research interests focus on the normal and aberrant organismal and cellular events and signaling pathways that can enhance or inhibit tumor development or other disease processes.
... sites identified as related to S ... Defense (DoD) Issuances (current and cancelled ... PILOT STUDIES, MICE, SENSE ORGANS, ANATOMICAL MODELS. ...
Two different methods have been derived and implemented for simulation of multipole imaging systems and aberration correctors. The first method uses an aberration theory for combinations of multipole lenses and deflectors, including primary and secondary aberrations up to the fifth order. A damped least-squares algorithm is used to ...
This paper is focus on analyzing the telescopes used in atmosphere, which studies the effect of optical aberration of telescopes to the laser radar. The method of numerical simulation is used to calculate and analyze the characters of backward wave when laser beam propagates through atmosphere and reflects back. Then make use of optical transfer function including quartic ...
Presented here is a characterization of aberration in medical ultrasound imaging. The characterization is optimal in the sense of maximizing the expected energy in a modified beamformer output of the received acoustic backscatter. Aberration correction based on this characterization takes the form of an aberration correction filter. ...
We present an analysis of the effects of aberrations in third harmonic generation (THG) microscopy by considering different specimen geometries. Numerical simulations show the general trend that signal intensity and resolution are reduced as aberrations increase in amplitude. It is also shown that there are certain combinations of ...
We examine the effects of aberrations induced by a refractive index mismatch on the signal level and resolution of single-photon (1-p) and two-photon (2-p), conventional and confocal scanning microscopes. In particular, we consider the aberrations introduced by an interface between oil/glass and water. Resolution is defined in terms of ...
The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and ...
The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for drug development. Until recently, we have relied largely on the use of rapamycin to study mTOR function and its anticancer potential. Recent insights now indicate that rapamycin is a partial inhibitor of mTOR ...
Reactive oxygen species (ROS) are generated as a by product of many cellular processes and can modulate cellular signaling pathways. However, high ROS levels are toxic; thus intracellular ROS need to be tightly controlled. Therefore, cells use a group of antioxidant molecules and detoxifying enzymes that remove or detoxify reactive species. We show that the level of the ...
Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR-inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master ...
We previously showed that the herpes simplex virus 1 (HSV-1) tegument protein VP11/12 activates the lymphocyte-specific Src family kinase (SFK) Lck and is tyrosine phosphorylated in an Lck-dependent manner during T cell infection. We now extend these findings to show that ectopic expression of Lck induces robust tyrosine phosphorylation of VP11/12 in Vero cells, strongly suggesting that VP11/12 ...
Constitutively active forms of Notch receptors have been shown to have oncogenic potential in several cell-types. Aberrant expression of Notch signaling pathway components has been detected in several human tumors, including breast cancer. Since Ras signa...
HypothesisImpaired wound healing in diabetics is due to pathological angiogenesis, which is a result of aberrant sphingosine-1-phosphate (S1P) signaling. Pharmacological modulation of sphingosine-1-phosphate-dependent signaling normalizes healing in diabetic wounds.
This is the final report on the grant 'Development of a novel diagnostic marker to link a potential tumor suppressor gene at chromosome 6q to aberrant signal transduction pathway in breast cancer.' The purpose of the grant proposal is to examine the hypot...
Disrupted or aberrant endocrine signaling has profound effects on the health of both children and adults. This issue focuses attention on endocrine signaling mediated by G protein–coupled receptor and receptor tyrosine kinase pathways involved in endocrine signaling, especially those critical in child ...
Specimen-induced aberrations cause a reduction in signal levels and resolution in fluorescence microscopy. Aberrations also affect the image contrast achieved by these microscopes. We model the effects of aberrations on the fluorescence signals acquired from different specimen structures, such ...
Postexercise protein feeding regulates the skeletal muscle adaptive response to endurance exercise, but the transcriptome guiding these adaptations in well-trained human skeletal muscle is uncharacterized. In a crossover design, eight cyclists ingested beverages containing protein, carbohydrate and fat (PTN: 0.4, 1.2, 0.2 g/kg, respectively) or isocaloric carbohydrate and fat (CON: 1.6, 0.2 g/kg) ...
The mammalian target of rapamycin (mTOR) kinase acts as a cellular rheostat that integrates signals from a variety of cellular signal transduction pathways that sense growth factor and nutrient availability as well as intracellular energy status. It was previously reported that the human papillomavirus type 16 (HPV16) E6 oncoprotein may activate the S6 ...
Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism.Subjects: Subjects were healthy young adults (n = 14) aged 31 � 2 yr.Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric ...
BackgroundmTORC1 (mammalian target of rapamycin complex 1) activation has been demonstrated in response to endotoxin challenge, but the mechanism and significance are unclear. We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling.Methodology/Principal FindingsMice were treated with the mTORC1 inhibitor ...
