Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream target of phosphatidylinositol 3-kinase/Akt signaling, has been reported to suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 regulates myogenesis is not fully understood. We have previously demonstrated that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the autocrine production of IGF-II and the subsequent phosphatidylinositol 3-kinase/Akt signaling downstream of IGF-II in myogenesis. Here we report a regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation at an early stage and meanwhile leads to proteasome-dependent degradation of a specific subset of components in the mTOR signaling network, including mTOR, raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of FoxO1 requires new protein synthesis, consistent with the idea that a transcriptional target of FoxO1 may be responsible for the degradation of mTOR. We further show that active FoxO1 inhibits IGF-II expression at the transcriptional activation level, through the modulation of mTOR protein levels. Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is a major mediator of FoxO's inhibitory function in skeletal myogenesis.
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PMID:Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. 1807 93

The leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) has been extensively used as an ergogenic aid; particularly among bodybuilders and strength/power athletes, who use it to promote exercise performance and skeletal muscle hypertrophy. While numerous studies have supported the efficacy of HMB in exercise and clinical conditions, there have been a number of conflicting results. Therefore, the first purpose of this paper will be to provide an in depth and objective analysis of HMB research. Special care is taken to present critical details of each study in an attempt to both examine the effectiveness of HMB as well as explain possible reasons for conflicting results seen in the literature. Within this analysis, moderator variables such as age, training experience, various states of muscle catabolism, and optimal dosages of HMB are discussed. The validity of dependent measurements, clustering of data, and a conflict of interest bias will also be analyzed. A second purpose of this paper is to provide a comprehensive discussion on possible mechanisms, which HMB may operate through. Currently, the most readily discussed mechanism has been attributed to HMB as a precursor to the rate limiting enzyme to cholesterol synthesis HMG-coenzyme A reductase. However, an increase in research has been directed towards possible proteolytic pathways HMB may operate through. Evidence from cachectic cancer studies suggests that HMB may inhibit the ubiquitin-proteasome proteolytic pathway responsible for the specific degradation of intracellular proteins. HMB may also directly stimulate protein synthesis, through an mTOR dependent mechanism. Finally, special care has been taken to provide future research implications.
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PMID:Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review. 1817 41

Gain or loss of skeletal muscle mass occurs in situations of altered use such as strength training, aging, denervation, or immobilization. This review examines our current understanding of the cellular and molecular events involved in the control of muscle mass under conditions of muscle use and disuse, with particular attention to the effects of resistance exercise/training. The DNA content, which is a critical determinant of protein synthesis by providing the amount of DNA necessary to sustain gene transcription, can be either increased (activation of satellite cells) or decreased (apoptosis) depending on muscle activity and ongoing physiological processes. In addition, several transcription factors are sensitive to functional demand and may control muscle-specific protein expression to promote or repress myofiber enlargement. The control of skeletal muscle mass is also markedly mediated by the regulation of transduction pathways that promote the synthesis and/or the degradation of proteins. Insulin-like growth factor-I plays a key role in this balance by activating the Akt/tuberous sclerosis complex 2/mammalian target of rapamycin pathway. Stimulation of this pathway leads to the concomitant activation of initiation and elongation factors resulting in the elevation of protein translation and the downregulation of ubiquitin proteasome components through Forkhead-box O transcription factors.
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PMID:Cellular and molecular events controlling skeletal muscle mass in response to altered use. 1819 72

There is no consensus treatment for newly diagnosed mantle cell lymphoma. The CHOP + rituximab and hyperCVAD + rituximab regimens are most commonly used. The former is limited by relatively lower rates of complete remission (CR) and frequent relapses. The latter is limited by toxicities, especially in older patients, and relapses that occur later than those usually seen with CHOP + rituximab. Thus, improved therapies are needed. The purine analog cladribine (2-cda) + rituximab has been studied as an alternative frontline regimen in MCL and is quite active with minimal toxicity. Cladribine has epigenetic activity in that it inhibits DNA methylation. Cladribine + rituximab should be further studied in newly diagnosed mantle cell lymphoma in combination with new agents such as inhibitors of histone deacetylation, the mTOR pathway, and the proteasome.
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PMID:The epigenetics of mantle cell lymphoma. 1821 89

The rapid loss of muscle mass, which occurs with disuse and systemically with fasting, cancer and many other diseases, results primarily from accelerated breakdown of muscle proteins. In atrophying muscles, the ubiquitin-proteasome pathway catalyzes the accelerated degradation of myofibrillar proteins, but the possible importance of the autophagic/lysosomal pathway in atrophy has received little attention. Our prior studies demonstrate that activation of FoxO transcription factors is essential for muscle atrophy, and that activated FoxO3 by itself causes dramatic atrophy of muscles and cultured myotubes via transcription of a set of atrophy-related genes ("atrogenes") including critical ubiquitin ligases. Using selective inhibitors, we measured isotopically the actual contribution of proteasomes and lysosomes to the FoxO3-induced increase in protein breakdown in myotubes and found that FoxO3 coordinately activates both proteolytic systems, but especially lysosomal proteolysis. Activated FoxO3 stimulates autophagy through a transcription-dependent mechanism and increases the transcription of many autophagy-related genes, which are also induced in mouse muscles atrophying due to denervation or fasting. Thus, in atrophying muscles, decreased IGF1-PI3K-Akt signaling stimulates autophagy, not only through mTOR, but also more slowly by FoxO3-dependent transcription. These findings on muscle provide the first evidence for coordinate regulation of proteasomal and lysosomal systems, although in neuronal and hepatic cells, FoxO3 stimulates the autophagic process selectively.
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PMID:Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor. 1822 43

Ribosomal protein S6 kinase (S6K) is a key player in the regulation of cell growth and energy metabolism via the mTOR and PI3K signalling pathways. The activity and subcellular localization of S6K are regulated by multiple S/T phosphorylations in response to diverse extracellular stimuli. Downregulation of S6K signalling occurs through the action of S/T phosphatases (PP2A and PP1) and tumor suppressors (TSC1/2 and PTEN). We report here that, in addition to phosphorylation, S6Ks are ubiquitinated in cells. The pattern of ubiquitination and the effect of proteasomal inhibitors on the steady-state level of transiently overexpressed and endogenous S6Ks point to proteasome-mediated degradation of ubiquitinated S6Ks. Furthermore, we found that the site(s) of ubiquitination are located in the kinase domain and that the N- and C-terminal regulatory regions modulate the efficiency of S6K ubiquitination. This study suggests that S6K signalling also could be regulated through the proteasome-mediated turnover of S6Ks.
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PMID:Regulation of ribosomal protein S6 kinases by ubiquitination. 1828 Aug 3

When grown as three-dimensional structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ribotoxic stressors, histone deacetylase, and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by small interference RNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of three dimensional spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase-8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in three-dimensional, not in two-dimensional, cultures. The three-dimensional model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.
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PMID:Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids. 1833 27

Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.
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PMID:Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. 1833 99

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies. In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
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PMID:Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. 1834 18

The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. Muscle atrophy occurs when the degradation rate is higher than the synthesis rate, for example during disuse, fasting or systemic diseases such as diabetes, cancer and renal failure. The two main catabolic systems that are activated during atrophy are the ubiquitin-proteasome and the autophagy-lysosome pathways. FoxO3 transcription factor causes marked atrophy in adult skeletal muscle and induces the muscle-specific ubiquitin ligase Atrogin-1/MAFbx.(1) In addition, we recently reported that FoxO3 is necessary and sufficient for the induction of autophagy in skeletal muscle.(2) Transcription of autophagy related genes, such as LC3B and Bnip3, is activated during fasting and is mediated by FoxO3. In particular, Bnip3 induces autophagosome formation and is responsible for the induction of autophagy by FoxO3. Surprisingly, rapamycin is not able to induce autophagy in skeletal muscle in vivo, indicating that the Akt-FoxO axis, rather than the Akt-mTOR pathway, is involved in this process. Here we discuss the major implications of our recent work.
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PMID:Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. 1836 68


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