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

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.
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PMID:Beyond monoclonal antibodies: new therapeutic agents in non-Hodgkin's lymphomas. 1941 16

Perinuclear aggresome formation is a key mechanism to dispose of misfolded proteins that exceed the degradative capacity of ubiquitin-proteasome and autophagy-lysosome systems. Functional blockade of either degradative system leads to an enhanced aggresome formation. The tuberous sclerosis complex-Ras homologue enriched in brain-mammalian target of rapamycin (TSC-Rheb-mTOR) pathway is known to play a central role in modulating protein synthesis and autophagy. However, in spite of the constitutive activation of mTOR and the abrogated autophagy activity in TSC1- or TSC2-deficient cells, the TSC mutant cells are defective in aggresome formation and undergo apoptosis upon misfolded protein accumulation both in vitro and in vivo. High Rheb activity in TSC mutant cells inhibits aggresome formation and sensitizes cell death in response to misfolded proteins. Surprisingly, this previously unrecognized function of Rheb is independent of TOR complex 1. Active Rheb disrupts the interaction between dynein and misfolded protein cargos, and therefore blocks aggresome formation by inhibiting dynein-dependent transportation of misfolded proteins. This study reveals a function of Rheb in controlling misfolded protein metabolism by modulating aggresome formation.
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PMID:Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. 1945 66

We investigated the effect of rapamycin, a specific inhibitor of the mammalian serine/threonine kinase, mammalian target of rapamycin (mTOR), on the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Pretreatment of cells with rapamycin significantly inhibited LPS-induced nitrite production and the expression of iNOS protein in a dose-dependent manner. However, LPS-induced mRNA expression of iNOS and its concomitant activation of nuclear factor (NF)-kappaB remained unchanged by rapamycin. Intriguingly, LPS-induced nitrite production and iNOS protein expression were partially blocked at nanomolar concentrations of rapamycin, whereas phosphorylation of both p70 S6 kinase and 4E-BP1 was completely abolished. The suppression of LPS-induced iNOS expression by rapamycin was reversed by the protease inhibitor lactacystin. Furthermore, rapamycin treatment stimulated 20S proteasome activity, which was slightly elevated by LPS. Taken together, our findings strongly suggest that rapamycin down-regulates LPS-induced iNOS protein expression via proteasomal activation, as well as through inhibition of the mTOR signaling pathway.
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PMID:Rapamycin down-regulates inducible nitric oxide synthase by inducing proteasomal degradation. 1948 3

Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of (35)S-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells.
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PMID:Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells. 1954 Jan 99

The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose- and time-dependent decreased viability after exposure to BEZ235 (IC(50), 25-800 nmol/L for 48 hours). MM cells highly sensitive (IC(50), <25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25-400 nmol/L) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC(50), >800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in MM.
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PMID:Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. 1958 92

Ionizing radiation (IR) is a physiologically important stress to which cells respond by the activation of multiple signaling pathways. Using a panel of immortalized and transformed breast epithelial cell lines, we demonstrate that IR regulation of protein synthesis occurs in nontransformed cells and is lost with transformation. In nontransformed cells, IR rapidly activates the MAP kinases ERK1/2, resulting in an early transient increase in cap-dependent mRNA translation that involves mTOR and is radioprotective, enhancing the translation of a subset of mRNAs encoding proteins involved in DNA repair and cell survival. Following a transient increase in translation, IR-sensitive (nontransformed) cells inhibit cap-dependent protein synthesis through a mechanism that involves activation of p53, induction of Sestrin 1 and 2 genes, and stimulation of AMP kinase, inhibiting mTOR and hypophosphorylating 4E-BP1. IR is shown to block proteasome-mediated decay of 4E-BP1, increasing its abundance and the sequestration of eIF4E. The IR signal that impairs mTOR-dependent protein synthesis at late times is assembly of the DNA damage response machinery, consisting of Mre11, Rad50, and NBS1 (MRN); activation of the MRN complex kinase ATM; and p53. These results link genotoxic signaling from the DNA damage response complex to the control of protein synthesis.
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PMID:Regulation of protein synthesis by ionizing radiation. 1970 5

Muscle wasting is a prominent feature of end-stage renal disease and is associated with muscle weakness and poor physical functioning. Potential reasons for muscle wasting include advancing age, sedentary behavior, inflammation, poor nutritional intake, androgen deficiency, oxidative stress, metabolic acidosis, and insulin resistance. Each of these conditions can be associated with decreased protein synthesis, increased protein degradation, or both. The primary muscle protein synthesis pathway is the insulin insulin-like growth factor-1/phosphatidyl inositol-3 kinase/Akt pathway, which results in the phosphorylation of the mammalian target of rapamycin and subsequent increased protein synthesis. The major protein degradation pathway is the ubiquitin-proteasome system. This review discusses the ways in which end-stage renal disease tips the balance of protein turnover towards catabolism and the mechanisms by which various interventions may work to mitigate wasting or even cause anabolism.
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PMID:Anabolic and catabolic mechanisms in end-stage renal disease. 1980 Nov 38

Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin (Dox)-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is, therefore, important to understand how NRG1, via erbB2, protects the heart against Dox cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins [cardiac troponin I (cTnI) and cardiac troponin T (cTnT)] and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT, and cardiac troponin C (cTnC) and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2, phosphoinositide 3-kinase (PI3K), Akt, and mTOR blocked the protective effects of NRG1 on cTnI and cTnT in NRVM. NRG1 significantly reduced Dox-induced caspase activation, which degraded troponins, in NRVM. NRG1 reduced Dox-induced proteasome degradation of cTnI. NRG1 attenuates Dox-induced decrease in cardiac troponins by increasing transcription and translation and by inhibiting caspase activation and proteasome degradation of troponin proteins. NRG1 maintains cardiac troponins by the erbB2-PI3K pathway, which may lessen Dox-induced cardiac dysfunction.
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PMID:Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins. 1980 90

The prefrontal cortex has been implicated in schizophrenia (SZ) and affective disorders by gene expression studies. Owing to reciprocal connectivity, the thalamic nuclei and their cortical fields act as functional units. Altered thalamic gene expression would be expected to occur in association with cortical dysfunction. We screened the expression of the entire human genome of neurons harvested by laser-capture microdissection (LCM) from the thalamic primary relay to dorsolateral prefrontal cortex in three psychiatric disease states as compared with controls. Microarray analysis of gene expression showed the largest number of dysregulated genes was in SZ, followed by major depression (MD) and bipolar mood bipolar (BP) (1152, 385 and 288, respectively). Significantly, IGF1-mTOR-, AKT-, RAS-, VEGF-, Wnt- and immune-related signaling, eIF2- and proteasome-related genes were unique to SZ. Vitamin D receptor and calcium signaling pathway were unique to BP. AKAP95 pathway and pantothenate and CoA biosynthesis were unique to MD. There are significant differences among the three psychiatric disorders in MDNp cells. These findings offer new insights into the transcriptional dysregulation in the thalamus of SZ/BP/MD subjects.
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PMID:Thalamic transcriptome screening in three psychiatric states. 1983

Pemetrexed is a novel third-generation multitargeted antifolate agent used in the first- and second-line treatment of unresectable pleural mesothelioma and advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this compound is a preferred partner in the multidrug regimens. In the last few decades, better understanding of molecular oncology and genetics has allowed for the development of an array of molecular targeted agents, many of which have been found active in NSCLC. It has been hoped that these compounds will disrupt tumor signaling pathways complementary to those targeted by chemotherapy. This review outlines the current preclinical and clinical studies using pemetrexed in combination with targeted agents in advanced NSCLC. Clinical experience with the use of these combinations is still limited and mostly includes phase I and II trials. These investigations have mainly focused on compounds previously shown to be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor (cetuximab and erlotinib). Preliminary results have shown the feasibility of these combinations and their promising activity but large phase III studies are warranted to verify the real value of this strategy. Combinations of pemetrexed with other targeted agents, such as mTOR inhibitors and compounds targeting proteasome are still at early stages of development.
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PMID:The role of pemetrexed combined with targeted agents for non-small cell lung cancer. 1983 32


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