IndraLab
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"In normal and adult kidney, PC1 functions by inducing the formation of PC1, tuberin, and mTOR complex thereby inhibiting mTOR activity XREF_BIBR, yet in human ADPKD patients and mouse models, null of PC1 leads to the inability to assemble this inhibitory complex thereby causing mTOR pathway inappropriately activated XREF_BIBR, XREF_BIBR."
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"Surprisingly, F-box proteins beta-TrCP and Fbw5 were reported as substrate receptors for CRL4 beta-TrCP [XREF_BIBR] and CRL4 Fbw5 [XREF_BIBR] targeting inhibitors of mTOR signalling REDD1 (regulated in development and DNA damage response 1) and TSC2 (tuberous sclerosis protein 2) respectively."
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"Metformin activates AMPK indirectly via a suppressor protein, liver kinase B1 (LKB1), and via the activation of tuberous sclerosis complex 2 (TSC-2) which inhibits the mammalian target of rapamycin (mTOR) protein, one of the key proteins in regulating cell division, protein synthesis, growth and angiogenic processes [ xref , xref ]."
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"Recent studies also indicate that REDD1 (RTP801), induced under hypoxic conditions in a HIF-1alpha dependent manner XREF_BIBR, plays a role in the TSC1 (hamartin)/TSC2 (tuberin)-mediated inhibition of mTOR XREF_BIBR, these indicating a reciprocal regulatory control between HIF-1alpha and mTOR."
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"Activation of AMPK, a target of several glucose lowering agents used in diabetes treatment, including metformin and the thiazolidenediones, stimulates insulin action in peripheral tissues, acting to phosphorylate and stimulate the TSC1 : TSC2 complex, which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR (mTOR and Raptor)."
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"AMPK promotes autophagy by at least the following ways : phosphorylating the tuberous sclerosis (TSC) complex proteins TSC1 and TSC2, which in turn downregulate mTOR activity and induce autophagy 59, phosphorylating FOXO3, phosphorylating ULK1, and dissociating Beclin1 and Bcl-2 by stimulating JNK1-Bcl-2 signaling XREF_BIBR - XREF_BIBR."
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"Therefore, in both assays, the TSC2 I820del and L1511H variants were unable to inhibit mTOR, indicating that both these variants are pathogenic, while the TSC2 R1772C and T993M variants were just as active as wild-type TSC2 and are therefore not pathogenic amino acid substitutions."
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"The tumor suppressor tuberin, the TSC2 gene product, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human chronic diseases, including cancer [XREF_BIBR]."
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"Supporting an increased protein degradation relative to synthesis due to food deprivation, starved trout muscle contained high levels of the transcript for tuberous sclerosis component 2 (TSC2) which has been shown, in mammals, to inhibit mTOR a positive regulator of cell growth and proliferation [XREF_BIBR], and of the transcript encoding the translational repressor 4E-BP1, which presumably reinforces the inhibition of cap dependent translation resulting from inactivation of Akt and mTOR [XREF_BIBR]."
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"We can not exclude that Tsc2 might have additional unidentified functions that compensate Tsc1-mutant phenotypes; however, since the loss of either Tsc1 or Tsc2 abolishes the Rheb-GTPase-activating activity, resulting in constitutively activated mTOR, it is unlikely that Tsc2 alone can suppress mTOR activation in the absence of Tsc1."
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"In line with cell size regulation and autophagy interplay induced by mechanical stress, we observed defaults in the mTORC1 pathway activation in FLCN knockdown cells, since phosphorylation of TSC2, known to inactivate the mTOR signaling sequence, was strongly diminished in siFLCN cells prone to shear stress (Supplemental Figure S4A and S4B)."
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"Recent studies have revealed that TSC2 plays an important role in the cell growth and proliferation pathway, in which TSC2 forms a functional complex with TSC1 and negatively regulates both growth factor and nutrient dependent activation of mTOR signalling to its downstream targets S6 kinase and 4EBP1 (Gao et al, 2002; Manning and Cantley, 2003; Saucedo et al, 2003; Stocker et al, 2003; Hay and Sonenberg, 2004)."
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"To investigate whether the suppressed AKT and mTOR pathway contributes to the reversibility of contact inhibition, they designed shRNA that silenced the expression of TSC2, an AKT substrate that inhibits mTOR activity by suppressing the mTOR activating small GTP binding protein Rheb."
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"The canonical pathway for mTOR regulation is independent of erk1/2 and involves PI3K-PDK1-Akt-dependent inactivation of the mTOR suppressor TSC2, which then leads to mTOR-p70S6K dependent translation of mRNAs and de novo protein synthesis at active synapses (Hoeffer and Klann, 2010)."
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"The down-regulation of PRAS40, Rictor, Raptor, and GbetaL, which further led to loss of mTOR complex (mTORC) 1/2 formation, activation of mTOR repressor TSC2 by suppressing Akt and activating AMPK, suppression of Cap dependent translation, and hypophosphorylation of 4EBP1 as well as induction of autophagic programmed cell death, was reported after fisetin treatment (Suh etal.,2010)."
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"Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5 ' adenosine monophosphate activated protein kinase (AMPK), we proposed that the activation of AMPK alpha1/2 by LKB1 and/or by calmodulin dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K."
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"Our study demonstrates that IFNbeta dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2 dependent inhibition of mTOR and S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation."
eidos
"54 In addition , phosphorylated AKT ( p-Akt ) can inhibit TSC2 and TSC to activate mTOR ,55 and mTOR can induce mRNA translation by phosphorylating S6K and then p70S6K to increase the adhesion of ribosomes to the endoplasmic reticulum and thereby inhibit both the formation of autophagic membranes and autophagy activity.56 ,57 The corresponding results from our study showed that LACTB might inhibit the level of PIK3R3 to reduce the levels of PI3K , p-AKT and mTOR and thereby promote autophagy ."
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"Activation of AMPK leads to suppression of mammalian target of rapamycin (mTOR) signaling, and the molecular mechanisms involve phosphorylation of tuberous sclerosis complex protein TSC2 at Thr 1227 and Ser 1345 that increases the activity of the TSC1 and TSC2 complex to inhibit mTOR [XREF_BIBR, XREF_BIBR]."
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"Results of this study demonstrated that Arg and rSPP1 act synergistically on oTr cells to : (1) stimulate (P \ 0.05) proliferation, migration and adhesion of oTr cells; (2) activate PDK1/Akt/MTORC1 (MTOR / Raptor) and MTORC2 (MTOR and Rictor) signaling pathways; (3) release inhibition of MTOR by phosphorylating TSC2; and (4) induce cytoskeletal reorganization (i.e., cytokeratin, a-tubulin, F-actin, integrin b3 and talin) to effect changes in morphology."
| PMC
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"We previously identified a novel interaction between tuberous sclerosis-2 (TSC2) and death associated protein kinase-1 (DAPK), the consequence being that DAPK catalyses the inactivating phosphorylation of TSC2 to stimulate mammalian target of rapamycin complex 1 (mTORC1) activity."
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"ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling, suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [XREF_BIBR]."
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"Since hamartin and tuberin negatively regulate mTOR activity, which in turn phosphorylates and thereby activates important translation factors such as p70 S6 kinase 1 (S6K1) and eukaryote initiation factor 4E binding protein (eIF4E-BP), a major role of the TSC-mTOR signaling pathway has been suggested for tumorigenesis, and both genes were initially recognized as tumor suppressors [XREF_BIBR]."
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"Thomas Weichhart from the Medical University of Vienna presented a mouse model in which deletion of the tuberous sclerosis 2 (TSC2) gene in myeloid cells induces constitutive mTOR activation, followed by spontaneous multiorgan granuloma formation that appears to be more chronic than many prior murine granuloma models."
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"The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner."
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"Muscle hypertrophy is also influenced by the availability of nutrients and the presence of endocrine and autocrine hormones such as IGF-I. A concerted anabolic signal is generated by leucine which facilitates the translocation of the kinase mTOR to the surface of the lysosome, where it is activated by Rheb, and by IGF-I which relieves the inherent inhibition of mTOR by TSC2."
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"First, in the nucleus, p53 has been reported to promote autophagy by transactivating genes encoding : DRAM1, which is induced by DNA damage and localized to lysosomes with autophagosome accumulation; and sestrin 1 and 2, AMPK beta1 and beta2, and TSC2, which act on the AMPK pathway to inhibit the autophagy suppressor mTOR, thus activating autophagy [XREF_BIBR, XREF_BIBR]."
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"Other downstream targets of AMPK include TSC2, which inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis; xref HMG-CoA reductase, which leads to the inhibition of cholesterol synthesis; xref peroxisome proliferator-activated receptor-gamma coactivator (PPARα) 1α, which stimulates mitochondrial biogenesis, xref , xref and many others."
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"In response to elevated ROS (both exogenous ROS such as H O or doxorubicin and endogenous ROS such as menadione or phenylethylisothiocyanate), cytoplasmic ATM acts as an ROS sensor and activates the tuberous sclerosis 2 (TSC2) tumor suppressor via the Liver kinase B1 (LKB1) / Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway to repress mammalian target of rapamycin complex 1 (mTORC1) and induce autophagy."
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"Interestingly, while we previously showed activation of AMPKalpha and downstream tumor suppressor TSC2 which act to inhibit mTOR in both U251 and U87 parental cells [XREF_BIBR], U87TMZ appears to have lost the ability to act through this pathway which suggests direct inhibition of the Akt and mTOR axis."
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"The activation of AMPK by LKB1 leads to phosphorylation of tuberous sclerosis complex 2 (TSC-2), which in turn inhibits the mTOR protein (mammalian target of rapamycin), a key protein which regulates processes of cell growth and angiogenesis, and promotes cell division and protein synthesis."
eidos
"Cell stress and Akt-mTORC1 / - mTORC2 signaling The serine / threonine kinase mTOR is a well-characterized substrate of Akt and it is known that Akt-mediated activation of mTOR occurs through phosphorylation and inactivation of tuberous sclerosis complex 2 ( TSC2 ) , which normally inhibits mTOR ( Hay 2005 ) ."
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"Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain (Rheb), a GTPase that activates mTOR, and tuberin (also known as TSC2), a GTPase activating protein, which, with its binding partner hamartin (also known as TSC1), acts to repress mTOR."
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"15 ATM is exported to the cytoplasm in response to high concentration of ROS and reactive nitrogen species (RNS) like nitric oxide (NO), and deactivates mTOR through a series of phosphorylation dependent activation processes involving liver kinase B1 (LKB1), AMPK and the tumor suppressor tuberous sclerosis 2 (TSC2)."
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"TSC1 and TSC2 negatively regulate the activity of the mammalian target of rapamycin complex 1 (mTORC1), and deletion of Tsc1 or Tsc2 from mouse oocytes in primordial and further developed follicles has been shown to cause overactivation of the entire ovarian pool and subsequent POF in early adulthood [69,70]."
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"In this study, we provided first evidence that MALAT1 epigenetically repress TSC2 transcription via recruiting EZH2 to TSC2 promoter regions to induce H3K27me3, and thereby induce mTOR activation and subsequent autophagy inhibition.Autophagy can be activated as a stress response shortly after AMI; however, sustained ischemia impaired cardiomyocyte autophagy flux, which exacerbated the post-infarct adverse cardiac modeling [27]."
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"It is possible that they express negative mTOR regulators such as TSC2, which limits mTOR signalling in Drosophila intestinal stem cells but not progenitors, or that stem cells are more adept than progenitors at using low levels of nutrients for proliferation, perhaps because of their slower cycling."
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"XREF_BIBR Both sestrins can trigger the AMPK and target it to phosphorylate and activate TSC1 and TSC2 complex, thereby inhibiting the signaling of mTOR, a critical autophagy inhibitor of cells, XREF_BIBR, XREF_BIBR and so CX-5461-induced autophagy through AMPK and mTOR signaling pathway in U2-OS cells might arise from the upregulation of Sesn1/2 by p53."
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"Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR activating GTP binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8 and Gbl and the scaffold protein Raptor."
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"In the presence of growth factors such as insulin or insulin like growth factors, stimulated Akt and extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2), which activates mTOR inhibition and thus inhibiting autophagy [XREF_BIBR]."
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"A great deal of ground breaking work has determined that the Tuberin and Hamartin Complex function as a negative regulator of protein synthesis and cell cycle progression through G1/S. This is largely attributed to the GTPase activity of Tuberin that indirectly inhibits the mammalian target of rapamycin (mTOR)."
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"Akt can directly phosphorylate and activate mTOR, as well as indirectly activating it by phosphorylating and inactivate tuberous sclerosis complex 2 (TSC2), also called tuberin, which normally inhibits mTOR through the GTP binding protein Ras homolog enriched in brain (Rheb) [XREF_BIBR]."
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"Other downstream targets of AMPK include TSC2, which inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis; XREF_BIBR HMG-CoA reductase, which leads to the inhibition of cholesterol synthesis; XREF_BIBR peroxisome proliferator activated receptor-gamma coactivator (PPARalpha) 1alpha, which stimulates mitochondrial biogenesis, XREF_BIBR, XREF_BIBR and many others."