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MTOR phosphorylates EIF4EBP1. 1000 / 1269
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"Accumulating evidence suggests a correlation between the aberrant nucleocytoplasmic transport and elevated XPO1 expression in tumours, leading to the occurrence and development of several cancers. xref The upregulation of XPO1 allows key cellular proteins, such as p27Kip1 and p53, to be transported into the cytoplasm and inactivates inappropriate cell growth or DNA repair. xref Similarly, oncogenes such as STAT3 and c‐myc activate downstream signalling pathways to stimulate proliferation and inhibit apoptosis upon export. xref Inhibition of XPO1 promotes the nuclear accumulation of TSPs and oncogenes and promotes the apoptosis of tumour cells. xref Several studies have shown that inhibiting XPO1 induces tumour cell apoptosis by triggering intranuclear accumulation of p53 or p27. xref , xref STAT3 phosphorylation or acetylation activates downstream growth signals, promotes cell proliferation and prevents apoptosis. xref The CREB‐binding protein (CBP) induces acetylation of STAT3 to regulate transcriptional activity. xref XPO1 inhibition represses STAT3 activation by affecting CBP activity to reduce the level of STAT3 acetylation, which blocks the interaction between STAT3 and the survivin promoter. xref C‐myc plays a key role as a regulator in a variety of tumours. xref mTOR‐dependent 4EBP1 phosphorylation has been shown to be a key factor by which myc maintains tumour survival. xref eIF4E, a translation regulator downstream of mTOR, plays an important role in myc transcriptional regulation. xref KPT‐330 inhibits the nuclear export of c‐myc mRNA by inducing the nuclear accumulation of XPO1 and eIF4E complexes. xref Subsequent studies have shown that inhibition of XPO1 also regulates c‐myc expression through other pathways, such as the upregulation of miR‐145. xref Therefore, inhibition of XPO1 may constitute a new strategy for tumour therapy (Figure xref )."
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"The phosphorylation of PHAS-I by mTOR ultimately upregulates the expression of proteins involved in cell proliferation.PolyP could also be involved in the regulation of the eukaryotic inositol polyphosphate multikinase (IPMK), which is a key enzyme in the formation of inositol polyP."
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"The heightened mTOR-dependent phosphorylation of 4EBP1 leads to increased translation and subsequently elevated protein levels of inflammatory receptors and cytokines in aged microglial cells compared to their younger counterparts, an effect that could be mitigated by the loss of Rheb1, the upstream positive regulator of mTORC1."
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"Suppression of mTOR kinase, decreased the phosphorylation of mTOR, p70S6K and 4EBP1, leading to the suppression of c-Myc translation.23 To test this hypothesis, RPMI 8226 and U266 cells were treated with montelukast / carfilzomib alone or in combination for 24h, and the results revealed that p-mTOR (Ser2448), and its downstream signaling members namely, p-p70S6K (Thr489), p-4EBP1 (Ser 65) were obviously diminished)."
sparser
"The phosphorylation of S6K1 by mTOR is confined to a single residue (T389)( xref ), and this phosphorylation was eliminated by pemetrexed ( xref ), whereas four residues on 4EBP1 are phosphorylated by mTOR ( xref ); the broader migration pattern seen in pemetrexed-treated cells with the pan-4EBP1 antibody ( xref ) suggests that several of these phosphorylation sites are affected by drug."
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"Even though Rh30 and RD cells are p53 negative; knockdown of NR4A1 in Rh30 cells or treatment with DIM-C-pPhOH induced sestrin 2 and increased phosphorylation of AMPKalpha and this resulted in decreased activation of mTOR dependent phosphorylation of both 4EBP1 and 6SRP which are kinases downstream from mTOR."
sparser
"When activated, mTOR phosphorylates S6K and 4E-BP1 to promote protein translation and is sensitive to rapamycin inhibition.[ xref ] Recent studies have shown that mTOR may regulate T-cell differentiation and adaptive immunity following the binding of the T-cell receptor to antigen.[ xref ] In preliminary experiments, we found that mTOR modulates lymphocyte differentiation in immunosuppressed animals with fungal infections by regulating the transcription factors T-box expressed in T-cells (T-bet) and eomesodermin.[ xref ] T-bet is a key transcription factor regulating T-cell differentiation and belongs to the T-box transcription factor family.[ xref ] Eomesodermin plays a synergistic role in T-bet function and regulates the differentiation of CD8 + T-cells into effector and memory T-cells."
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"Because mTOR is found to increase transcription of glycolytic enzymes, thereby enhancing the capacity of cells to execute glycolysis,12 21 and given the finding that NLRC3 inhibits mTOR pathways in colon epithelial cells24 25 and the gene transcription data (Figure S8), we assessed whether mTOR signaling highly depends on the phosphorylation of mTOR and the downstream effectors S6K and 4EBP1."
sparser
"Under the condition of stimuli, PI3K phosphorylates PIP2 to create PIP3 and recruits AKT to the plasma membrane to active PDK1 and mTOR complex which phosphorylates 4E-BP1 and p70 ribosomal S6 kinase that trigger ribosome biogenesis and translation in cell growth and division [ xref , xref ] ( Figs. xref & xref )."
sparser
"In-activation of tumor suppressors PTEN, TSC1, and TSC2 in TNBC is common and is associated with hyperactivation of PI3K/Akt/mTOR/4EBP1/p70S6K signaling pathway; phosphorylation of p70S6K/ 4EBP1 by mTOR has been shown to increase cancer cell survival and chemotherapy resistance in TNBC xref ."
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"In the EIF4-dependent translation initiation pathway, MTOR phosphorylates EIF4EBP1, and the phosphorylated EIF4EBP1 then releases EIF4E, which is freed to recruit 40S ribosomal subunit to the 5′ end of mRNAs, thereby initiating translation.44 Hence, the degree of EIF4EBP1 phosphorylation is an indication of MTOR-mediated translational activity."
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"ROS triggered PI3K activation can transduce oncogenic AKT-mTOR signaling; mTOR can increase the phosphorylation of both eukaryotic initiation factor 4E binding protein1 (4EBP-1) and S6K1, leading to the translation and expression of mRNAs encoding several major anti-apoptotic proteins including XIAP, c-IAP1, Bcl-XL, and BCl-2 [XREF_BIBR]."
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"We found that overexpression of 4EBP1 promoted the apoptosis rate as well as the VP1 expression after viral infection, and overexpression of p70S6K promoted apoptosis while decreased the VP1 expression at 24h p. i. Activated mTOR phosphorylates the downstream effectors 4EBP1 and p70S6K."
sparser
"MLN0128 effectively inhibits mTOR phosphorylation of 4EBP1, allowing eIF4G binding to eIF4E; however, there are eIF4E-independent mechanisms for c-Myc mRNA translation initiation, and so treatment with MLN0128 may fail to sufficiently inhibit c-Myc translation in some cancers. xref Inhibiting eIF4A directly can overcome this pitfall because unwinding the 5′UTR G-quadruplexes is indispensable for c-Myc translation."
sparser
"Vam6p (Vps39 in yeast) also functions as a Rag family GTPase nucleotide exchange factor to promote TORC1 activation in response to increased amino acid concentrations in the environment of yeast, leading to mTOR-dependent phosphorylation of the cap-binding protein 4EBP-1 ( xref )."
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"4E-BP1 and S6K1 are phosphorylated by mammalian target of rapamycin complex 1 (mTORC1) which regulates the binding of eIF4E to the mRNA 5 ' cap through phosphorylation of 4E-BP1 and stimulates protein synthesis through the phosphorylation of S6K1 XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR."
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"Phosphorylation of 4E-BP1 by mammalian target of rapamycin (mTOR), AKT, and extracellular signal–regulated kinase (ERK) prevents 4E-BP1 binding to the eIF-complex, leading to an aberrantly upregulated translational efficiency, which is an important characteristic of tumor growth, metastatic progression, and cancer stem cell enrichment [7,8]."
sparser
"Phosphorylation of S6K1 on Thr390 (human Thr389) is a primary activator of its kinase activity and appears to regulate translation of ribosome-related transcripts and ribosome biogenesis, although the mechanism underlying differential regulation of phosphorylation of Eif4ebp1 and S6K1 by Frap1 is currently unknown xref ."
sparser
"The heightened mTOR-dependent phosphorylation of 4EBP1 leads to increased translation and subsequently elevated protein levels of inflammatory receptors and cytokines in aged microglial cells compared to their younger counterparts, an effect that could be mitigated by the loss of Rheb1, the upstream positive regulator of mTORC1."
reach
"In human prostate cancer cells, constitutive expression of HIF-1alpha was found to require signal transduction via phosphatidylinositol-3-kinase (PI3K), AKT (protein kinase B), and the mammalian target of rapamycin (mTOR; also known as FKBP and rapamycin binding protein), a serine/threonine protein kinase that phosphorylates p70 ribosomal protein S6 kinase 1 (S6K1) and the eIF-4E binding protein 1 (4E-BP1), thereby stimulating protein synthesis."
sparser
"Mechanistic target of rapamycin (mTOR), as a serine/threonine kinase, is the dominating component of mTOR complex (mTORC1/2), which could phosphorylate ribosomal protein S6 kinase (S6K), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and other target proteins to modulate protein synthesis, nutrient metabolism, cell growth and migration [ xref ]."
sparser
"Since mTOR phosphorylates 4EBP1, resulting in its dissociation from eIF4E and leading to the formation of the translation initiation complex xref , we used mutant 4EBP1-5A, which lacks the five Ser/Thr phosphorylation sites targeted by mTOR and thus acts as a dominant negative inhibitor by binding elF4E to prevent translation initiation xref ."
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"The mTOR pathway, a significant controlling factor for MPS, stimulates the kinase activity of the complex and leads to the phosphorylation of 4E-BP1 and p70S6K, which are two enzymes that also modulate protein synthesis at the level of mRNA translation initiation [XREF_BIBR, XREF_BIBR]."
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"We found that phenformin could suppress the activation of the mTOR pathway, indicated by the reduced phosphorylated level of mTOR, as well as its downstream targets p70S6K and 4E-BP1, as early as 2 h after treatment, which was associated with the decreased expression of c-Myc in keratinocytes (Figure 6A,B)."
sparser
"Besides this, activation of mTOR by AKT can phosphorylate and inactivate 4E-BP1 (for eIF4E-Binding Proteins), a family of small acidic proteins that function as translational repressors of eIF4E. Phosphorylation of 4E-BP1 by mTOR releases 4E-BP1 from eIF4E thereby activating eIF4E involved translation-initiation complex and consequently the translational repertoire of a cell toward malignancy [ xref ]."
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"The mechanism distinguishing reversible quiescence-like contact inhibition and irreversible senescence is thought to be regulated by the activity of mammalian target of rapamycin (mTOR), which phosphorylates p70 S6 kinase (S6K) and eukaryotic translational initiation factor eIF4E-binding protein 1 (4E-BP1) to mediate eIF4E-mediated translation (Leontieva et al, 2014; Sun, 2014)."
sparser
"Another point of convergence of the PIM and PI3K pathways is mTOR, a molecule downstream of PI3K that is responsible for cellular processes, including cell survival and protein synthesis, and influences the pathogenesis of disorders such as cancer and type 2 diabetes. xref , xref Both PIM and AKT negatively regulate mTOR by phosphorylation of PRAS40 (proline-rich Akt substrate of 40 kDa) xref and TSC2 (tuberous sclerosis complex 2), xref the latter of which occurs by both directly and indirectly decreasing AMPK (5' adenosine monophosphate-activated protein kinase) activation. xref Moreover, mTOR and PIM can phosphorylate 4E-BP1 to allow for protein translation and MYC signaling. xref Another link between the pathways is the phosphorylation of c-MYC, which prevents apoptosis and allows the oncogene to drive tumorigenesis. xref , xref , xref , xref "
sparser
"We hypothesized that mechanism by which rapamycin induced the up-regulation of HSPs in PDAPP brains may involve rapamycin-induced inhibition of 4E-BP1 phosphorylation by mTOR, which would in turn inhibit cap-dependent protein synthesis and thus allow for the preferential translation of pre-existing HSP mRNAs ( xref ; xref ; xref )."
sparser
"Even though Rh30 and RD cells are p53-negative; knockdown of NR4A1 in Rh30 cells or treatment with DIM-C-pPhOH induced sestrin 2 and increased phosphorylation of AMPKα and this resulted in decreased activation of mTOR-dependent phosphorylation of both 4EBP1 and 6SRP which are kinases downstream from mTOR (Figure xref )."
sparser
"Additionally, mTOR phosphorylates the eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a protein that binds to and inhibits activity of the eukaryotic initiation factor eIF4E. When 4E-BP1 is phosphorylated by mTOR, it dissociates from eIF4E, allowing eIF4E to complex with other initiation factors to initiate mRNA translation."
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"Green
et al.
[38] found that a specific inhibitor of mTOR induces a multisite dephosphorylation of 4E-BP1, which markedly inhibits the initiation step of mRNA translation, resulting in a strong anti-leukemic activity against primary AML cells while sparing normal hematopoiesis
ex vivo and significantly reducing the growth of AML cells in nude mice."
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"Most cellular stress conditions block eIF4E activity by suppressing mTOR dependent phosphorylation of 4EBP1, which is thought to be mediated by AMP activated protein kinase (AMPK)-dependent activation of the mTOR inhibitor TSC2 (also known as tuberin) 168, although REDD1 (also known as DDIT4) and RAS GTPases, respectively, have also been implicated in mTOR control during hypoxia and amino acid deprivation XREF_BIBR, XREF_BIBR."
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"Notably, increased levels of phosphorylated TFEB were observed in these kidneys (Fig. 4d; Supplementary Fig. S10), suggesting that mTOR hyperactivation leads to increased 4E-BP1 phosphorylation but not to translocation of TFEB to the nucleus (phosphorylation of TFEB sequesters it to the cytoplasm) ."
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"As described in the Introduction, mTOR dependent increases in 4E-BP1 phosphorylation can lead to the dissociation of 4E-BP1 from eIF4E while simultaneously enhancing the association of eIF4E with eIF4G (i.e. the formation of eIF4F complex, which is crucial for the cap dependent initiation of translation)."
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"While p70S6K phosphorylation at Thr389 is required for its activity and is blocked by rapamycin, 4E-BP1 is phosphorylated on multiple sites by mTOR, and it is the largely rapamycin-insensitive phosphorylation of Thr46 that prevents inhibitory binding to the 5 ' mRNA cap binding protein eIF4E [XREF_BIBR, XREF_BIBR]."
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"Phospho-4E-BP1 expression was reduced after treatment (mean -2.3; range -6 to +1; p < 0.001), suggesting a reduction in mTOR dependent phosphorylation of 4E-BP1, but this reduction in phospho-4E-BP1 was not significantly correlated with the reduction in estimated eIF4E activity, and changes in levels of the other components had strong influences on estimated eIF4E activity."
sparser
"Recent findings suggest that the two proteins known to function downstream of mammalian mTOR (p70S6K and PHAS-I) may represent two distinct signaling pathways, because the phosphorylation of PHAS-I by mTOR is still rapamycin sensitive in cells expressing a rapamycin-resistant form of p70S6K [ xref ]."
sparser
"Alleviation of MYC-induced ER stress is driven by enhanced phosphorylated levels of p70S6K and EIF4EBP1 (4E-BP1), a downstream substrate of mammalian target of rapamycin complex 1 (mTORC1) which hyperphosphorylate 4E-BP1 by its dissociation from eIF4E. Targeting the ISR can be achieved by drugging the translational machinery ( xref ) or by targeting autophagy ( xref , xref ), but recently more specific inhibitors of ISR have entered clinical trials."
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"Increased mTOR-dependent phosphorylation of 4EBP1 resulted in higher translation, and, therefore, higher protein levels, of inflammatory receptors and cytokines in aged microglia compared to younger counterparts, an effect that could be reduced by loss of Rheb1, the upstream positive regulator of mTORC1."
sparser
"Phospho-4E-BP1 expression was reduced after treatment (mean -2.3; range -6 to +1; p < 0.001), suggesting a reduction in mTOR-dependent phosphorylation of 4E-BP1, but this reduction in phospho-4E-BP1 was not significantly correlated with the reduction in estimated eIF4E activity, and changes in levels of the other components had strong influences on estimated eIF4E activity."
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"MTOR is then activated as a kinase and can phosphorylate p70-S6 kinase, which then phosphorylates downstream targets like S6 (to form phosphorylated S6, or phospho-S6) and the eukaryotic initiation factor 4E (4EBP1, to form phospho-4EBP1) that increase protein translation and also activate mTOR activity by a positive feedback loop."
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"Since mTOR phosphorylates 4EBP1, resulting in its dissociation from eIF4E and leading to the formation of the translation initiation complex XREF_BIBR, we used mutant 4EBP1-5A, which lacks the five Ser/Thr phosphorylation sites targeted by mTOR and thus acts as a dominant negative inhibitor by binding elF4E to prevent translation initiation XREF_BIBR."
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"Pre-treatment with LY294002, an inhibitor of PI3K, or with MK2206, an inhibitor of AKT (XREF_SUPPLEMENTARY), or with rapamycin or RAD001 (XREF_SUPPLEMENTARY), the inhibitor of mTOR, blocked the phosphorylation of 4E-BP1 mediated by the PI3K and AKT pathway, and disrupted upregulation of USP15 synthesis mediated by TGF-beta (XREF_FIG)."
sparser
"Phosphorylation of 4E-BP1 by mammalian target of rapamycin (mTOR), AKT, and extracellular signal–regulated kinase (ERK) prevents 4E-BP1 binding to the eIF-complex, leading to an aberrantly upregulated translational efficiency, which is an important characteristic of tumor growth, metastatic progression, and cancer stem cell enrichment [ xref , xref ]."
sparser
"Unlike the previously proposed canonical model for the dissociation of eIF4E from 4E-BP1, wherein higher-order phosphorylations are entirely predicated upon priming phosphorylations at Thr-37 and Thr-46, these priming phosphorylations are not required for 4E-BP1 hyperphosphorylation during mitosis because CDK1/cyclin B can substitute for mTOR to phosphorylate 4E-BP1 at multiple sites ( xref )."
sparser
"The mechanism distinguishing reversible quiescence-like contact inhibition and irreversible senescence is thought to be regulated by the activity of mammalian target of rapamycin (mTOR), which phosphorylates p70 S6 kinase (S6K) and eukaryotic translational initiation factor eIF4E-binding protein 1 (4E-BP1) to mediate eIF4E-mediated translation (Leontieva et al, xref ; Sun, xref )."
reach
"One of the most important effector molecules downstream of PI3K and Akt pathway appears to be the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis, which can subsequently phosphorylate S6 kinase (S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1)."
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"In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap binding protein eIF4E as well as an ERK dependent phosphorylation of eIF4E, thus promoting translation initiation."
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"We found that AKT and mTOR signaling was significantly inhibited in the MMQ and GH3 cells by CAB in a time dependent manner as indicated by decreased phosphorylation of AKT and mTOR as well as decreased phosphorylation of p70S6K and 4EBP1, two key downstream effectors of the mTOR pathway."
sparser
"In addition, mTOR phosphorylates and inactivates eukaryotic initiation factor 4E-BP1, resulting in the release of inhibition on eIF4E, and promotes translation initiation.[ xref ] To confirm the role of the IGF-1/IGF-1R axis in the CD26-regulating pathway, the IGF-1Rs in CD26 − and CD26 + KFs were knocked down; the results revealed that stably silenced IGF-1Rs in CD26 − KFs (CD26 − /sh-IGF1R) and CD26 + KFs (CD26 + /sh-IGF1R) were established ( xref )."
sparser
"It was recently reported that protein-binding function of PKR promotes the proliferation of pancreatic β cells through TNF receptor-associated factor 2 (TRAF2)/receptor-interacting protein 1 (RIP1)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B)/c-Myc pathway [ xref ], while cancer cell survival requires mTOR-dependent phosphorylation of 4EBP1 in Myc-dependent tumor, and PP2A-B56 α holoenzyme can negatively regulate c-Myc protein accumulation [ xref , xref ]."
sparser
"Since S9 is capable of inhibiting the activity of PI3K, we detected whether S9 inhibits the activity of mTOR, which bears a highly homologous COOH-terminal catalytic domain with PI3K. As shown in xref , phosphorylation of 4E-BP1 by mTOR was greatly down-regulated by S9 treatment."
sparser
"To promote this type of translation, eukaryotic translation initiation factor 4E (eIF4E) has to bind with eIF4A and eIF4G, creating multisubunit eIF4F. By mTOR phosphorylation of 4E-binding protein 1 (4E-BP1), it releases eIF4E, allowing it to start the cap-dependent translation."
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"Both pathways enable mTOR to carry out kinase activity by directly phosphorylating 4E-BP1 and ribosomal protein S6 kinase 1 (p70S6k), thus initiating the eukaryotic translation via phosphorylations of S6 and eIF4 (Follo et al., 2019; Shi et al., 2019; Yoder et al., 2019; Iffland et al., 2020)."
sparser
"SESN2 inhibits mTOR-dependent phosphorylation of p70S6K and 4E-BP1,( xref )and knockdown of SESN2 resulted in the activation of mTOR signaling indicating that the important role of SESN2 on mTOR inhibition.( xref )Our results from western blotting demonstrated that mTOR was down-regulated by fisetin treatment in HNCCs consistent with other previous studies showing tumor inhibiting potentials of fisetin through mTOR pathway.( xref , xref , xref )These results suggest that fisetin-induced apoptotic potentials is through SESN2/mTOR signaling axis."
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"Inhibition of mTOR decreases phosphorylation of two downstream targets, 4E-BP1 and S6K, resulting in inhibition of protein synthesis [XREF_BIBR], which does not necessarily induce apoptosis, but it can be considered in combination with other drugs as it induces cell arrest and sensitizes cells to apoptosis [XREF_BIBR]."
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"The phosphorylation of 4EBP1 by mTOR in response to growth factor and nutrient status causes it to dissociate from eIF4E allowing eIF4G and associated factors to bind to the 5 ' cap, recruit the 40S subunit of the ribosome, and scan the mRNA for the start codon to initiate translation."
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"By contrast, LY294002, a direct inhibitor of many PI3K family members including mTOR, was equally effective at inhibiting the phosphorylation of S6K and 4EBP1 by mTOR in vitro [XREF_BIBR] and in cells [XREF_BIBR], although this finding is complicated by LY294002 's inhibition of multiple lipid and protein kinases [XREF_BIBR] including PIM, a kinase potentially upstream of 4EBP1 phosphorylation [XREF_BIBR, XREF_BIBR]."
sparser
"In addition, mTOR, another substrate subjected to phosphorylation by AKT, enhances phosphorylation of S6K1 and 4E-BP1 [ xref ] and plays crucial roles in the regulation of ribosomal protein synthesis, for example, production of cyclin D1 and VEGF-A at both transcriptional and translational levels [ xref , xref ]."
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"In addition, mTOR, another substrate subjected to phosphorylation by Akt, enhances phosphorylation of S6K1 and 4E-BP1 and plays a crucial role in the regulation of ribosomal protein synthesis, for example, production of cyclin D1 and VEGF-A at both the transcriptional and translational levels XREF_BIBR."
sparser
"To the extent that the pathway enables LPS-activated macrophages to carry out essential protein translation, it likely works in concert with complementary LPS-induced mechanisms that enhance translation initiation, such as mTOR-induced phosphorylation of 4E-BP1, which activates the initiation factor eIF4E xref ."
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"p70 S6K phosphorylates the ribosomal protein S6 (RPS6), resulting in increased translation of mRNAs containing a 5 ' oligopyrimidine tract, whereas phosphorylation of 4E-BP1 by mTOR relieves inhibition on the initiation factor eIF4E, resulting in more efficient cap dependent translation."
sparser
"p70 S6K phosphorylates the ribosomal protein S6 (rpS6), resulting in increased translation of mRNAs containing a 5’ olygopyrimidine tract, whereas phosphorylation of 4E-BP1 by mTOR relieves inhibition on the initiation factor eIF4E resulting in more efficient cap-dependent translation xref ."
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"The immunohistochemical expression of mTOR related proteins tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4EBP1), phosphorylated mTOR (p-mTOR), and phosphorylated ribosomal protein S6 kinase B1 (p-P70S6K) were analyzed using Image-Pro Plus software."
sparser
"In effect, mTOR-mediated phosphorylation of HOXB13 is better aligned with 4EBP1 phosphorylation by mTOR, whereby T37/T46 phosphorylation primes its further phosphorylation at T70/S65 with the second kinase proposed to be mTOR or another proline-directed kinase like ERK2 ( xref )."
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"AZD8055 (XREF_FIG) is a prototypic, orally-available, ATP-competitive mTOR kinase inhibitor, that suppresses phosphorylation of the mTORC1 substrates p70S6K and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), as well as phosphorylation of the mTORC2 substrate AKT (S473)."
sparser
"Activated mTOR phosphorylates the downstream effectors 4EBP1 and p70S6K. Being responsible for the cap-dependent translation of mRNA and the protein synthesis, they are critical components in a pathway regularly co-opted by viruses to ensure translation of their own mRNA. xref , xref Our previous work has shown that CVB3 infection can activate mTOR/4EBP1 pathway to promote the synthesis and release of the viral protein. xref In this study, CVB3 infection directly stimulated PI3K/Akt pathway, keeping the mTOR/4EBP1 pathway activating."
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"4E-BP1 is a downstream target of the Akt-mTOR (mammalian target of rapamycin) signaling pathway : When 4E-BP1 is hyperphosphorylated by mTOR, it releases the protein translation initiation factor eIF4E, thereby allowing eIF4E to bind to 7-methyl guanosine capped messenger RNA and to recruit the ribosomal machinery required for translation."
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"MTORC1 phosphorylates 4E-BP1 at several residues which promotes the dissociation of eIF4E from 4E-BP1 consequently mitigating the inhibitory effect of 4E-BP1 on eIF4E dependent translation initiation whereas the inhibition of mTOR by rapamycin is believed to cause 4E-BP1 dephosphorylation, which results in inhibition of protein translation (XREF_FIG) [XREF_BIBR]."
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"Overall, these data suggest that the upregulation of TCTP during mechanical overload induced muscle growth occurs via both a rapamycin-insensitive mechanism (possibly mTOR mediated phosphorylation of 4E-BP1) and a rapamycin sensitive mTOR kinase dependent mechanism (e.g., p70 S6K1 and/or eIF4G phosphorylation)."
sparser
"While some studies suggest that mitotic and/or CDK1-dependent phosphorylation of 4EBP1 replaces mTOR-dependent phosphorylation of 4EBP1 during mitosis ( xref ; xref ) and thus relieves the inhibitory effect of 4EBP1 on cap-dependent translation; others ( xref , xref ) do not observe a measurable difference in cap-dependent translation in the presence or absence of mitotic 4EBP1 phosphorylation, which is characterized by an additional phosphorylation event on S83."
sparser
"When mTOR protein phosphorylates 4E-BP1, it dissociates from eIF4E. Once eIF4E is freed from 4e-BP1, it can form complex structures with several other proteins, including eIF4G or eIF4F. When mTOR phosphorylates p70S6K, this kinase phosphorylates S6 ribosomal protein in return [ xref , xref ]."
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"p70 S6K phosphorylates the ribosomal protein S6 (rpS6), resulting in increased translation of mRNAs containing a 5 ' olygopyrimidine tract, whereas phosphorylation of 4E-BP1 by mTOR relieves inhibition on the initiation factor eIF4E resulting in more efficient cap dependent translation XREF_BIBR."
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"The effect of androgens on translation is mediated through several mechanisms including changes in miRNA expression or processing XREF_BIBR - XREF_BIBR, phosphorylation of translation factors like eEF2 XREF_BIBR, or mTOR activation mediated phosphorylation of p70S6 and 4E-BP1 XREF_BIBR."
sparser
"On the other hand, 4EBP1 binds to the eukaryotic translation initiation factor 4E (EIF4E) to prevent the formation of the translation initiation complex, mTOR phosphorylates 4EBP1 to separate it from EIF4E, thereby forming the translation initiation complex. xref Therefore, we can further deduce that the changes in biological behaviors after RRM2 downregulation may be connected to Akt/mTORC1/4EBP1 signaling pathway."
reach
"MLN0128 effectively inhibits mTOR phosphorylation of 4EBP1, allowing eIF4G binding to eIF4E; however, there are eIF4E-independent mechanisms for c-Myc mRNA translation initiation, and so treatment with MLN0128 may fail to sufficiently inhibit c-Myc translation in some cancers.110 Inhibiting eIF4A directly can overcome this pitfall because unwinding the 5′UTR G-quadruplexes is indispensable for c-Myc translation."
sparser
"In addition, mTOR, another substrate subjected to phosphorylation by Akt, enhances phosphorylation of S6K1 and 4E-BP1 and plays a crucial role in the regulation of ribosomal protein synthesis, for example, production of cyclin D1 and VEGF-A at both the transcriptional and translational levels xref ."
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"Thus, the lack of a difference in the EIF4EBP1 and EIF4EBP2 mRNA abundances across tissues suggested that the proteins encoded by these genes may work in a similar fashion to affect protein synthesis.The kinase mTOR, which phosphorylates EIF4EBP1, prevents EIF4EBP1 binding to EIF4E and phosphorylates RPS6KB1, thus promoting protein synthesis [55]."
sparser
"Most cellular stress conditions block eIF4E activity by suppressing mTOR-dependent phosphorylation of 4EBP1, which is thought to be mediated by AMP-activated protein kinase (AMPK)-dependent activation of the mTOR inhibitor TSC2 (also known as tuberin) xref , although REDD1 (also known as DDIT4) and RAS GTPases, respectively, have also been implicated in mTOR control during hypoxia and amino acid deprivation xref , xref ."
reach
"In addition, mTOR, another substrate subjected to phosphorylation by AKT, enhances phosphorylation of S6K1 and 4E-BP1 [XREF_BIBR] and plays crucial roles in the regulation of ribosomal protein synthesis, for example, production of cyclin D1 and VEGF-A at both transcriptional and translational levels [XREF_BIBR, XREF_BIBR]."
sparser
"In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap-binding protein eIF4E as well as an ERK-dependent phosphorylation of eIF4E, thus promoting translation initiation."
sparser
"In the EIF4-dependent translation initiation pathway, MTOR phosphorylates EIF4EBP1, and the phosphorylated EIF4EBP1 then releases EIF4E, which is freed to recruit 40S ribosomal subunit to the 5′ end of mRNAs, thereby initiating translation. xref Hence, the degree of EIF4EBP1 phosphorylation is an indication of MTOR-mediated translational activity."
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"The mTOR system includes the rapamycin-sensitive complex 1 (mTORC1), which is activated by glutamine (Gln)(
Figure 1
), arginine (Arg) and leucine (Leu) and activates protein synthesis by phosphorylating eIF4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) to activate protein synthesis (72)."
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"(1) PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin): A study of nocifensive behaviors in a formalin-induced inflammatory pain mouse model [43] revealed that EREG upregulation in the blood might activate EGFRs on DRG neurons through the mTOR signaling pathway, which increases phosphorylation of 4E-BP1 and then MMP-9 translation."