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Journal articles on the topic '4EBP'

Author: Grafiati

Published: 4 June 2021

Last updated: 21 February 2023

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1

Carroll, Matthew, John Dyer, and Wayne S. Sossin. "Serotonin Increases Phosphorylation of Synaptic 4EBP through TOR, but Eukaryotic Initiation Factor 4E Levels Do Not Limit Somatic Cap-Dependent Translation in Aplysia Neurons." Molecular and Cellular Biology 26, no. 22 (2006): 8586–98. http://dx.doi.org/10.1128/mcb.00955-06.

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ABSTRACT The target of rapamycin (TOR) plays an important role in memory formation in Aplysia californica. Here, we characterize one of the downstream targets of TOR, the eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP) from Aplysia. Aplysia 4EBP contains the four critical phosphorylation sites regulated by TOR as well as an N-terminal RAIP motif and a C-terminal TOS site. Aplysia 4EBP was hypophosphorylated in synaptosomes, and serotonin addition caused a rapamycin-sensitive increase in 4EBP phosphorylation both in synaptosomes and in isolated neurites. Aplysia 4EBP was regulate

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2

Bi, Chengfeng, Xiaoyan Zhang, Zhang Xuan, Wing C. Chan, Timothy McKeithan, and Kai Fu. "Prediction and Optimization of the Therapeutic Effect of mTOR Inhibitors in Aggressive B-Cell Lymphomas." Blood 126, no. 23 (2015): 4441. http://dx.doi.org/10.1182/blood.v126.23.4441.4441.

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Abstract Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechan

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3

Shives, Katherine, Aaron Massey, Nicholas May, Thomas Morrison, and J. Beckham. "4EBP-Dependent Signaling Supports West Nile Virus Growth and Protein Expression." Viruses 8, no. 10 (2016): 287. http://dx.doi.org/10.3390/v8100287.

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4

Rivera-Calderón, Luis G., Carlos E. Fonseca-Alves, Priscila E. Kobayashi, Márcio Carvalho, Rosemeri O. Vasconcelos, and Renée Laufer-Amorim. "p-mTOR, p-4EBP-1 and eIF4E expression in canine prostatic carcinoma." Research in Veterinary Science 122 (February 2019): 86–92. http://dx.doi.org/10.1016/j.rvsc.2018.11.006.

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5

Grech, Godfrey, Montserrat Blázquez-Domingo, Andrea Kolbus, et al. "Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation." Blood 112, no. 7 (2008): 2750–60. http://dx.doi.org/10.1182/blood-2008-01-133140.

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Abstract Stem cell factor (SCF)–induced activation of phosphoinositide-3-kinase (PI3K) is required for transient amplification of the erythroblast compartment. PI3K stimulates the activation of mTOR (target of rapamycin) and subsequent release of the cap-binding translation initiation factor 4E (eIF4E) from the 4E-binding protein 4EBP, which controls the recruitment of structured mRNAs to polysomes. Enhanced expression of eIF4E renders proliferation of erythroblasts independent of PI3K. To investigate which mRNAs are selectively recruited to polysomes, we compared SCF-dependent gene expression

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6

Toshniwal, Ashish G., Sakshi Gupta, Lolitika Mandal, and Sudip Mandal. "ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development." Developmental Cell 49, no. 3 (2019): 473–89. http://dx.doi.org/10.1016/j.devcel.2019.04.008.

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7

Yadav, Anil, Vinoth Kumar, David Bailey, and Byeong-Churl Jang. "AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK." International Journal of Molecular Sciences 20, no. 2 (2019): 363. http://dx.doi.org/10.3390/ijms20020363.

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Overexpression of Pim kinases has an oncogenic/pro-survival role in many hematological and solid cancers. AZD1208 is a pan-Pim kinase inhibitor that has anti-cancer and anti-adipogenic actions. Here, we investigated the effects of AZD1208 on the growth of 93T449 cells, a differentiated human liposarcoma cell line. At 20 µM, AZD1208 was cytotoxic (cytostatic) but not apoptotic, reducing cell survival without DNA fragmentation, caspase activation or increasing cells in the sub G1 phase; known apoptotic parameters. Notably, AZD1208 reduced phosphorylation of signal transducer and activator of tra

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8

Zhou, Yonglan, Hongyi Fang, Shenghui Lin, et al. "Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway." Cellular Physiology and Biochemistry 37, no. 2 (2015): 454–64. http://dx.doi.org/10.1159/000430368.

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Background/Aims: Qiliqiangxin (QL) has been used for the treatment of chronic heart failure in China. Accumulating evidence suggests QL's cardio-protective effects on continuous myocardial ischemia. However, it is unclear whether QL has beneficial effects on cardiac ischemia-reperfusion (I/R) injury. Methods: A mouse model of cardiac I/R was established by ligation of the left anterior descending coronary artery for 45 minutes followed by reperfusion. The mice were treated with QL for three days before surgery and continually after I/R. Triphenyltetrazolium chloride staining, echocardiography

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9

Ananieva-Stoyanova, Elitsa A., Christie Adam, Rebekah Betar, Alexander Martin, Susan Hutson, and Michael Boyer. "Emerging role of the mitochondrial branched-chain aminotransferase (BCATm) as an immunosuppressive enzyme during CD4+ T cell activation." Journal of Immunology 206, no. 1_Supplement (2021): 53.04. http://dx.doi.org/10.4049/jimmunol.206.supp.53.04.

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Abstract The mitochondrial branched-chain aminotransferase (BCATm) catalyzes the transamination of leucine, an amino acid that is essential for the upregulation of complex 1 of the mammalian target of rapamycin (mTORC1) during T cell activation. Because BCATm is responsible for the mitochondrial degradation of leucine, we hypothesized that BCATm limits leucine availability for mTORC1 signaling and subsequently suppresses T cell activation. To test the hypothesis, we isolated CD4+T cells from the global BCATmKO mouse and measured the rates of leucine transamination/oxidation, the activity of th

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10

Hsieh, Andrew C., Maria Costa, Ornella Zollo, et al. "Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E." Cancer Cell 17, no. 3 (2010): 249–61. http://dx.doi.org/10.1016/j.ccr.2010.01.021.

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11

Huang, XianBo, Wei He, Jie Jin, and Wenbin Qian. "MNK1 Inhibitor CGP57380 Overcomes the Activation of eIF4E Induced By mTORC1 Inhibitor: The Mechanism of Synergic Killing on T-ALL Cells." Blood 124, no. 21 (2014): 5215. http://dx.doi.org/10.1182/blood.v124.21.5215.5215.

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Abstract Background: In spite of the impressive outcomes achieved in acute lymphoblastic leukemia (ALL), current therapeutic strategies are never adequate for patients with higher risk ALL, including T-ALL. Meanwhile, toxicities and high rates of relapse of chemotherapy pose an enormous challenge to us. Therefore, novel and effective therapeutic approaches are needed for the patients suffering from this disease. Aberrantly activation of mTOR pathway in T-ALL promotes tumor progression, thus targeting mTOR is thought as an effective therapeutic strategy for the treatment of T-ALL. But to our di

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12

Daveri, E., E. Maellaro, G. Valacchi, F. Ietta, M. Muscettola, and E. Maioli. "Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing." Cancer Letters 380, no. 1 (2016): 106–13. http://dx.doi.org/10.1016/j.canlet.2016.06.018.

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13

Yoshimura, Ryoji, Kimiko Minami, Junichiro Matsuda, Naoki Sawada, Shinji Miura та Yasutomi Kamei. "Phosphorylation of 4EBP by oral leucine administration was suppressed in the skeletal muscle of PGC-1α knockout mice". Bioscience, Biotechnology, and Biochemistry 80, № 2 (2015): 288–90. http://dx.doi.org/10.1080/09168451.2015.1083397.

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14

Ikari, Sumiko, Qiang Yang, Shiou-Ling Lu, et al. "Quercetin in Tartary Buckwheat Induces Autophagy against Protein Aggregations." Antioxidants 10, no. 8 (2021): 1217. http://dx.doi.org/10.3390/antiox10081217.

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Tartary buckwheat is used as an ingredient in flour and tea, as well as in traditional Chinese medicine for its antioxidant effects. Here, we found that an ethanol extract of tartary buckwheat (TBE) potently induced autophagy flux in HeLa cells by suppressing mTORC1 activity, as revealed by dephosphorylation of the mTORC1 substrates Ulk1, S6K, and 4EBP, as well as by the nuclear translocation of transcriptional factor EB. In addition to non-selective bulk autophagy, TBE also induced aggrephagy, which is defined as autophagy against aggregated proteins. Quercetin is a flavonol found at high lev

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15

Culjkovic, Biljana, and Katherine L. Borden. "Understanding and Targeting the Eukaryotic Translation Initiation Factor eIF4E in Head and Neck Cancer." Journal of Oncology 2009 (2009): 1–12. http://dx.doi.org/10.1155/2009/981679.

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The eukaryotic translation initiation factor eIF4E is elevated in about 30% of human malignancies including HNSCC where its levels correlate with poor prognosis. Here, we discuss the biochemical and molecular underpinnings of the oncogenic potential of eIF4E. Studies in human leukemia specimens, and later in a mouse model of prostate cancer, strongly suggest that cells with elevated eIF4E develop an oncogene dependency to it, making them more sensitive to targeting eIF4E than normal cells. We describe several strategies that have been suggested for eIF4E targeting in the clinic: the use of a s

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16

Martin, D., Q. Nguyen, A. Molinolo, and J. S. Gutkind. "Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene." Oncogene 33, no. 18 (2013): 2405–12. http://dx.doi.org/10.1038/onc.2013.193.

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17

Bi, Chengfeng, Xuan Zhang, Ting Lu, et al. "Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas." Haematologica 102, no. 4 (2017): 755–64. http://dx.doi.org/10.3324/haematol.2016.159160.

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18

Jung, Mi-Young, Lori Lorenz, and Joel D. Richter. "Translational Control by Neuroguidin, a Eukaryotic Initiation Factor 4E and CPEB Binding Protein." Molecular and Cellular Biology 26, no. 11 (2006): 4277–87. http://dx.doi.org/10.1128/mcb.02470-05.

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ABSTRACT CPEB-mediated translation is important in early development and neuronal synaptic plasticity. Here, we describe a new eukaryotic initiation factor 4E (eIF4E) binding protein, Neuroguidin (Ngd), and its interaction with CPEB. In the mammalian nervous system, Ngd is detected as puncta in axons and dendrites and in growth cones and filopodia. Ngd contains three motifs that resemble those present in eIF4G, 4EBP, Cup, and Maskin, all of which are eIF4E binding proteins. Ngd binds eIF4E directly, and all three motifs must be deleted to abrogate the interaction between these two proteins. In

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19

Kim, Hyun-Jung. "Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control." Biomolecules 9, no. 11 (2019): 665. http://dx.doi.org/10.3390/biom9110665.

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Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational in

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20

Zhou, Qianmei, Weihong Zhang, Tian Li, et al. "Formononetin Enhances the Tumoricidal Effect of Everolimus in Breast Cancer MDA-MB-468 Cells by Suppressing the mTOR Pathway." Evidence-Based Complementary and Alternative Medicine 2019 (March 17, 2019): 1–8. http://dx.doi.org/10.1155/2019/9610629.

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Background. Formononetin, an active ingredient isolated from the traditional Chinese medicinal herb Astragalus membranaceus, has anticancer and chemoresistance-reducing biological activities. We evaluated the efficacy of formononetin in improving the tumoricidal effect of everolimus by suppressing the mTOR pathway in breast cancer cells. Methods. Cell survival was assessed using an MTT assay. Apoptosis was detected using flow cytometry. Proteins related to the mTOR pathway were detected and assessed using real-time PCR and Western blot analysis. Results. The results showed that formononetin en

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21

Rajput, S. K., H. Fernandes, R. Kile, et al. "57 Proteomic analysis reveals metabolic dysregulation in invitro-cultured bovine embryos." Reproduction, Fertility and Development 33, no. 2 (2021): 135. http://dx.doi.org/10.1071/rdv33n2ab57.

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Invitro culture (IVC) systems fail to completely recapitulate the invivo environment, resulting in metabolic stress during pre-implantation development and reduced blastocyst quality. We hypothesised that IVC-induced metabolic dysregulation in bovine embryos is mediated by changes in expression and/or activity of protein biomarkers associated with key metabolic pathways. Our objectives were to determine (1) expression of enzymes involved in glycolysis (HK-2, PKM2, LDHA, B and C isoforms), entry into the tricarboxylic acid (TCA) cycle (PDH), energy sensing/fatty acid oxidation (AMPK), and the m

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22

Rajput, S. K., H. Fernandes, R. Kile, et al. "57 Proteomic analysis reveals metabolic dysregulation in invitro-cultured bovine embryos." Reproduction, Fertility and Development 33, no. 2 (2021): 135. http://dx.doi.org/10.1071/rdv33n2ab57.

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Invitro culture (IVC) systems fail to completely recapitulate the invivo environment, resulting in metabolic stress during pre-implantation development and reduced blastocyst quality. We hypothesised that IVC-induced metabolic dysregulation in bovine embryos is mediated by changes in expression and/or activity of protein biomarkers associated with key metabolic pathways. Our objectives were to determine (1) expression of enzymes involved in glycolysis (HK-2, PKM2, LDHA, B and C isoforms), entry into the tricarboxylic acid (TCA) cycle (PDH), energy sensing/fatty acid oxidation (AMPK), and the m

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23

Xu, Qing, Serge-Emile Simpson, Timothy J. Scialla, Adam Bagg, and Martin Carroll. "Survival of acute myeloid leukemia cells requires PI3 kinase activation." Blood 102, no. 3 (2003): 972–80. http://dx.doi.org/10.1182/blood-2002-11-3429.

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Abstract The mechanisms that regulate the growth and survival of acute myeloid leukemia (AML) cells are largely unknown. We hypothesized that constitutive activation of phosphatidyl-inositide 3 kinase (PI3 kinase) could regulate survival in primary cells from patients with AML. Here we demonstrate that Akt, a critical substrate of PI3 kinase, is activated in AML blasts. In a short-term culture system, most AML patient samples showed a dose-dependent decrease in survival after incubation with the PI3 kinase inhibitor LY294002. This decrease in survival was partially due to the induction of apop

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Sikalidis, Angelos K., Kevin M. Mazor, Minji Kang, Hongyun Liu, and Martha H. Stipanuk. "Total 4EBP1 Is Elevated in Liver of Rats in Response to Low Sulfur Amino Acid Intake." Journal of Amino Acids 2013 (September 8, 2013): 1–11. http://dx.doi.org/10.1155/2013/864757.

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Translation initiation is known to be regulated by the binding of eukaryotic initiation factor 4E (eIF4E) by binding proteins (4EBPs), and there is evidence that amino acid deprivation and other cellular stresses upregulate 4EBP1 expression. To pursue the question of whether diets limited in an essential amino acid lead to induction of 4EBP1 expression in vivo, diets that varied in methionine and cystine content were fed to rats for 7 days, and 4EBP1 mRNA and protein levels and 4EBP1 phosphorylation state were determined. Total 4EBP1 mRNA and protein abundance increased in liver of rats with s

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25

Nho, Richard Seonghun, and Mark Peterson. "Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP-1) Function Is Suppressed by Src and Protein Phosphatase 2A (PP2A) on Extracellular Matrix." Journal of Biological Chemistry 286, no. 37 (2011): 31953–65. http://dx.doi.org/10.1074/jbc.m111.222299.

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Roolf, Catrin, Christin Kretzschmar, Tina-Susann Langhammer, et al. "Newly Synthesized Indolylmalemide PDA-66 and Its Derivates Induce Antiproliferative Effects In Acute Lymphoblastic Leukemia." Blood 122, no. 21 (2013): 4932. http://dx.doi.org/10.1182/blood.v122.21.4932.4932.

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Abstract The PI3K/Akt pathway is dysregulated is some acute lymphoblastic leukemias (ALL) and might therefore serve as therapeutic target. Indolylmaleimides exhibit inhibitory potencies against different protein kinases -like glycogen synthase kinase 3 (GSK3β) or protein kinase c- influencing thereby several cellular processes. Recently, it was demonstrated that PDA-66, a newly synthesized indolylmalemide based on the well known GSK3β inhibitor SB-216763, hinders microtubule polymerization in human neuronal progenitor and neuroblastoma cells. GSK3β is a downstream substrate of the PI3K/Akt and

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27

Hammerman, Peter S., Casey J. Fox, Morris J. Birnbaum, and Craig B. Thompson. "Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival." Blood 105, no. 11 (2005): 4477–83. http://dx.doi.org/10.1182/blood-2004-09-3706.

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Abstract The Akt kinases promote hematopoietic cell growth and accumulation through phosphorylation of apoptotic effectors and stimulation of mTOR-dependent translation. In Akt-transformed leukemic cells, tumor growth can be inhibited by the mTOR inhibitor rapamycin, and clinical trials of rapamycin analogs for the treatment of leukemia are under way. Surprisingly, nontransformed hematopoietic cells can grow and proliferate in the presence of rapamycin. Here, we show that Pim-2 is required to confer rapamycin resistance. Primary hematopoietic cells from Pim-2– and Pim-1/Pim-2–deficient animals

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28

Koštál, Vladimír, Tomáš Štětina, Rodolphe Poupardin, Jaroslava Korbelová, and Alexander William Bruce. "Conceptual framework of the eco-physiological phases of insect diapause development justified by transcriptomic profiling." Proceedings of the National Academy of Sciences 114, no. 32 (2017): 8532–37. http://dx.doi.org/10.1073/pnas.1707281114.

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Insects often overcome unfavorable seasons in a hormonally regulated state of diapause during which their activity ceases, development is arrested, metabolic rate is suppressed, and tolerance of environmental stress is bolstered. Diapausing insects pass through a stereotypic succession of eco-physiological phases termed “diapause development.” The phasing is varied in the literature, and the whole concept is sometimes criticized as being too artificial. Here we present the results of transcriptional profiling using custom microarrays representing 1,042 genes in the drosophilid fly, Chymomyza c

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Schäbler, Stefan, Kelechi M. Amatobi, Melanie Horn, et al. "Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation." Cellular and Molecular Life Sciences 77, no. 23 (2020): 4939–56. http://dx.doi.org/10.1007/s00018-019-03441-6.

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Abstract The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period01 (per01) clock mutants and Canton-S wildtype (WTCS) flies in an isogenic and non-isogenic background using LC–MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, a

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Saraf, Amit, Jie Luo, David R. Morris, and Daniel R. Storm. "Phosphorylation of Eukaryotic Translation Initiation Factor 4E and Eukaryotic Translation Initiation Factor 4E-binding Protein (4EBP) and Their Upstream Signaling Components Undergo Diurnal Oscillation in the Mouse Hippocampus." Journal of Biological Chemistry 289, no. 29 (2014): 20129–38. http://dx.doi.org/10.1074/jbc.m114.552638.

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Cho, Sung-Yup, Seungun Lee, Jeonghun Yeom, et al. "Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs." Life Science Alliance 3, no. 3 (2020): e201900565. http://dx.doi.org/10.26508/lsa.201900565.

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Hypoxia selectively enhances mRNA translation despite suppressed mammalian target of rapamycin complex 1 activity, contributing to gene expression reprogramming that promotes metastasis and survival of cancer cells. Little is known about how this paradoxical control of translation occurs. Here, we report a new pathway that links hypoxia to selective mRNA translation. Transglutaminase 2 (TG2) is a hypoxia-inducible factor 1–inducible enzyme that alters the activity of substrate proteins by polyamination or crosslinking. Under hypoxic conditions, TG2 polyaminated eukaryotic translation initiatio

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Zeng, Zhihong, Zeev Estrov, David Harris, Frank Giles, Michael Andreeff, and Marina Konopleva. "Intra-Pathway Inhibition of Upstream (PI3K) and Downstream (mTOR) Kinases Synergistically Induces Apoptosis in AML." Blood 106, no. 11 (2005): 2477. http://dx.doi.org/10.1182/blood.v106.11.2477.2477.

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Abstract Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway regulates the growth and survival of acute myeloid leukemia (AML). We hypothesized that targeting this pathway with both PI3K and mTOR inhibitors may greatly enhance the effectiveness of these two inhibitors in the treatment of AML. PI3KI1 is a novel PI3K inhibitor that induced apoptosis in AML cell lines and primary AML cells at an IC50 of 5μM. It directly inhibited AKT at Ser473, however had limited effects on pGSK3b and on the mTOR downstream targe

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Baumann, Philipp, Sonja Mandl-Weber, Felix Meinel, Ruediger Jankowsky, Fuat S. Oduncu, and Ralf Schmidmaier. "The Novel Histone Deacetylase Inhibitor RAS2410 (Resminostat) Interferes with Important Signalling Pathways and Induces Apoptosis in Multiple Myeloma Cells." Blood 114, no. 22 (2009): 4928. http://dx.doi.org/10.1182/blood.v114.22.4928.4928.

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Abstract Abstract 4928 Inhibition of histone deacetylase (HDAC) is a promising target for novel, anti-myeloma agents. In this study we investigated the biologic effects of the novel HDAC inhibitor RAS2410 (also known as “4SC-201”, “resminostat”) on Multiple Myeloma (MM) cells in vitro. RAS2410 is a potent, direct inhibitor of HDACs 1, 3 and 6 (IC50 = 43-72nM) representing the HDAC classes I and II. Accordingly, RAS2410 induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of RAS2410 abrogate cell growth and strongly induce apoptosis (IC50 = 2.5-3μM in 3 out of 4 cel

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Lv, Jinlin, Lixia Yang, Ruiwei Guo, Yankun Shi, Ziwei Zhang, and Jinshan Ye. "Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1436–48. http://dx.doi.org/10.1159/000481875.

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Background/Aims: Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress. Methods: The study included human endothelial cells surrogate EA.hy926 li

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Maiso, Patricia, Yi Liu, Abdel Kareem Azab, et al. "Role of TORC1 and TORC2 in Multiple Myeloma." Blood 118, no. 21 (2011): 1815. http://dx.doi.org/10.1182/blood.v118.21.1815.1815.

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Abstract Abstract 1815 Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment. Mechanistically, mTOR operates in two distinct multi-protein complexes, TORC1 (Raptor) and TORC2 (Rictor). TORC1 leads to the phosphorylation of p70S6 kinase and 4E- BP1, while TORC2 regulates phosphorylation of Akt and other kinases. In multiple myeloma (MM), PI3K/Akt plays an essential role enhancing cell growth and survival and is activated by the loss of the tumor suppressor gene PTEN and by the bone marrow micr

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Solomon, Hilla, Radha Mukherjee, Xiaoping Chen, et al. "Abstract LB089: Effective in vivo treatment of endometrial tumor models with coexistent mutant PI3K and PTEN inactivation with a selective bi-steric mTORC1 kinase inhibitor." Cancer Research 82, no. 12_Supplement (2022): LB089. http://dx.doi.org/10.1158/1538-7445.am2022-lb089.

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Abstract Dysregulation of PI3K signaling is a common event in human cancer, but feedback inhibition of receptor kinase signaling and/or induction of PTEN translation by activated PI3K/AKT/mTOR signaling reduces pathway output and tumor dependency. In some cancers, including the majority of endometrial carcinomas, these lesions coexist and cause synergistic hyperactivation of pathway output, particularly mTORC1 kinase signaling. Although this suggests that PI3K signaling is a driver of these endometrial cancers, standard inhibitors have had only marginal activity in patients with advanced disea

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Netto, G., A. Armstrong, D. Wood, et al. "Pharmacodynamic (PD) study of pre-prostatectomy rapamycin in men with advanced localized prostate cancer (PC): A DOD Prostate Cancer Clinical Trials Consortium Trial." Journal of Clinical Oncology 27, no. 15_suppl (2009): 5001. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.5001.

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5001 Background: Rapamycin is an orally bioavailable and generic mTOR inhibitor with an MTD of 6 mg daily and anticancer activity in solid tumors. We sought to determine the optimal biologic dose (OBD) in the pre-operative setting in men with PC. Methods: We explored the safety and PD activity of 3 and 6 mg of daily oral rapamycin for 14 days prior to radical prostatectomy (RP) in cohorts of 21 men with intermediate risk localized PC. Ten untreated control subjects were included using identical inclusion criteria. Men had Gleason >6 PC involving multiple cores. PD markers in pre-treatment p

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Nassar, Nicolas, Shailaja N. Hegde, Anjelika Gasilina, et al. "The Small Molecule IODVA1 Inhibits the Rac Guanine Nucleotide Exchange Factor Vav3 and Overcomes TKI-Resistance in Ph+(BCR-ABL1) B-ALL." Blood 134, Supplement_1 (2019): 4647. http://dx.doi.org/10.1182/blood-2019-130250.

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Aberrant activation of Rho guanine nucleotide exchange factors (RhoGEFs) is a chief mechanism driving abnormal activation of their RhoGTPase targets in cancer. Thus, small molecule inhibitor of RhoGEF activities can be used as a drug lead to treat leukemia and other malignancies. We have identified an active small molecule, IODVA1, in several xenograft mouse models of cancer including Ras-driven cancers. Here, we used cellular and mouse models of Ph+(BCR-ABL1) B-ALL to identify Vav3, the multi-domain tyrosine phosphorylation-dependent RacGEF as the target of the small molecule IODVA1. IODVA1 s

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Skavland, Jørn, Håkon Reikvam, Øystein Bruserud, and Bjorn T. Gjertsen. "Survival Stratification In Acute Myeloid Leukemia By Single Cell Signal Profiling." Blood 122, no. 21 (2013): 2625. http://dx.doi.org/10.1182/blood.v122.21.2625.2625.

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Abstract Introduction Dysregulation and mutations in signaling genes of cancer cells characterize more than half of the acute myeloid leukemia (AML) patients, and contribute to chemoresistance through regulation of cellular processes including apoptosis and DNA repair. We investigated if determination of single cell basal phosphorylation of signaling proteins reflected mutation of FLT3 and NPM1, cytogenetics, response to first course of chemotherapy or overall survival. Methods We employed flow cytometric single cell analysis of phosphoproteins central to signal transduction pathways in myeloi

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Fan, Qi Wen, Theodore P. Nicolaides, and William A. Weiss. "Inhibiting 4EBP1 in Glioblastoma." Clinical Cancer Research 24, no. 1 (2017): 14–21. http://dx.doi.org/10.1158/1078-0432.ccr-17-0042.

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Mohan, Prathibha, Joyce Pasion, Giovanni Ciriello, et al. "Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer." Cancers 14, no. 10 (2022): 2397. http://dx.doi.org/10.3390/cancers14102397.

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The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This i

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Xing, Hongyun, Yuping Gong, and Ting Liu. "To Study Resistant Mechanisms and Reversal In An Imatinib Resistant Ph+ Positive Acute Lymphoblastic Leukemia Cell Line." Blood 116, no. 21 (2010): 2135. http://dx.doi.org/10.1182/blood.v116.21.2135.2135.

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Abstract Abstract 2135 Objective To establish an imatinib resistant Bcr-Abl positive acute lymphoblastic leukemia (ALL) cell line in vitro and to study imatibin resistance in Ph+ ALL. The reversal of the imatinib resistance by rapamycin, the second generation tyrosine kinase inhibitor and proteasome inhibitor was studied. Methods Ph(+) ALL SUP-B15 cell line was cultured in gradually increasing concentrations of imatinib to generate the imatinib resistant cell line at 6 μM imatinib. The cytotoxic effect of imatinib and other drugs was analyzed by MTT assay. RT-PCR, flow cytometry, Western blot

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Weiss, Benjamin, George Edward Allen, Joachim Kloehn, Karim Abid, Pascale Jaquier-Gubler, and Joseph Alphonsus Curran. "eIF4E3 forms an active eIF4F complex during stresses (eIF4FS) targeting mTOR and re-programs the translatome." Nucleic Acids Research 49, no. 9 (2021): 5159–76. http://dx.doi.org/10.1093/nar/gkab267.

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Abstract The eIF4E are a family of initiation factors that bind the mRNA 5′ cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not

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Tang, Yaoxiang, Jiadi Luo, Yang Yang, et al. "Overexpression of p-4EBP1 associates with p-eIF4E and predicts poor prognosis for non-small cell lung cancer patients with resection." PLOS ONE 17, no. 6 (2022): e0265465. http://dx.doi.org/10.1371/journal.pone.0265465.

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Eukaryotic initiation factor 4E (eIF4E) and its phosphorylated form (p-eIF4E) play a crucial role in the protein synthesis, both are under regulation of eIF4E-binding protein 1 (4EBP1) and mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs). This study aims to explore the potential prognostic significance of p-4EBP1 and p-eIF4E in NSCLC patients. The expression of p-4EBP1 and p-eIF4E in NSCLC patients was detected by immunohistochemistry (IHC) staining in tissue microarrays (TMAs) containing 354 NSCLC and 53 non-cancerous lung tissues (Non-CLT). The overexpression percentage of

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Okumura, F., W. Zou, and D. E. Zhang. "ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP." Genes & Development 21, no. 3 (2007): 255–60. http://dx.doi.org/10.1101/gad.1521607.

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Lim, Megan S., Charles Seiler, Sheryl Tripp, Sherrie L. Perkins, Mitchell S. Cairo, and Kojo S. Elenitoba-Johnson. "Constitutive Activation of FRAP/mTOR Pathway in Pediatric Anaplastic Large Cell Lymphomas: Potential Role as a Therapeutic Target." Blood 108, no. 11 (2006): 290. http://dx.doi.org/10.1182/blood.v108.11.290.290.

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Abstract Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p23;q35) is a key oncogenic event in the majority of pediatric anaplastic large cell lymphomas (ALCL). To determine the pathogenetic mechanisms involved in NPM/ALK-mediated lymphomagenesis we employed a mass spectrometry (MS)-based proteomics approach to identify changes in protein expression caused by the overexpression of NPM/ALK. We identified many proteins which were downstream targets of the FRAP/mTOR pathway including ribosomal S6 kinase (1.6-fold), translational initiation factor eIF (4.8-fold)

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Falk, Franziska, Kevin Kamanyi Marucha, and Christine Clayton. "The EIF4E1-4EIP cap-binding complex of Trypanosoma brucei interacts with the terminal uridylyl transferase TUT3." PLOS ONE 16, no. 11 (2021): e0258903. http://dx.doi.org/10.1371/journal.pone.0258903.

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Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3’-UTR, whethe

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Chapat, Clément, Seyed Mehdi Jafarnejad, Edna Matta-Camacho, et al. "Cap-binding protein 4EHP effects translation silencing by microRNAs." Proceedings of the National Academy of Sciences 114, no. 21 (2017): 5425–30. http://dx.doi.org/10.1073/pnas.1701488114.

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MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4–NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4–NOT complex. Our resu

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Singh, Kamini, Prathibha Mohan, Viraj R. Sanghvi, et al. "Abstract 878: Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer." Cancer Research 82, no. 12_Supplement (2022): 878. http://dx.doi.org/10.1158/1538-7445.am2022-878.

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Abstract The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We notice that 4EBP1 gains are genetically linked to gains in neighboring genes including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites.

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Ruscica, Vincenzo, Praveen Bawankar, Daniel Peter, Sigrun Helms, Cátia Igreja, and Elisa Izaurralde. "Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression." Nucleic Acids Research 47, no. 13 (2019): 7035–48. http://dx.doi.org/10.1093/nar/gkz429.

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Abstract The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5′-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila m

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