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Stefan Grüner, Daniel Peter, Ramona Weber, Lara Wohlbold, Min-Yi Chung, Oliver Weichenrieder, Eugene Valkov, Cátia Igreja, Elisa Izaurralde
Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E...
October 19, 2016: Molecular Cell
Katherine D Shives, Aaron R Massey, Nicholas A May, Thomas E Morrison, J David Beckham
West Nile virus (WNV) is a (+) sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an (m7)GpppNm 5' cap with 2'-O-methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1) for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown...
October 18, 2016: Viruses
Lyne Jossé, Jianling Xie, Christopher Gregory Proud, C Mark Smales
Many protein-based biotherapeutics are produced in cultured Chinese hamster ovary (CHO) cell lines. Recent reports have demonstrated that translation of recombinant mRNAs and global control of the translation machinery via mammalian target of rapamycin (mTOR) signalling are important determinants of the amount and quality of recombinant protein such cells can produce. mTOR complex 1 (mTORC1) is a master regulator of cell growth/division, ribosome biogenesis and protein synthesis, but the relationship between mTORC1 signalling, cell growth and proliferation and recombinant protein yields from mammalian cells, and whether this master regulating signalling pathway can be manipulated to enhance cell biomass and recombinant protein production (rPP) are not well explored...
October 19, 2016: Biochemical Journal
Kristen T Crowell, David I Soybel, Charles H Lang
Muscle deconditioning is commonly observed in patients surviving sepsis. Little is known regarding the molecular mechanisms regulating muscle protein homeostasis during the recovery or convalescence phase. We adapted a sepsis-recovery mouse model that uses cecal ligation and puncture (CLP), followed 24 h later by cecal resection and antibiotic treatment, to identify putative cellular pathways regulating protein synthesis and breakdown in skeletal muscle. Ten days after CLP, body weight and food consumption did not differ between control and sepsis-recovery mice, but gastrocnemius weight was reduced...
October 5, 2016: Shock
Bing Chen, Jin Zhao, Shengbin Zhang, Yonggang Zhang, Zonghai Huang
Cap-dependent translation has an essential role in the control of cell proliferation by initiating the translation of oncogenes involved in the regulation of cell cycle progression, such as cyclin D1, and its deregulation contributes to the development and progression of various types of cancers. Hematopoietic pre-B-cell leukemia transcription factor interacting protein (HPIP) was found to be overexpressed in gastric cancer (GC) tissues compared to normal tissues and to promote GC growth in vitro and in vivo...
October 11, 2016: Oncology Reports
Huangai Li, Hideki Kondo, Thomas Kühne, Yukio Shirako
In this study, we investigated the barley yellow mosaic virus (BaYMV, genus Bymovirus) factor(s) responsible for breaking eIF4E-mediated recessive resistance genes (rym4/5/6) in barley. Genome mapping analysis using chimeric infectious cDNA clones between rym5-breaking (JT10) and rym5-non-breaking (JK05) isolates indicated that genome-linked viral protein (VPg) is the determinant protein for breaking the rym5 resistance. Likewise, VPg is also responsible for overcoming the resistances of rym4 and rym6 alleles...
2016: Frontiers in Plant Science
Romain A Studer, Ricard A Rodriguez-Mias, Kelsey M Haas, Joanne I Hsu, Cristina Viéitez, Carme Solé, Danielle L Swaney, Lindsay B Stanford, Ivan Liachko, René Böttcher, Maitreya J Dunham, Eulàlia de Nadal, Francesc Posas, Pedro Beltrao, Judit Villén
Living organisms have evolved protein phosphorylation, a rapid and versatile mechanism that drives signaling and regulates protein function. We report the phosphoproteomes of 18 fungal species and a phylogenetic-based approach to study phosphosite evolution. We observe rapid divergence, with only a small fraction of phosphosites conserved over hundreds of millions of years. Relative to recently acquired phosphosites, ancient sites are enriched at protein interfaces and are more likely to be functionally important, as we show for sites on H2A1 and eIF4E...
October 14, 2016: Science
Maneesh Gujrati, Amita M Vaidya, Margaret Mack, Dayton Snyder, Anthony Malamas, Zheng-Rong Lu
RNAi-mediated knockdown of oncogenes associated with drug resistance can potentially enhance the efficacy of chemotherapy. Here, we have designed and developed targeted dual pH-sensitive lipid-siRNA self-assembly nanoparticles, RGD-PEG(HZ)-ECO/siRNA, which can efficiently silence the oncogene, eukaryotic translation initiation factor 4E (eIF4E), and consequently resensitize triple-negative breast tumors to paclitaxel. The dual pH-sensitive function of these nanoparticles facilitates effective cytosolic siRNA delivery in cancer cells, both in vitro and in vivo...
October 10, 2016: Advanced Healthcare Materials
Gali Epstein Shochet, Oded Komemi, Dana Sadeh-Mestechkin, Meir Pomeranz, Ami Fishman, Liat Drucker, Michael Lishner, Shelly Tartakover Matalon
During placental implantation, cytotrophoblast cells differentiate to extravillous trophoblast (EVT) cells that invade from the placenta into the maternal uterine blood vessels. The heat shock protein-27 (HSP27), the signal transducer and activator of transcription-3 (STAT3) and the eukaryotic translation initiation factor 4E (EIF4E) are involved in regulating EVT cell differentiation/migration. EIF4E and EIF4G compose the translation initiation complex, which is a major control point in protein translation...
October 6, 2016: Journal of Molecular Histology
Tomas Erban, Karel Harant, Julie Chalupnikova, Frantisek Kocourek, Jitka Stara
: Insecticide resistance is an increasingly global problem that hampers pest control. We sought the mechanism responsible for survival following pyrethroid treatment and the factors connected to paralysis/death of the pollen beetle Meligethes aeneus through a proteome-level analysis using nanoLC coupled with Orbitrap Fusion™ Tribrid™ mass spectrometry. A tolerant field population of beetles was treated with deltamethrin, and the ensuing proteome changes were observed in the survivors (resistant), dead (paralyzed) and control-treated beetles...
October 2, 2016: Journal of Proteomics
Yeon-Ho Chung, Dong-Hyun Kim, Won-Woo Lee
IL-1β is a key mediator of sterile inflammation in response to endogenous particulates, a type of damage-associated molecular pattern (DAMPs) molecule derived from damaged cells. Despite the well-known role of sterile particulates such as monosodium urate (MSU) crystals as inflammasome inducers in monocytes/macrophages, little is known regarding how pro-IL-1β synthesis is induced under sterile inflammatory conditions. We provide evidence that MSU crystals post-transcriptionally induce the rapid production of pro-IL-1β in human primary monocytes...
October 3, 2016: Scientific Reports
Yongdong Liu, Liling Sun, Xingwang Su, Sien Guo
Mnk kinase is required for the phosphorylation and activation of the eukaryotic initiation factor 4E (eIF4E), which regulates translation of proteins involve in important aspects of hepatocellular carcinoma (HCC). Here we investigated whether an antifungal agent, cercosporamide, which had been recently identified as a potent Mnk inhibitor, is active against HCC and angiogenesis. We showed that cercosporamide significantly inhibited growth and induced caspase-dependent apoptosis on numerous HCC cell lines, while sparing normal liver cells...
September 20, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Susana Llanos, Juana M García-Pedrero
We have identified a novel mechanism of regulation of the protein CDKN1A (also known as p21) by the serine/threonine kinase complex mammalian target of rapamycin complex 1 (mTORC1). Our results demonstrate that the mTORC1 substrate EIF4E-binding protein 1 (4E-BP1) in its non-phosphorylated state interacts with p21 and promotes p21 degradation. In addition, we demonstrate the prevalence of this mechanism in head and neck squamous cell carcinomas and show that it strongly and significantly associates with improved disease-specific survival, providing evidence for its clinical relevance...
July 2016: Molecular & Cellular Oncology
Hui-Jun Xu, Wei-Dan Jiang, Lin Feng, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xiao-Qiu Zhou
This study explored the effects of vitamin C on the physical barriers and immune barriers, and relative mRNA levels of signaling molecules in the gill of grass carp (Ctenopharyngodon idella) under infection of Flavobacterium columnare. The results indicated that compared with optimal vitamin C supplementation, vitamin C deficiency (2.9 mg/kg diet) (1) increased reactive oxygen species, malondialdehyde and protein carbonyl (PC) contents (P < 0.05), decreased the copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities and mRNA levels (P < 0...
September 15, 2016: Fish & Shellfish Immunology
X-C Hu, C-Q Gao, X-H Wang, H-C Yan, Z-S Chen, X-Q Wang
1. The experiment was conducted to study whether IRS1/Akt/TOR signalling pathway activation stimulates crop milk protein synthesis in the domestic pigeon (Columba livia). 2. Crop milk was collected from 10 1-d-old squabs and analysed for nutrient content. During the non-breeding period and the first day of the lactation, blood samples were collected from 5 pairs of breeding pigeons and the levels of prolactin and insulin were determined. 3. Crop samples were collected from 5 pairs of breeders at days 14 and 16 of the incubation period and days 1, 3 and 7 of the lactation period...
September 16, 2016: British Poultry Science
Jienny Lee, Moon Sam Shin, Mi Ok Kim, Sunghee Jang, Sae Woong Oh, Mingyeong Kang, Kwangseon Jung, Yong Seek Park, Jongsung Lee
Tissue regeneration using adult stem cells (ASCs) has significant potential as a novel treatment for many degenerative diseases. Previous studies have established that age negatively affects the proliferation status and differentiation potential of ASCs, suggesting a possible limitation in their potential therapeutic use. Therefore, we hypothesized that apple extract might exert beneficial effects on ASCs. The specific objectives were to investigate the proliferative effect of apple ethanol extract on human adipose tissue-derived mesenchymal stem cells (ADSCs) and human cord blood-derived mesenchymal stem cells (CB-MSCs), and identify the possible molecular mechanisms...
September 2016: Nutrition Research
Adriana D Hernandez-García, Daniel A Columbus, Rodrigo Manjarín, Hanh V Nguyen, Agus Suryawan, Renán A Orellana, Teresa A Davis
Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight-fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps...
October 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
Andrew K Kwegyir-Afful, Robert D Bruno, Puranik Purushottamachar, Francis N Murigi, Vincent C O Njar
Metastatic castration-resistant prostate cancer (mCRPC) accounts for a high percentage of prostate cancer mortality. The proprietary compound galeterone (gal) was designed to inhibit proliferation of androgen/androgen receptor (AR)-dependent prostate cancer cell in vitro and in vivo and is currently in phase III clinical development. Additionally, clinical studies with gal revealed its superb efficacy in four different cohorts of patients with mCRPC, including those expressing splice variant AR-V7. Preclinical studies with gal show that it also exhibits strong antiproliferative activities against AR-negative prostate cancer cells and tumors through a mechanism involving phosphorylation of eIF2α, which forms an integral component of the eukaryotic mRNA translation complex...
September 12, 2016: FEBS Journal
Ahmed Hadidi, Ricardo Flores, Thierry Candresse, Marina Barba
Next-generation sequencing (NGS) has been applied to plant virology since 2009. NGS provides highly efficient, rapid, low cost DNA, or RNA high-throughput sequencing of the genomes of plant viruses and viroids and of the specific small RNAs generated during the infection process. These small RNAs, which cover frequently the whole genome of the infectious agent, are 21-24 nt long and are known as vsRNAs for viruses and vd-sRNAs for viroids. NGS has been used in a number of studies in plant virology including, but not limited to, discovery of novel viruses and viroids as well as detection and identification of those pathogens already known, analysis of genome diversity and evolution, and study of pathogen epidemiology...
2016: Frontiers in Microbiology
Xue-Mei Jiang, Xiang-Nan Yu, Ren-Zheng Huang, Hai-Rong Zhu, Xiao-Peng Chen, Ju Xiong, Zheng-Yi Chen, Xiao-Xi Huang, Xi-Zhong Shen, Ji-Min Zhu
PURPOSE: Aberrant expression of eukaryotic initiation factor 4E (eIF4E) has been observed in human malignancies. However, its role in hepatocellular carcinoma (HCC) remains to be established. The purpose of this study was to detect eIF4E expression and to evaluate its clinical relevance. METHODS: The eIF4E expression was studied in ninety HCC and randomly selected thirty-one non-tumor tissues from the same patient cohort, as well as in normal hepatic and HCC cell lines...
November 2016: Journal of Cancer Research and Clinical Oncology
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