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Yi-Ming Ren, Yuan-Hui Duan, Yun-Bo Sun, Tao Yang, Wen-Jun Zhao, Dong-Liang Zhang, Zheng-Wei Tian, Meng-Qiang Tian
BACKGROUND: Human osteosarcoma (OS) is one of the most common primary bone sarcoma, because of early metastasis and few treatment strategies. It has been reported that the tumorigenicity and self-renewal capacity of side population (SP) cells play roles in human OS via regulating of target genes. This study aims to complement the differentially expressed genes (DEGs) that regulated between the SP cells and the non-SP cells from primary human OS and identify their functions and molecular pathways associated with OS...
June 19, 2018: Journal of Orthopaedic Surgery and Research
Yilin Zhao, Deyou Zheng, Ales Cvekl
Elucidation of both the molecular composition and organization of the ocular lens is a prerequisite to understand its development, function, pathology, regenerative capacity, as well as to model lens development and disease using in vitro differentiation of pluripotent stem cells. Lens is comprised of the anterior lens epithelium and posterior lens fibers, which form the bulk of the lens. Lens fibers differentiate from lens epithelial cells through cell cycle exit-coupled differentiation that includes cellular elongation, accumulation of crystallins, cytoskeleton and membrane remodeling, and degradation of organelles within the central region of the lens...
June 5, 2018: Experimental Eye Research
Kevin M Mazor, Leiming Dong, Yuanhui Mao, Robert V Swanda, Shu-Bing Qian, Martha H Stipanuk
Although amino acids are known regulators of translation, the unique contributions of specific amino acids are not well understood. We compared effects of culturing HEK293T cells in medium lacking either leucine, methionine, histidine, or arginine on eIF2 and 4EBP1 phosphorylation and measures of mRNA translation. Methionine starvation caused the most drastic decrease in translation as assessed by polysome formation, ribosome profiling, and a measure of protein synthesis (puromycin-labeled polypeptides) but had no significant effect on eIF2 phosphorylation, 4EBP1 hyperphosphorylation or 4EBP1 binding to eIF4E...
May 24, 2018: Scientific Reports
Cole Peters, Max Paget, Kizito-Tshitoko Tshilenge, Dipongkor Saha, Slawomir Antoszczyk, Anouk Baars, Thomas Frost, Robert L Martuza, Hiroaki Wakimoto, Samuel D Rabkin
Oncolytic viruses, including herpes simplex viruses (HSVs), are a new class of cancer therapeutic engineered to infect and kill cancer cells, while sparing normal tissue. To ensure that oncolytic HSV (oHSV) is safe in the brain, all oHSVs in clinical trial for glioma lack the γ34.5 genes responsible for neurovirulence. However, loss of γ34.5 attenuates growth in cancer cells. Glioblastoma (GBM) is a lethal brain tumor that is heterogeneous and contains a subpopulation of cancer stem cells, termed GBM stem-like cells (GSCs), that likely promote tumor progression and recurrence...
May 23, 2018: Journal of Virology
Sophie Gay, Daniele Piccini, Christopher Bruhn, Sara Ricciardi, Paolo Soffientini, Walter Carotenuto, Stefano Biffo, Marco Foiani
Cell survival to replication stress depends on the activation of the Mec1ATR -Rad53 checkpoint response that protects the integrity of stalled forks and controls the origin firing program. Here we found that Mad2, a member of the spindle assembly checkpoint (SAC), contributes to efficient origin firing and to cell survival in response to replication stress. We show that Rad53 and Mad2 promote S-phase cyclin expression through different mechanisms: while Rad53 influences Clb5,6 degradation, Mad2 promotes their protein synthesis...
May 17, 2018: Molecular Cell
Meir Rozenbaum, Marek Rajman, Ida Rishal, Indrek Koppel, Sandip Koley, Katalin F Medzihradszky, Juan A Oses-Prieto, Riki Kawaguchi, Paul S Amieux, Alma L Burlingame, Giovanni Coppola, Mike Fainzilber
Transcriptional events leading to outgrowth of neuronal axons have been intensively studied, but the role of translational regulation in this process is not well understood. Here, we use translatome analyses by ribosome pull-down and protein synthesis characterization by metabolic isotopic labeling to study nerve injury and axon outgrowth proteomes in rodent dorsal root ganglia (DRGs) and sensory neurons. We identify over 1600 gene products that are primarily translationally regulated in DRG neurons after nerve injury, many of which contain a 5'UTR cytosine-enriched regulator of translation (CERT) motif, implicating the translation initiation factor Eif4e in the injury response...
March 2018: ENeuro
Xiao-Feng Xu, Ru-Bin Cheng, Xue-Jin Zhang, Rui-Lan Gao
OBJECTIVE: To investigate the anti-leukemia effect of total saponins of Rubus parvifolius L. (TSRP) on K562 cell xenografts in nude mice and the mechanisms of action. METHODS: The K562 cell xenografts in nude mice were established, and then randomly divided into 5 groups, the control group, the cytosine arabinoside group(Ara-c) and 3 TSRP groups (20, 40 and 100 mg/kg). The tumor volume and mass of each group of nude mice were measured and the anti-tumor rates of TSRP were calculated subsequently...
May 11, 2018: Chinese Journal of Integrative Medicine
Leandro S D'Abronzo, Paramita M Ghosh
Prostate cancer (PCa) progression involves a shift from endocrine to paracrine and eventually autocrine control resulting from alterations in molecular mechanisms in the cells. Deregulation of RNA translation is crucial for tumor cells to grow and proliferate; therefore, overactivation of the translation machinery is often observed in cancer. The two most important signal transduction pathways regulating PCa progression are PI3K/Akt/mTOR and Ras/MAPK. These two pathways converge on the eukaryotic translation initiation factor 4E (eIF4E) which binds to the protein scaffold eIF4G upon mechanistic target of rapamycin (mTOR) activation and is phosphorylated by the mitogen-activated protein kinase (MAPK) interacting protein kinases (Mnk1/2)...
May 3, 2018: Neoplasia: An International Journal for Oncology Research
Rodrigo Manjarín, Daniel A Columbus, Jessica Solis, Adriana D Hernandez-García, Agus Suryawan, Hanh V Nguyen, Molly M McGuckin, Rafael T Jimenez, Marta L Fiorotto, Teresa A Davis
The objective of this study was to determine if enteral leucine or branched-chain amino acid (BCAA) supplementation increases muscle protein synthesis in neonates who consume less than their protein and energy requirements, and whether this increase is mediated via the upregulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway or the decrease in muscle protein degradation signaling. Neonatal pigs were fed milk replacement diets containing reduced energy and protein (R), R supplemented with BCAA (RBCAA), R supplemented with leucine (RL), or complete protein and energy (CON) at 4-h intervals for 9 (n = 24) or 21 days (n = 22)...
May 4, 2018: Amino Acids
Astrid A Glück, Eleonora Orlando, Dominic Leiser, Michaela Poliaková, Lluís Nisa, Aurélie Quintin, Jacopo Gavini, Deborah M Stroka, Sabina Berezowska, Lukas Bubendorf, Andree Blaukat, Daniel M Aebersold, Michaela Medová, Yitzhak Zimmer
Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets...
May 2, 2018: Oncogene
Nick Arndt, Daniela Ross-Kaschitza, Artyom Kojukhov, Anton A Komar, Michael Altmann
Yeast p20 is a small, acidic protein that binds eIF4E, the cap-binding protein. It has been proposed to affect mRNA translation and degradation, however p20's function as an eIF4E-binding protein (4E-BP) and its physiological significance has not been clearly established. In this paper we present data demonstrating that p20 is capable of binding directly to mRNA due to electrostatic interaction of a stretch of arginine and histidine residues in the protein with negatively charged phosphates in the mRNA backbone...
April 30, 2018: Scientific Reports
Mirtha William, Louis-Philippe Leroux, Visnu Chaparro, Julie Lorent, Tyson E Graber, Marie-Noël M'Boutchou, Tania Charpentier, Aymeric Fabié, Charles M Dozois, Simona Stäger, Léon C van Kempen, Tommy Alain, Ola Larsson, Maritza Jaramillo
Macrophages represent one of the first lines of defense during infections and are essential for resolution of inflammation following pathogen clearance. Rapid activation or suppression of protein synthesis via changes in translational efficiency allows cells of the immune system, including macrophages, to quickly respond to external triggers or cues without de novo mRNA synthesis. The translational repressors eIF4E-binding proteins 4E-BP1 and 4E-BP2 (4E-BP1/2) are central regulators of proinflammatory cytokine synthesis during viral and parasitic infections...
June 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Tal Frolinger, Chad Smith, Carmen Freire Cobo, Steven Sims, Justin Brathwaite, Sterre de Boer, Jing Huang, Giulio M Pasinetti
Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E) -binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase β-1 (p70S6K)...
April 27, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Haiyan Yang, Lohitha Rao Chennamaneni, Melvyn Wai Tuck Ho, Shi Hua Ang, Eldwin Sum Wai Tan, Duraiswamy Athisayamani Jeyaraj, Yoon Sheng Yeap, Boping Liu, Esther Hq Ong, Joma Kanikadu Joy, John Liang Kuan Wee, Perlyn Kwek, Priya Retna, Nurul Dinie, Thuy Thi Hanh Nguyen, Shi Jing Tai, Vithya Manoharan, Vishal Pendharkar, Choon Bing Low, Yun Shan Chew, Susmitha Vuddagiri, Kanda Sangthongpitag, Meng Ling Choong, May Ann Lee, Srinivasaraghavan Kannan, Chandra S Verma, Anders Poulsen, Sharon Lim, Charles Chuah, Tiong Sin Ong, Jeffrey Hill, Alex Matter, Kassoum Nacro
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition...
May 24, 2018: Journal of Medicinal Chemistry
Blazej A Wojtczak, Pawel J Sikorski, Kaja Fac-Dabrowska, Anna Nowicka, Marcin Warminski, Dorota Kubacka, Elzbieta Nowak, Marcin Nowotny, Joanna Kowalska, Jacek Jemielity
The 5' cap consists of 7-methylguanosine (m7 G) linked by a 5'-5'-triphosphate bridge to messenger RNA (mRNA) and acts as the master regulator of mRNA turnover and translation initiation in eukaryotes. Cap analogues that influence mRNA translation and turnover (either as small molecules or as part of an RNA transcript) are valuable tools for studying gene expression, which is often also of therapeutic relevance. Here, we synthesized a series of 15 dinucleotide cap (m7 GpppG) analogues containing a 5'-phosphorothiolate (5'-PSL) moiety (i...
May 9, 2018: Journal of the American Chemical Society
Gigin Lin, Kun-Ju Lin, Frank Wang, Tse-Ching Chen, Tzu-Chen Yen, Ta-Sen Yeh
Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated in vitro using six cholangiocarcinoma cell lines. In vivo therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model...
May 14, 2018: Disease Models & Mechanisms
Xue Feng, Gardenia Orellana, James Myers, Alexander V Karasev
Recessive resistance to Bean common mosaic virus (BCMV) in common bean (Phaseolus vulgaris L.) is governed by four genes that include one strain-nonspecific helper gene bc-u, and three strain-specific genes bc-1, bc-2, and bc-3. The bc-3 gene was identified as an eIF4E translation initiation factor gene mediating resistance through disruption of the interaction between this protein and the VPg protein of the virus. The mode of action of bc-1 and bc-2 in expression of BCMV resistance is unknown, although bc-1 gene was found to affect systemic spread of a related potyvirus, Bean common mosaic necrosis virus...
April 12, 2018: Phytopathology
Ella Lineham, Graham J Tizzard, Simon J Coles, John Spencer, Simon J Morley
The study of eukaryotic initiation factor 4E (eIF4E) is a key focus in cancer research due to its role in controlling the translation of tumour-associated proteins, that drive an aggressive migratory phenotype. eIF4E is a limiting component of the eIF4F complex which is a critical determinant for the translation of mRNAs. Mitogen-activated protein kinase interacting protein kinases (MNK1/2) phosphorylate eIF4E on Ser209, promoting the expression of oncogenic proteins, whereas mTORC1 phosphorylates and de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression...
March 6, 2018: Oncotarget
Mi-Kyoung You, Hwa-Jin Kim, Ji Hyun Kook, Hyeon-A Kim
St. John's Wort (SJW) has been used as an estrogen agonist in the systems affected by menopause. Also, hypericin, a bioactive compound of SJW, has been used as a photosensitizer in photodynamic therapy. In the present study, we investigate the anti-proliferative and pro-apoptotic effects of SJW to demonstrate the chemo-preventive effect in human breast cancer cells. MCF-7 cells were cultured with DMSO or various concentrations of SJW ethanol extract (SJWE). Cell viability, proliferation, apoptosis, the expression of proteins involved in cell growth and apoptosis, and caspase-3/7 activity were examined...
March 23, 2018: International Journal of Molecular Sciences
Celia Pinto-Díez, Eva M García-Recio, M Isabel Pérez-Morgado, Marta García-Hernández, Lara Sanz-Criado, Silvia Sacristán, M Val Toledo-Lobo, Belén Pérez-Mies, Isabel Esteban-Rodríguez, Alejandro Pascual, Mercedes Garcia-Villanueva, Noelia Martínez-Jañez, Víctor M González, M Elena Martín
MAP kinase interacting kinases (MNKs) modulate the function of oncogene eukaryotic initiation factor 4E (eIF4E) through phosphorylation, which is necessary for oncogenic transformation. MNK1 gives rise to two mRNAs and thus two MNK1 isoforms, named MNK1a and MNK1b. MNK1b, the splice variant of human MNK1a, is constitutively active and independent of upstream MAP kinases. In this study, we have analyzed the expression of both MNK1 isoforms in 69 breast tumor samples and its association with clinicopathologic/prognostic characteristics of breast cancer...
March 2, 2018: Oncotarget
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