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https://www.readbyqxmd.com/read/29676910/5-phosphorothiolate-dinucleotide-cap-analogs-reagents-for-mrna-modification-and-potent-small-molecular-inhibitors-of-decapping-enzymes
#1
Blazej Andrzej 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 (m7G) linked by a 5'-5'-triphosphate bridge to mRNA and acts as the master regu-lator of mRNA turnover and translation initiation in eukaryotes. Cap analogs 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 (m7GpppG) analogs containing a 5'-phosphorothiolate (5'-PSL) moiety (i...
April 20, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29666220/synergistic-anti-proliferative-effect-of-mtor-inhibitor-rad001-plus-gemcitabine-on-cholangiocarcinoma-by-decreasing-choline-kinase-activity
#2
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 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, rad001 alone and combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model...
April 12, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29648948/recessive-resistance-to-bean-common-mosaic-virus-conferred-by-the-bc-1-and-bc-2-genes-in-common-bean-phaseolus-vulgaris-l-affects-long-distance-movement-of-the-virus
#3
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
https://www.readbyqxmd.com/read/29581834/synergistic-effects-of-inhibiting-the-mnk-eif4e-and-pi3k-akt-mtor-pathways-on-cell-migration-in-mda-mb-231-cells
#4
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
https://www.readbyqxmd.com/read/29570671/st-john-s-wort-regulates-proliferation-and-apoptosis-in-mcf-7-human-breast-cancer-cells-by-inhibiting-ampk-mtor-and-activating-the-mitochondrial-pathway
#5
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
https://www.readbyqxmd.com/read/29568373/increased-expression-of-mnk1b-the-spliced-isoform-of-mnk1-predicts-poor-prognosis-and-is-associated-with-triple-negative-breast-cancer
#6
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
https://www.readbyqxmd.com/read/29545752/identification-of-a-novel-protein-arginine-methyltransferase-5-inhibitor-in-non-small-cell-lung-cancer-by-structure-based-virtual-screening
#7
Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29545132/non-conventional-rottlerin-anticancer-properties
#8
REVIEW
Maioli E, Daveri E, Maellaro E, Ietta F, Cresti L, Valacchi G
In the past few years, we focused the interest on rottlerin, an old/new natural substance that, over the time, has revealed a number of cellular and molecular targets, all potentially implicated in the fight against cancer. Past and recent literature well demonstrated that rottlerin is an inhibitor of enzymes, transcription factors and signaling molecules that control cancer cell life and death. Although the rottlerin anticancer activity has been mainly ascribed to apoptosis and/or autophagy induction, recent findings unveiled the existence of additional mechanisms of toxicity...
March 12, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29544771/dietary-myo-inositol-deficiency-decreased-intestinal-immune-function-related-to-nf-%C3%AE%C2%BAb-and-tor-signaling-in-the-intestine-of-young-grass-carp-ctenopharyngodon-idella
#9
Shuang-An Li, Wei-Dan Jiang, Lin Feng, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Juan Yang, Xu Tang, He-Qun Shi, Xiao-Qiu Zhou
In this study, we investigated the effects of dietary myo-inositol on the intestinal immune barrier function and related signaling pathway in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.33 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila. The results indicated that compared with the optimal dietary myo-inositol level, myo-inositol deficiency (27...
March 12, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29538717/sorafenib-inhibits-proliferation-and-invasion-in-desmoid-derived-cells-by-targeting-ras-mek-erk-and-pi3k-akt-mtor-pathways
#10
Laura Rosenberg, Charles H Yoon, Gaurav Sharma, Monica M Bertagnolli, Nancy L Cho
Desmoid tumors (DTs) are unusual neoplasms of mesenchymal origin that exhibit locally invasive behavior. Surgical resection is the initial treatment of choice for DTs. For patients with recurrent or unresectable disease, however, medical options are limited. Sorafenib is a multikinase inhibitor with known anti-tumor activity in various cancers via suppression of the PI3K/Akt/mTOR pathway. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and molecular mechanism of action...
March 10, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29527921/a-blood-pact-the-significance-and-implications-of-eif4e-on-lymphocytic-leukemia
#11
V Venturi, T Masek, M Pospisek
Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials...
March 12, 2018: Physiological Research
https://www.readbyqxmd.com/read/29526098/structure-based-design-of-pyridone-aminal-eft508-targeting-dysregulated-translation-by-selective-mitogen-activated-protein-kinase-interacting-kinases-1-and-2-mnk1-2-inhibition
#12
Siegfried H Reich, Paul A Sprengeler, Gary G Chiang, Jim R Appleman, Joan Chen, Jeff Clarine, Boreth Eam, Justin T Ernst, Qing Han, Vikas K Goel, Edward Zr Han, Vera Huang, Ivy Nj Hung, Adrianna Jemison, Katti A Jessen, Jolene Molter, Douglas Murphy, Melissa Neal, Gregory S Parker, Michael Shaghafi, Samuel Sperry, Jocelyn Staunton, Craig R Stumpf, Peggy A Thompson, Chinh Tran, Stephen E Webber, Christopher J Wegerski, Hong Zheng, Kevin R Webster
Dysregulated translation of mRNA plays a major role in tumorigenesis. MNK1/2 kinases are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA which control tumor/stromal cell signaling. 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation...
March 10, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29510985/molecular-architecture-of-lsm14-interactions-involved-in-the-assembly-of-mrna-silencing-complexes
#13
Tobias Brandmann, Hana Fakim, Zoya Padamsi, Ji-Young Youn, Anne-Claude Gingras, Marc R Fabian, Martin Jinek
The LSM domain-containing protein LSM14/Rap55 plays a role in mRNA decapping, translational repression, and RNA granule (P-body) assembly. How LSM14 interacts with the mRNA silencing machinery, including the eIF4E-binding protein 4E-T and the DEAD-box helicase DDX6, is poorly understood. Here we report the crystal structure of the LSM domain of LSM14 bound to a highly conserved C-terminal fragment of 4E-T. The 4E-T C-terminus forms a bi-partite motif that wraps around the N-terminal LSM domain of LSM14. We also determined the crystal structure of LSM14 bound to the C-terminal RecA-like domain of DDX6...
March 6, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29508246/a-phase-ii-study-of-the-dual-mtor-inhibitor-mln0128-in-patients-with-metastatic-castration-resistant-prostate-cancer
#14
Laura Graham, Kalyan Banda, Alba Torres, Brett S Carver, Yu Chen, Katie Pisano, Greg Shelkey, Tracy Curley, Howard I Scher, Tamara L Lotan, Andrew C Hsieh, Dana E Rathkopf
Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily...
March 6, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29507660/flt3-itd-induces-expression-of-pim-kinases-through-stat5-to-confer-resistance-to-the-pi3k-akt-pathway-inhibitors-on-leukemic-cells-by-enhancing-the-mtorc1-mcl-1-pathway
#15
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29494492/importance-of-erk1-2-in-regulation-of-protein-translation-during-oocyte-meiosis
#16
REVIEW
Jaroslav Kalous, Anna Tetkova, Michal Kubelka, Andrej Susor
Although the involvement of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in the regulation of cytostatic factor (CSF) activity; as well as in microtubules organization during meiotic maturation of oocytes; has already been described in detail; rather less attention has been paid to the role of ERK1/2 in the regulation of mRNA translation. However; important data on the role of ERK1/2 in translation during oocyte meiosis have been documented. This review focuses on recent findings regarding the regulation of translation and the role of ERK1/2 in this process in the meiotic cycle of mammalian oocytes...
March 1, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29487714/ribavirin-as-a-potential-therapeutic-for-atypical-teratoid-rhabdoid-tumors
#17
Joshua Casaos, Sakibul Huq, Tarik Lott, Raphael Felder, John Choi, Noah Gorelick, Michael Peters, Yuanxuan Xia, Russell Maxwell, Tianna Zhao, Chenchen Ji, Thomas Simon, Julie Sesen, Sarah J Scotland, Richard E Kast, Jeffrey Rubens, Eric Raabe, Charles G Eberhart, Eric M Jackson, Henry Brem, Betty Tyler, Nicolas Skuli
Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth in vitro and in vivo . Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both in vitro and in vivo ...
January 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29487419/functional-screening-of-fgfr4-driven-tumorigenesis-identifies-pi3k-mtor-inhibition-as-a-therapeutic-strategy-in-rhabdomyosarcoma
#18
Timothy McKinnon, Rosemarie Venier, Marielle Yohe, Sivasish Sindiri, Berkley E Gryder, Jack F Shern, Leah Kabaroff, Brendan Dickson, Krista Schleicher, Guillaume Chouinard-Pelletier, Serena Menezes, Abha Gupta, Xiaohu Zhang, Rajarashi Guha, Marc Ferrer, Craig J Thomas, Yuhong Wei, Dariush Davani, Cynthia J Guidos, Javed Khan, Rebecca A Gladdy
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice...
February 28, 2018: Oncogene
https://www.readbyqxmd.com/read/29484383/the-transcription-factor-cmaf-is-targeted-by-mtor-and-regulates-the-inflammatory-response-via-the-tlr4-signaling-pathway
#19
Yan Wang, Caifu Luan, Guili Zhang, Chengming Sun
cMaf is a leucine-zipper transcription factor that is involved in cell differentiation, oncogenic transformation, and human diseases; however, the functions of cMaf in inflammatory responses in macrophages are still not fully understood. Western blot analysis showed that cMaf expression was induced by lipopolysaccharide (LPS) stimulation in mouse macrophages. An enzyme-linked immunosorbent assay was performed to detect the level of expression of inflammatory cytokines after knockdown of cMaf expression in macrophages using a small interfering RNA (siRNA)...
February 23, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29478426/effects-of-in-ovo-feeding-of-l-arginine-on-breast-muscle-growth-and-protein-deposition-in-post-hatch-broilers
#20
L L Yu, T Gao, M M Zhao, P A Lv, L Zhang, J L Li, Y Jiang, F Gao, G H Zhou
In ovo feeding (IOF) of l-arginine (Arg) can affect growth performance of broilers, but the response of IOF of Arg on breast muscle growth is unclear, and the mechanism involved in protein deposition remains unknown. Hense, this experiment was conducted to evaluate the effects of IOF of Arg on breast muscle growth and protein-deposited signalling in post-hatch broilers. A total of 720 fertile eggs were collected from 34-week-old Arbor Acres breeder hens and distributed to three treatments: (1) non-injected control group; (2) 7...
February 26, 2018: Animal: An International Journal of Animal Bioscience
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