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https://www.readbyqxmd.com/read/29169064/eukaryotic-initiation-factor-4f-sidestepping-resistance-mechanisms-arising-from-expression-heterogeneity
#1
REVIEW
Jennifer Chu, Santiago Ramon Y Cajal, Nahum Sonenberg, Jerry Pelletier
There is enormous diversity in the genetic makeup and gene expression profiles between and within tumors. This heterogeneity leads to phenotypic variation and is a major mechanism of resistance to molecular targeted therapies. Here we describe a conceptual framework for targeting eukaryotic initiation factor (eIF) 4F in cancer-an essential complex that drives and promotes multiple Cancer Hallmarks. The unique nature of eIF4F and its druggability bypasses several of the heterogeneity issues that plague molecular targeted drugs developed for cancer therapy...
November 20, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29142127/epstein-barr-virus-protein-eb2-stimulates-translation-initiation-of-mrnas-through-direct-interactions-with-both-pabp-and-eif4g
#2
Fabrice Mure, Baptiste Panthu, Isabelle Zanella-Cléon, Frédéric Delolme, Evelyne Manet, Théophile Ohlmann, Henri Gruffat
Epstein-Barr virus (EBV) expresses several mRNAs produced from intronless genes that could potentially be unfavorably translated compared to cellular spliced mRNAs. To overcome this situation, the virus encodes an RNA-binding protein (RBP) called EB2, previously found to both facilitate the export of nuclear mRNAs and increase their translational yield. Here, we show that EB2 binds both nuclear and cytoplasmic cap-binding complexes (respectively, CBC and eIF4F) as well as the poly(A)-binding protein (PABP) to enhance translation initiation of a given mRNP...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29116477/4egi-1-represses-cap-dependent-translation-and-regulates-genome-wide-translation-in-malignant-pleural-mesothelioma
#3
Arpita De, Blake A Jacobson, Mark S Peterson, Joe Jay-Dixon, Marian G Kratzke, Ahad A Sadiq, Manish R Patel, Robert A Kratzke
Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29107534/m-6-a-facilitates-eif4f-independent-mrna-translation
#4
Ryan A Coots, Xiao-Min Liu, Yuanhui Mao, Leiming Dong, Jun Zhou, Ji Wan, Xingqian Zhang, Shu-Bing Qian
In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m(7)G) cap found on the 5' end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap-independent translation mediated by internal ribosome entry sites (IRESs). Here, we report that N(6)-methyladenosine (m(6)A) facilitates mRNA translation that is resistant to eIF4F inactivation...
October 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29078784/dynamic-changes-in-eif4f-mrna-interactions-revealed-by-global-analyses-of-environmental-stress-responses
#5
Joseph L Costello, Christopher J Kershaw, Lydia M Castelli, David Talavera, William Rowe, Paul F G Sims, Mark P Ashe, Christopher M Grant, Simon J Hubbard, Graham D Pavitt
BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses...
October 27, 2017: Genome Biology
https://www.readbyqxmd.com/read/29077018/the-role-of-cytoplasmic-mrna-cap-binding-protein-complexes-in-trypanosoma-brucei-and-other-trypanosomatids
#6
REVIEW
Eden R Freire, Nancy R Sturm, David A Campbell, Osvaldo P de Melo Neto
Trypanosomatid protozoa are unusual eukaryotes that are well known for having unusual ways of controlling their gene expression. The lack of a refined mode of transcriptional control in these organisms is compensated by several post-transcriptional control mechanisms, such as control of mRNA turnover and selection of mRNA for translation, that may modulate protein synthesis in response to several environmental conditions found in different hosts. In other eukaryotes, selection of mRNA for translation is mediated by the complex eIF4F, a heterotrimeric protein complex composed by the subunits eIF4E, eIF4G, and eIF4A, where the eIF4E binds to the 5'-cap structure of mature mRNAs...
October 27, 2017: Pathogens
https://www.readbyqxmd.com/read/29062139/ddx3-regulates-endoplasmic-reticulum-stress-induced-atf4-expression
#7
Pauline Adjibade, Valérie Grenier St-Sauveur, Jonathan Bergeman, Marc-Etienne Huot, Edouard W Khandjian, Rachid Mazroui
Accumulation of unfolded and potentially toxic proteins in the endoplasmic reticulum (ER) activates a cell stress adaptive response, which involves a reprogramming of general gene expression. ATF4 is a master stress-induced transcription factor that orchestrates gene expression in cells treated with various ER stress inducers including those used to treat cancers. ER stress-induced ATF4 expression occurs mainly at the translational level involving the activity of the phosphorylated (P) translation initiation factor (eIF) eIF2α...
October 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930151/perk-signal-modulated-protein-translation-promotes-the-survivability-of-dengue-2-virus-infected-mosquito-cells-and-extends-viral-replication
#8
Jiun-Nan Hou, Tien-Huang Chen, Yi-Hsuan Chiang, Jing-Yun Peng, Tsong-Han Yang, Chih-Chieh Cheng, Eny Sofiyatun, Cheng-Hsun Chiu, Chuan Chiang-Ni, Wei-June Chen
Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5'-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells...
September 20, 2017: Viruses
https://www.readbyqxmd.com/read/28903455/targeting-eif4f-complex-in-non-small-cell-lung-cancer-cells
#9
REVIEW
Lu Dai, Zhen Lin, Yueyu Cao, Yihan Chen, Zengguang Xu, Zhiqiang Qin
Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, which represents the leading cause of cancer-related death in the world. The majority of lung cancer patients doesn't respond well to conventional chemo-/radio-therapeutic regimens and have a poor prognosis. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but their outcome/prognosis is far from satisfactory. The translation initiation EIF4F complex has been shown to play important roles in cancer progression, but its functional role and therapeutic effect in lung cancers especially NSCLC remain largely unknown...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28827335/cellular-cap-binding-protein-eif4e-promotes-picornavirus-genome-restructuring-and-translation
#10
Brian C Avanzino, Gabriele Fuchs, Christopher S Fraser
Picornaviruses use internal ribosome entry sites (IRESs) to translate their genomes into protein. A typical feature of these IRESs is their ability to bind directly to the eukaryotic initiation factor (eIF) 4G component of the eIF4F cap-binding complex. Remarkably, the hepatitis A virus (HAV) IRES requires eIF4E for its translation, but no mechanism has been proposed to explain this. Here we demonstrate that eIF4E regulates HAV IRES-mediated translation by two distinct mechanisms. First, eIF4E binding to eIF4G generates a high-affinity binding conformation of the eIF4F complex for the IRES...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28757063/atp-competitive-marine-derived-natural-products-that-target-the-dead-box-helicase-eif4a
#11
Joseph Tillotson, Magdalena Kedzior, Larissa Guimarães, Alison B Ross, Tara L Peters, Andrew J Ambrose, Cody J Schmidlin, Donna D Zhang, Letícia V Costa-Lotufo, Abimael D Rodríguez, Jonathan H Schatz, Eli Chapman
Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28698298/gigyf1-2-proteins-use-auxiliary-sequences-to-selectively-bind-to-4ehp-and-repress-target-mrna-expression
#12
Daniel Peter, Ramona Weber, Felix Sandmeir, Lara Wohlbold, Sigrun Helms, Praveen Bawankar, Eugene Valkov, Cátia Igreja, Elisa Izaurralde
The eIF4E homologous protein (4EHP) is thought to repress translation by competing with eIF4E for binding to the 5' cap structure of specific mRNAs to which it is recruited through interactions with various proteins, including the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins 1 and 2 (GIGYF1/2). Despite its similarity to eIF4E, 4EHP does not interact with eIF4G and therefore fails to initiate translation. In contrast to eIF4G, GIGYF1/2 bind selectively to 4EHP but not eIF4E. Here, we present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP...
June 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28646650/requirement-for-eukaryotic-translation-initiation-factors-in-cap-independent-translation-differs-between-bipartite-genomic-rnas-of-red-clover-necrotic-mosaic-virus
#13
Yuri Tajima, Hiro-Oki Iwakawa, Kiwamu Hyodo, Masanori Kaido, Kazuyuki Mise, Tetsuro Okuno
The bipartite genomic RNAs of red clover necrotic mosaic virus (RCNMV) lack a 5' cap and a 3' poly(A) tail. RNA1 encodes viral replication proteins, and RNA2 encodes a movement protein (MP). These proteins are translated in a cap-independent manner. We previously identified two cis-acting RNA elements that cooperatively recruit eukaryotic translation initiation factor (eIF) complex eIF4F or eIFiso4F to RNA1. Such cis-acting RNA elements and host factors have not been identified in RNA2. Here we found that translation of RNA1 was significantly compromised in Arabidopsis thaliana carrying eif4f mutation...
September 2017: Virology
https://www.readbyqxmd.com/read/28610844/overexpression-of-eif4f-components-in-meningiomas-and-suppression-of-meningioma-cell-growth-by-inhibiting-translation-initiation
#14
Janet L Oblinger, Sarah S Burns, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, A Douglas Kinghorn, D Bradley Welling, Long-Sheng Chang
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation...
June 10, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28607208/targeting-eif4f-complex-in-non-small-cell-lung-cancer-cells
#15
REVIEW
Lu Dai, Zhen Lin, Yueyu Cao, Yihan Chen, Zengguang Xu, Zhiqiang Qin
Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, which represents the leading cause of cancer-related death in the world. The majority of lung cancer patients doesn't respond well to conventional chemo-/radio-therapeutic regimens and have a poor prognosis. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but their outcome/prognosis is far from satisfactory. The translation initiation EIF4F complex has been shown to play important roles in cancer progression, but its functional role and therapeutic effect in lung cancers especially NSCLC remain largely unknown...
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28577281/acquired-tamoxifen-resistance-in-mcf-7-breast-cancer-cells-requires-hyperactivation-of-eif4f-mediated-translation
#16
Dedra H Fagan, Lynsey M Fettig, Svetlana Avdulov, Heather Beckwith, Mark S Peterson, Yen-Yi Ho, Fan Wang, Vitaly A Polunovsky, Douglas Yee
While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor-positive breast cancer, the development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic messenger RNA translation...
August 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28559306/a-helicase-independent-activity-of-eif4a-in-promoting-mrna-recruitment-to-the-human-ribosome
#17
Masaaki Sokabe, Christopher S Fraser
In the scanning model of translation initiation, the decoding site and latch of the 40S subunit must open to allow the recruitment and migration of messenger RNA (mRNA); however, the precise molecular details for how initiation factors regulate mRNA accommodation into the decoding site have not yet been elucidated. Eukaryotic initiation factor (eIF) 3j is a subunit of eIF3 that binds to the mRNA entry channel and A-site of the 40S subunit. Previous studies have shown that a reduced affinity of eIF3j for the 43S preinitiation complex (PIC) occurs on eIF4F-dependent mRNA recruitment...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28515298/crimean-congo-hemorrhagic-fever-virus-nucleocapsid-protein-augments-mrna-translation
#18
Subbiah Jeeva, Erdong Cheng, Safder S Ganaie, Mohammad A Mir
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne Nairovirus of the Bunyaviridae family, causing severe illness with high mortality rates in humans. Here, we demonstrate that CCHFV nucleocapsid protein (CCHFV-NP) augments mRNA translation. CCHFV-NP binds to the viral mRNA 5' untranslated region (UTR) with high affinity. It facilitates the translation of reporter mRNA both in vivo and in vitro with the assistance of the viral mRNA 5' UTR. CCHFV-NP equally favors the translation of both capped and uncapped mRNAs, demonstrating the independence of this translation strategy on the 5' cap...
August 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28461326/eif2%C3%AE-phosphorylation-mediates-il24-induced-apoptosis-through-inhibition-of-translation
#19
Leah Persaud, Xuelin Zhong, Giselle Alvarado, Winchie Do, Jordan Dejoie, Anna Zybtseva, Bertal Huseyin Aktas, Moira Sauane
IL24 is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor-suppressor activities of IL24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis...
May 1, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28450740/the-centrosomal-ofd1-protein-interacts-with-the-translation-machinery-and-regulates-the-synthesis-of-specific-targets
#20
Daniela Iaconis, Maria Monti, Mario Renda, Arianne van Koppen, Roberta Tammaro, Marco Chiaravalli, Flora Cozzolino, Paola Pignata, Claudia Crina, Piero Pucci, Alessandra Boletta, Vincenzo Belcastro, Rachel H Giles, Enrico Maria Surace, Simone Gallo, Mario Pende, Brunella Franco
Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells...
April 27, 2017: Scientific Reports
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