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Cap-dependent translation

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
Benjamin R E Harris, Defeng Wang, Ye Zhang, Marina Ferrari, Aniekan Okon, Margot P Cleary, Carston R Wagner, Da-Qing Yang
The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5' -untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA...
February 26, 2018: Molecular and Cellular Biology
Gesine Behrens, Reinhard Winzen, Nina Rehage, Anneke Dörrie, Monika Barsch, Anne Hoffmann, Jörg Hackermüller, Christopher Tiedje, Vigo Heissmeyer, Helmut Holtmann
The expression of proteins during inflammatory and immune reactions is coordinated by post-transcriptional mechanisms. A particularly strong suppression of protein expression is exerted by a conserved translational silencing element (TSE) identified in the 3' UTR of NFKBIZ mRNA, which is among the targets of the RNA-binding proteins Roquin-1/2 and MCPIP1/Regnase-1. We present evidence that in the context of the TSE MCPIP1, so far known for its endonuclease activity toward mRNAs specified by distinct stem-loop (SL) structures, also suppresses translation...
February 19, 2018: Nucleic Acids Research
Jamie K Moy, Arkady Khoutorsky, Marina N Asiedu, Gregory Dussor, Theodore J Price
Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5' cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG...
2018: Frontiers in Cellular Neuroscience
Fangfang Duan, Hao Wu, Dongwei Jia, Weicheng Wu, Shifang Ren, Lan Wang, Shushu Song, Xinying Guo, Fenglin Liu, Yuanyuan Ruan, Jianxin Gu
BACKGROUND & AIMS: Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal RACK1 promoted the chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis...
February 14, 2018: Journal of Hepatology
Jyotsna Vinayak, Stefano A Marrella, Rawaa H Hussain, Leonid Rozenfeld, Karine Solomon, Mark A Bayfield
In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3'OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3'OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode...
February 13, 2018: Nucleic Acids Research
Nadezda Dolgikh, Manuela Hugle, Meike Vogler, Simone Fulda
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here we report that co-inhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wildtype, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wildtype RMS tumors in vivo...
February 6, 2018: Cancer Research
Boris Eliseev, Lahari Yeramala, Alexander Leitner, Manikandan Karuppasamy, Etienne Raimondeau, Karine Huard, Elena Alkalaeva, Ruedi Aebersold, Christiane Schaffitzel
Eukaryotic translation initiation is tightly regulated, requiring a set of conserved initiation factors (eIFs). Translation of a capped mRNA depends on the trimeric eIF4F complex and eIF4B to load the mRNA onto the 43S pre-initiation complex comprising 40S and initiation factors 1, 1A, 2, 3 and 5 as well as initiator-tRNA. Binding of the mRNA is followed by mRNA scanning in the 48S pre-initiation complex, until a start codon is recognised. Here, we use a reconstituted system to prepare human 48S complexes assembled on capped mRNA in the presence of eIF4B and eIF4F...
February 1, 2018: Nucleic Acids Research
Veronica Venturi, Richard Little, Peter W Bircham, Juliana Rodigheri Brito, Paul H Atkinson, David R Maass, Paul H Teesdale-Spittle
The translation initiation machinery is emerging as an important target for therapeutic intervention, with potential in the treatment of cancer, viral infections, and muscle wasting. Amongst the targets for pharmacological control of translation initiation is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is essential for cap-dependent translation initiation. We set out to explore the system-wide impact of a reduction of functional eIF4A. To this end, we investigated the effect of deletion of TIF1, one of the duplicate genes that produce eIF4A in yeast, through synthetic genetic array interactions and system-wide changes in GFP-tagged protein abundances...
January 31, 2018: Biochemical and Biophysical Research Communications
Arianna Piserà, Adele Campo, Salvatore Campo
In eukaryotic cells, protein synthesis is a complex and multi-step process that has several mechanisms to start the translation including cap-dependent and cap-independent initiation. The translation control of eukaryotic gene expression occurs principally at the initiation step. In this context, it is critical that the eukaryotic translation initiation factor eIF4E bind to the 7-methylguanosine (m7G) cap present at the 5'-UTRs of most eukaryotic mRNAs. Combined with other initiation factors, eIF4E mediates the mRNA recruitment on ribosomes to start the translation...
January 29, 2018: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Sebastian Lampe, Michael Kunze, Anica Scholz, Thilo F Brauß, Sofia Winslow, Stefan Simm, Mario Keller, Juliana Heidler, Ilka Wittig, Bernhard Brüne, Tobias Schmid
Translation is a tightly regulated process and is predominantly controlled at the level of its initiation. Translation initiation mostly occurs in a cap-dependent manner. Under stress conditions when cap-dependent translation is hampered, internal ribosome entry sites (IRESes) allow for cap-independent translation of certain mRNAs. IRES-dependent translation is commonly regulated by RNA-interacting proteins, known as IRES trans-acting factors (ITAFs). In the present study, we found the 5' untranslated region (UTR) of the thioredoxin-interacting protein (TXNIP) mRNA to be bound by the ITAF hnRNPA1...
January 26, 2018: Biochimica et Biophysica Acta
Inês Silva Amorim, Sonal Kedia, Stella Kouloulia, Konstanze Simbriger, Ilse Gantois, Seyed Mehdi Jafarnejad, Yupeng Li, Agniete Kampaite, Tine Pooters, Nicola Romanò, Christos G Gkogkas
The MAPK/ERK (Mitogen Activated Protein Kinases/Extracellular signal-Regulated Kinases) pathway is a cardinal regulator of synaptic plasticity, learning and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5' mRNA cap-binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of long-term potentiation (L-LTP)...
January 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jinghua Hu, D Jo Merriner, Anne E O'Connor, Brendan J Houston, Luc Furic, Mark P Hedger, Moira K O'Bryan
STUDY QUESTION: What is the role of epididymal cysteine-rich secretory proteins (CRISPs) in male fertility? SUMMARY ANSWER: While epididymal CRISPs are not absolutely required for male fertility, they are required for optimal sperm function. WHAT IS KNOWN ALREADY: CRISPs are members of the CRISP, Antigen 5 and Pathogenesis related protein 1 (CAP) superfamily and are characterised by the presence of an N-terminal CAP domain and a C-terminal CRISP domain...
January 18, 2018: Molecular Human Reproduction
Fabrizio Damiano, Mariangela Testini, Romina Tocci, Gabriele V Gnoni, Luisa Siculella
Acetyl-CoA carboxylase 1 (ACC1) is a cytosolic enzyme catalyzing the rate limiting step in de novo fatty acid biosynthesis. There is mounting evidence showing that ACC1 is susceptible to dysregulation and that it is over-expressed in liver diseases associated with lipid accumulation and in several cancers. In the present study, ACC1 regulation at the translational level is reported. Using several experimental approaches, the presence of an internal ribosome entry site (IRES) has been established in the 5' untranslated region (5' UTR) of the ACC1 mRNA...
January 14, 2018: Biochimica et Biophysica Acta
Ricardos Tabet, Laure Schaeffer, Fernande Freyermuth, Melanie Jambeau, Michael Workman, Chao-Zong Lee, Chun-Chia Lin, Jie Jiang, Karen Jansen-West, Hussein Abou-Hamdan, Laurent Désaubry, Tania Gendron, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne
Expansion of G4C2 repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. G4C2 translation operates through a 5'-3' cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNAMeti...
January 11, 2018: Nature Communications
Mohammad Seyedabadi, Reza Rahimian, Jean-Eric Ghia
Autonomic imbalance plays a pivotal role in the pathophysiology of inflammatory bowel diseases (IBD). The central nervous system (CNS) cooperates dynamically with the immune system to regulate inflammation through humoral and neural pathways. In particular, acetylcholine (Ach), the main neurotransmitter in the vagus nerve, decreases the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic Ach receptors (α7nAChRs). Areas covered: Here, we review the evidence for involvement of the cholinergic anti-inflammatory pathway (CAP) in IBD...
February 2018: Expert Opinion on Therapeutic Targets
Kinga Winczura, Manfred Schmid, Claudia Iasillo, Kelly R Molloy, Lea Mørch Harder, Jens S Andersen, John LaCava, Torben Heick Jensen
Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins...
January 2, 2018: Cell Reports
J J David Ho, Nathan C Balukoff, Grissel Cervantes, Petrice D Malcolm, Jonathan R Krieger, Stephen Lee
The eukaryotic translation initiation factor 5B (eIF5B) is a homolog of IF2, an ancient translation factor that enables initiator methionine-tRNAiMet (met-tRNAiMet) loading on prokaryotic ribosomes. While it can be traced back to the last universal common ancestor, eIF5B is curiously dispensable in modern aerobic yeast and mammalian cells. Here, we show that eIF5B is an essential element of the cellular hypoxic cap-dependent protein synthesis machinery. System-wide interrogation of dynamic translation machineries by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) demonstrated augmented eIF5B activity in hypoxic translating ribosomes...
January 2, 2018: Cell Reports
Paulino Barragán-Iglesias, Tzu-Fang Lou, Vandita D Bhat, Salim Megat, Michael D Burton, Theodore J Price, Zachary T Campbell
Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3' end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP...
January 2, 2018: Nature Communications
Eden R Freire, Danielle M N Moura, Maria J R Bezerra, Camila C Xavier, Mariana C Morais-Sobral, Ajay A Vashisht, Antonio M Rezende, James A Wohlschlegel, Nancy R Sturm, Osvaldo P de Melo Neto, David A Campbell
Trypanosomatids are parasitic protozoans characterized by several unique structural and metabolic processes that include exquisite mechanisms associated with gene expression and regulation. During the initiation of protein synthesis, for instance, mRNA selection for translation seems to be mediated by different eIF4F-like complexes, which may play a significant role in parasite adaptation to different hosts. In eukaryotes, the heterotrimeric eIF4F complex (formed by eIF4E, eIF4G, and eIF4A) mediates mRNA recognition and ribosome binding and participates in various translation regulatory events...
December 29, 2017: Current Genetics
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