Distinctive tRNA Repertoires in Proliferating versus Differentiating Cells

Transfer RNAs (tRNAs) deliver amino acids to the ribosome during mRNA translation. Gingold et al. now provide evidence that alterations in the cellular tRNA repertoire are tightly coordinated with changes in mRNA expression. These changes in the tRNA repertoire dictate translational programs that distinguish differentiating from proliferating cells

eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR

The eukaryotic translation initiation factor eIF4E is a critical modulator of cellular growth with functions in the nucleus and cytoplasm. In the cytoplasm, recognition of the 5′ m7G cap moiety on all mRNAs is sufficient for their functional interaction with eIF4E. In contrast, we have shown that in the nucleus eIF4E associates and promotes the nuclear export of cyclin D1, but not GAPDH or actin mRNAs. We determined that the basis of this discriminatory interaction is an ∼100-nt sequence in the 3′ untranslated region (UTR) of cyclin D1 mRNA, we refer to as an eIF4E sensitivity element (4E-SE). We found that cyclin D1 mRNA is enriched at eIF4E nuclear bodies, suggesting these are functional sites for organization of specific ribonucleoproteins. The 4E-SE is required for eIF4E to efficiently transform cells, thereby linking recognition of this element to eIF4E mediated oncogenic transformation. Our studies demonstrate previously uncharacterized fundamental differences in eIF4E-mRNA recognition between the nuclear and cytoplasmic compartments and further a novel level of regulation of cellular proliferation

METTL13 methylation of eEF1A increases translational output to promote tumorigenesis

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.We thank Pal Falnes, Jerry Pelletier, and Julien Sage for helpful discussion, Lauren Brown and William Devine for SDS-1-021, and members of the Gozani and Mazur laboratories for critical reading of the manuscript. This work was supported in part by grants from the NIH to S.M.C. (K99CA190803), M.P.K. (5K08CA218690-02), J.A.P. (R35GM118173), M.C.B. (1DP2HD084069-01), J.S. (1R35GM119721), I.T. (R01CA202021), P.K.M. (R00CA197816, P50CA070907, and P30CA016672), and O.G. (R01GM079641). J.E.E. received support from Stanford ChEM-H, and A.M. was supported by the MD Anderson Moonshot Program. I.T. is a Junior 2 Research Scholar of the Fonds de Recherche du Quebec - Sante (FRQ-S). P.K.M. is supported by the Neuroendocrine Tumor Research Foundation and American Association for Cancer Research and is the Andrew Sabin Family Foundation Scientist and CPRIT scholar (RR160078). S.H. is supported by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship. J.W.F. is supported by 5T32GM007276. (K99CA190803 - NIH; 5K08CA218690-02 - NIH; R35GM118173 - NIH; 1DP2HD084069-01 - NIH; 1R35GM119721 - NIH; R01CA202021 - NIH; R00CA197816 - NIH; P50CA070907 - NIH; P30CA016672 - NIH; R01GM079641 - NIH; Stanford ChEM-H; MD Anderson Moonshot Program; Neuroendocrine Tumor Research Foundation; American Association for Cancer Research; Deutsche Forschungsgemeinschaft Postdoctoral Fellowship; 5T32GM007276)Supporting documentationAccepted manuscrip

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

SummaryTranslational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5′ UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment

Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non-AUG initiation rate genome-wide

Citation: Tang, L., Morris, J., Wan, J., Moore, C., Fujita, Y., Gillaspie, S., … Asano, K. (2017). Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non-AUG initiation rate genome-wide. Nucleic Acids Research, 45(20), 11941–11953. https://doi.org/10.1093/nar/gkx808In the human genome, translation initiation from nonAUG codons plays an important role in various gene regulation programs. However, mechanisms regulating the non-AUG initiation rate remain poorly understood. Here, we show that the non-AUG initiation rate is nearly consistent under a fixed nucleotide context in various human and insect cells. Yet, it ranges from <1% to nearly 100% compared to AUG translation, depending on surrounding sequences, including Kozak, and possibly additional nucleotide contexts. Mechanistically, this range of non-AUG initiation is controlled in part, by the eIF5-mimic protein (5MP). 5MP represses non-AUG translation by competing with eIF5 for the Met-tRNAi-binding factor eIF2. Consistently, eIF5 increases, whereas 5MP decreases translation of NAT1/EIF4G2/DAP5, whose sole start codon is GUG. By modulating eIF5 and 5MP1 expression in combination with ribosome profiling we identified a handful of previously unknown non-AUG initiation sites, some of which serve as the exclusive start codons. If the initiation rate for these codons is low, then an AUG-initiated downstream ORF prevents the generation of shorter, AUGinitiated isoforms. We propose that the homeostasis of the non-AUG translatome is maintained through balanced expression of eIF5 and 5MP

Dizajn, klasifikacija, perspektiva i moguća aplikacija dronova u poljoprivredu Srbije

The paper analyzes the possibility and the needs for the use of specific types of robots (mini unmanned aircraft with different designs and the designation of UAVs) and the possibility of using in agriculture (agrodrone). The year 2015 was proclaimed (Fortune Magazine, 2016) as the year of increasing and widespread use of UAVs in various areas of human activity, especially in agriculture and forestry (75% of use). This is important for large farm areas, where UAV has many useful functions and a very cost-effective commercial application. Today, the needs for UAVs have increased sharply with various opportunities for both civilian and military needs. There is also a significant interest in the development of new drones that can autonomously fly in different environments and locations and can perform various missions and tasks. Over the past decade, a wide range of applications for drones has gained the significance that led to the discovery of various types of unmanned UAVs of different sizes and weights. In this review, the classification of UAVs ranging based on a detailed overview of the development of the drone industry in recent years, this paper demonstrates the evolution of drones and differents application technologies. Of course, this development is very advanced and revolutionary, as well as the development of mobile and smart phones and the Internet, which will open the way for many users to participate in defining the future of UAV implementation. LIVONA Company, Belgrade, Serbia (and Institute of Agricultural Engineering, Faculty of Agriculture in Belgrade, in tehnical cooperation) has a study and plans on the implementation of the model micro drone EBee SQ Livona RTK in the future general plans for inspection of protection Soils of territory Minicipality of Stara Pazova (351 km2), and agricultural company Napredak , and exspecially plans for soils of agriculture of R. Serbia. VEKOM GeoCompany from Belgrade, (in cooperation with Institute of Agricultural Engineering, Faculty of Agriculture in Belgrade), has a study and plans on the implementation of the model of the drone Aibot KX6 model, in the future of application of agricultural soils of region Open pit Kolubara for area from app. 600 km2 and the other soils of Region). Institute of Agricultural Engineering, Faculty of Agriculture in Belgrade, in cooperation with Municipality of Ub, has a study and plans on the implementation of the model micro drone Hubsan H109S X4 PRO in the future plans general inspection of protection Soils and Waters of territory of Municipality Ub (456 km2).U radu su analizirane mogućnosti i potrebe upotrebe specifičnih vrsta robota (mini bespilotnih letelica sa različitim dizajnom, označane kao UAV) i način korištenja u poljoprivredi (agrodron). Časopis Fortune je 2015.godinu proglasio kao godinu sve većeg i široko rasprostranjene upotrbe UAV letelica, u različitim oblastima ljudske delatnosti, posebno u poljoprivredi i šumarstvu (75% upotrebe). Ovo je naročito važno za velike farme i oblasti pod šumama, gde UAV ima mnogo korisnih funkcija i veoma isplative komercijalne aplikacije. Danas, potrebe za UAV imaju nagli porast sa različitim mogućnostima kako za civilne tako i za vojne potrebe. Takođe postoji značajan interes za razvoj novih bespilotnih letelica koji mogu autonomno leteti u različitim okruženjima i lokacijama i obaviti različite misije i zadatke. Tokom protekle decenije XXI veka, širok spektar aplikacija za bespilotne letelice je dobio značaj koji je doveo do konstrukcija različitih tipova bespilotnih UAV, različitih veličina i težina i svakako namene. Naravno, tehnološki razvoj kod dron sistema je veoma tehničko-tehnološki napredan i revolucionaran, uz razvoj mobilnih i pametnih (android) telefona i interneta, brzo otvora puteve i mogućnosti za mnoge korisnike u definisanju nove budućnosti implementacije UAV u različitim oblastima primene . Kompanija Livona d.o.o., Beograd i Institut za poljoprivrednu tehniku, Poljoprivredni fakultet u Beogradu, u tehničkoj saradnji imaju planove o implementaciji modela mikro drona EBee SK Livona RTK u narednim generalnim planovima za inspekciju, zaštitu i korišćenje poljoprivrednih zemljišta Republike Srbije, i posebno teritorije Opštine Stara Pazova (351 km2), gde je posebno mesto poljoprivrednog preduzeća Napredak a.d. VekomGeo d.o.o, Beograd u saradnji sa Institutom za poljoprivrednu tehniku Poljoprivrednog fakulteta u Beogradu ima planove o budućoj upotrebi drona model Aibot X6, za nadzor na površinama od 600 km2 (i poljoprivredna zemljišta) otvorenog kopa R.B. Kolubara ili drugih objekata. Institut za poljoprivrednu tehniku, Poljoprivredni fakultet u Beogradu, ima planove o saradnji sa opštinom Ub, zbog upotrebe modela mikro drona Hubsan H109S Ks4 PRO u inspekciji oko zaštite i načina korišćenja zemljišta i voda na ovoj teritoriji (456 km2)

Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway

Largen: A Molecular Regulator of Mammalian Cell Size Control

Little is known about how mammalian cells maintain cell size homeostasis. We conducted a novel genetic screen to identify cell-size-controlling genes and isolated Largen, the product of a gene (PRR16) that increased cell size upon overexpression in human cells. Invitro evidence indicated that Largen preferentially stimulates the translation of specific subsetsof mRNAs, including those encoding proteins affecting mitochondrial functions. The involvement of Largen in mitochondrial respiration was consistentwith the increased mitochondrial mass and greater ATP production in Largen-overexpressing cells. Furthermore, Largen overexpression led to increased cell size invivo, as revealed by analyses of conditional Largen transgenic mice. Our results establish Largen as an important link between mRNA translation, mitochondrial functions, and the control of mammalian cell size