Genomes and Genes
eukaryotic initiation factor 2
Summary: Eukaryotic initiation factor of protein synthesis. In higher eukaryotes the factor consists of three subunits: alpha, beta, and gamma. As initiation proceeds, eIF-2 forms a ternary complex with Met-tRNAi and GTP.
- Zeng Y, Sankala H, Zhang X, Graves P. Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. Biochem J. 2008;413:429-36 pubmed publisher..These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway. ..
- Rüdel S, Flatley A, Weinmann L, Kremmer E, Meister G. A multifunctional human Argonaute2-specific monoclonal antibody. RNA. 2008;14:1244-53 pubmed publisher..With the anti-Ago2(11A9) antibody we have generated a potent tool that is useful for many biochemical or cell biological applications. ..
- Macrae I, Ma E, Zhou M, Robinson C, Doudna J. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008;105:512-7 pubmed publisher..Furthermore, once Ago2 is loaded with an miRNA, it tends to dissociate from the rest of the complex. These results lay the groundwork for future structural and functional dissection of RISC loading in humans. ..
- Nallagatla S, Hwang J, Toroney R, Zheng X, Cameron C, Bevilacqua P. 5'-triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science. 2007;318:1455-8 pubmed..The evidence presented here suggests that this form of RNA-based discrimination may be a critical step in mounting an early immune response. ..
- Su Q, Wang S, Gao H, Kazemi S, Harding H, Ron D, et al. Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem. 2008;283:469-75 pubmed..Thus, our data classify PERK as a dual specificity kinase whose regulation by tyrosine phosphorylation contributes to its optimal activation in response to ER stress. ..
- Lee Y, Cevallos R, Jan E. An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem. 2009;284:6661-73 pubmed publisher..This mechanism may serve as a model for understanding how other 5'UTR uORF-containing mRNAs are regulated during cellular stress. ..
- Su H, Trombly M, Chen J, Wang X. Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 2009;23:304-17 pubmed publisher..Thus, our results demonstrate that mammalian Agos all contribute to miRNA silencing, and individual Agos have largely overlapping functions in this process. ..
- Zaborske J, Narasimhan J, Jiang L, Wek S, Dittmar K, Freimoser F, et al. Genome-wide analysis of tRNA charging and activation of the eIF2 kinase Gcn2p. J Biol Chem. 2009;284:25254-67 pubmed publisher..These results also depict a complex cellular relationship between tRNA charging, amino acid availability, and non-nutrient stress. These relationships are best revealed by simultaneous monitoring of the charging level of all tRNAs. ..
- Nelson P, De Planell Saguer M, Lamprinaki S, Kiriakidou M, Zhang P, O DOHERTY U, et al. A novel monoclonal antibody against human Argonaute proteins reveals unexpected characteristics of miRNAs in human blood cells. RNA. 2007;13:1787-92 pubmed..We report the characterization of 2A8 and its use to clone miRNAs from human brain and from preparations of human polymorphonuclear leukocytes (neutrophils), which revealed a prevalent miRNA with unusual features. ..
- Sikalidis A, Stipanuk M. Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response. J Nutr. 2010;140:1080-5 pubmed publisher..nutritional stress, via pathways that are initiated by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 complex (eIF2alpha)...
- O Carroll D, Mecklenbrauker I, Das P, Santana A, Koenig U, Enright A, et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 2007;21:1999-2004 pubmed..Collectively, our data identify Ago2 as a highly specialized member of the Argonaute family with an essential nonredundant Slicer-independent function within the mammalian miRNA pathway...
- Montero H, Rojas M, Arias C, Lopez S. Rotavirus infection induces the phosphorylation of eIF2alpha but prevents the formation of stress granules. J Virol. 2008;82:1496-504 pubmed
- Takimoto K, Wakiyama M, Yokoyama S. Mammalian GW182 contains multiple Argonaute-binding sites and functions in microRNA-mediated translational repression. RNA. 2009;15:1078-89 pubmed publisher..Together, these results strongly suggested that the interactions of GW182 with Argonautes may induce the formation of large complexes containing miRNA target mRNAs, and may be critical for miRNA-mediated translational repression. ..
- Wu L, Fan J, Belasco J. Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Curr Biol. 2008;18:1327-32 pubmed publisher..These findings have important implications for the efficacy and specificity of RNA interference. ..
- Qi H, Ongusaha P, Myllyharju J, Cheng D, Pakkanen O, Shi Y, et al. Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature. 2008;455:421-4 pubmed publisher..These findings identify hydroxylation as a post-translational modification important for Ago2 stability and effective RNA interference. ..
- Kang M, Lee C, Lee J, Dela Cruz C, Chen Z, Enelow R, et al. Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest. 2008;118:2771-84 pubmed publisher..These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses. ..
- Yoda M, Kawamata T, Paroo Z, Ye X, Iwasaki S, Liu Q, et al. ATP-dependent human RISC assembly pathways. Nat Struct Mol Biol. 2010;17:17-23 pubmed publisher..All these features of human AGO proteins are highly reminiscent of fly Ago1 but not fly Ago2. ..
- Seo E, Liu F, Kawagishi Kobayashi M, Ung T, Cao C, Dar A, et al. Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L protein. Proc Natl Acad Sci U S A. 2008;105:16894-9 pubmed publisher..We propose that these paradoxical effects of the PKR mutations on pseudosubstrate vs. substrate interactions reflect differences between the rigid K3L protein and the plastic nature of eIF2alpha around the Ser-51 phosphorylation site...
- Azuma Mukai A, Oguri H, Mituyama T, Qian Z, Asai K, Siomi H, et al. Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing. Proc Natl Acad Sci U S A. 2008;105:7964-9 pubmed publisher..The hAgo antibodies we raised are valuable tools for ascertaining the functional behavior of endogenous Argonautes and miRNAs in RNA silencing. ..
- Kang J, Kwon S, Park S, Kim Y, Choi S, Kim J, et al. PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control. Virus Res. 2009;142:51-6 pubmed publisher..Together, these results demonstrate that PKR is activated by HCV infection and plays a critical antiviral role through inhibition of viral protein translation. ..
- Paukku K, Kalkkinen N, Silvennoinen O, Kontula K, Lehtonen J. p100 increases AT1R expression through interaction with AT1R 3'-UTR. Nucleic Acids Res. 2008;36:4474-87 pubmed publisher..In summary, p100 is a multifunctional regulator of gene expression that regulates transcription, mRNA maturation, and as described in this article, also mRNA stability and translation. ..
- Ranganathan A, Ojha S, Kourtidis A, Conklin D, Aguirre Ghiso J. Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Res. 2008;68:3260-8 pubmed publisher..This is an important consideration in the development of PERK-based therapies, as its inhibition may facilitate the proliferation of slow-cycling or dormant tumor cells. ..
- Höck J, Weinmann L, Ender C, Rüdel S, Kremmer E, Raabe M, et al. Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO Rep. 2007;8:1052-60 pubmed..Using reporter assays and knockdown experiments, we showed that the putative RNA-binding protein RBM4 is required for microRNA-guided gene regulation. ..
- Sutton M, Taylor A, Ito H, Pham A, Schuman E. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron. 2007;55:648-61 pubmed
- Lu W, László C, Miao Z, Chen H, Wu S. The role of nitric-oxide synthase in the regulation of UVB light-induced phosphorylation of the alpha subunit of eukaryotic initiation factor 2. J Biol Chem. 2009;284:24281-8 pubmed publisherUV light induces phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha) and inhibits global protein synthesis...
- Wakiyama M, Takimoto K, Ohara O, Yokoyama S. Let-7 microRNA-mediated mRNA deadenylation and translational repression in a mammalian cell-free system. Genes Dev. 2007;21:1857-62 pubmed..Our work suggests that let-7 miRNPs containing Argonaute and GW182 impair the synergistic enhancement of translation by the 5'-cap and 3'-poly(A) tail, resulting in translational repression. ..
- Zhang Y, Wang Y, Kanyuka K, Parry M, Powers S, Halford N. GCN2-dependent phosphorylation of eukaryotic translation initiation factor-2alpha in Arabidopsis. J Exp Bot. 2008;59:3131-41 pubmed publisher..Analysis of wild-type and GT8359 plants infected with Turnip yellow mosaic virus or Turnip crinkle virus showed that AteIF2alpha was not phosphorylated. ..
- Medigeshi G, Lancaster A, Hirsch A, Briese T, Lipkin W, DeFilippis V, et al. West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J Virol. 2007;81:10849-60 pubmed
- Mazroui R, Di Marco S, Kaufman R, Gallouzi I. Inhibition of the ubiquitin-proteasome system induces stress granule formation. Mol Biol Cell. 2007;18:2603-18 pubmed..Hence, our findings suggest that SGs could be considered as one of the players that mediate the early response of the cell to proteasome inhibitors by interfering temporarily with mRNA decay pathways. ..
- Weinmann L, Höck J, Ivacevic T, Ohrt T, Mütze J, Schwille P, et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell. 2009;136:496-507 pubmed publisher..Therefore, we provide evidence that Imp8 is required for cytoplasmic miRNA-guided gene silencing and affects nuclear localization of Ago proteins. ..
- Garaigorta U, Chisari F. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe. 2009;6:513-22 pubmed publisher..These results suggest that the ability of HCV to activate PKR may, paradoxically, be advantageous for the virus during an IFN response by preferentially suppressing the translation of ISGs. ..
- Koritzinsky M, Rouschop K, van den Beucken T, Magagnin M, Savelkouls K, Lambin P, et al. Phosphorylation of eIF2alpha is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother Oncol. 2007;83:353-61 pubmed..Disruption of eIF2alpha phosphorylation caused sensitivity to hypoxia and anoxia. Disruption of eIF2alpha phosphorylation is a potential target for hypoxia-directed molecular cancer therapy. ..
- Sequeira S, Ranganathan A, Adam A, Iglesias B, Farias E, Aguirre Ghiso J. Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PLoS ONE. 2007;2:e615 pubmed..The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer. ..
- Garcia Bonilla L, Cid C, Alcazar A, Burda J, Ayuso I, Salinas M. Regulatory proteins of eukaryotic initiation factor 2-alpha subunit (eIF2 alpha) phosphatase, under ischemic reperfusion and tolerance. J Neurochem. 2007;103:1368-80 pubmed..Of particular interest is the potential role of GADD34/PP1c complexes after tolerance acquisition. ..
- Kiriakidou M, Tan G, Lamprinaki S, De Planell Saguer M, Nelson P, Mourelatos Z. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell. 2007;129:1141-51 pubmed..We propose that Ago2 represses the initiation of mRNA translation by binding to the m(7)G cap of mRNA targets, thus likely precluding the recruitment of eIF4E. ..
- Ender C, Krek A, Friedländer M, Beitzinger M, Weinmann L, Chen W, et al. A human snoRNA with microRNA-like functions. Mol Cell. 2008;32:519-28 pubmed publisher..We further identify a number of human snoRNAs with microRNA (miRNA)-like processing signatures. We have, therefore, identified a class of small RNAs in human cells that originate from snoRNAs and can function like miRNAs. ..
- Adams B, Claffey K, White B. Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells. Endocrinology. 2009;150:14-23 pubmed publisher..These data indicate that Ago2 is regulated at both the transcriptional and posttranslational level, and also implicate Ago2 and enhanced micro-RNA activity in the tumorigenic progression of breast cancer cell lines. ..
- Vasudevan S, Tong Y, Steitz J. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931-4 pubmed..Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle. ..
- Terenin I, Dmitriev S, Andreev D, Shatsky I. Eukaryotic translation initiation machinery can operate in a bacterial-like mode without eIF2. Nat Struct Mol Biol. 2008;15:836-41 pubmed publisher..The switch from the conventional eukaryotic mode of translation initiation to the eIF2-independent mechanism occurs when eIF2 is inactivated by phosphorylation under stress conditions. ..
- Cheloufi S, Dos Santos C, Chong M, Hannon G. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature. 2010;465:584-9 pubmed publisher..Our findings link the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development. ..
- Frank F, Sonenberg N, Nagar B. Structural basis for 5'-nucleotide base-specific recognition of guide RNA by human AGO2. Nature. 2010;465:818-22 pubmed publisher..6 mM) or GMP (3.3 mM). This study provides structural evidence for nucleotide-specific interactions in the MID domain of eukaryotic AGO proteins and explains the observed preference for U or A at the 5' end of miRNAs. ..
- Lian S, Fritzler M, Katz J, Hamazaki T, Terada N, Satoh M, et al. Small interfering RNA-mediated silencing induces target-dependent assembly of GW/P bodies. Mol Biol Cell. 2007;18:3375-87 pubmed..We propose that RNAi is a key regulatory mechanism for the assembly of GWB, and in some cases, GWB may serve as markers for RNAi in mammalian cells...
- Schewe D, Aguirre Ghiso J. Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res. 2009;69:1545-52 pubmed publisher..Thus, strategies that maintain eIF2alpha in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer. ..
- Zhang P, Samuel C. Protein kinase PKR plays a stimulus- and virus-dependent role in apoptotic death and virus multiplication in human cells. J Virol. 2007;81:8192-200 pubmed..Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 on serine 51 was not detectably increased in response to dsRNA in PKR-deficient HeLa cells but was ..
- Rasmussen K, Simmini S, Abreu Goodger C, Bartonicek N, Di Giacomo M, Bilbao Cortes D, et al. The miR-144/451 locus is required for erythroid homeostasis. J Exp Med. 2010;207:1351-8 pubmed publisher..Thus, the miR-144/451 cluster tunes gene expression to impart a robustness to erythropoiesis that is critical under conditions of stress. ..
- Zhu K, Chan W, Heymach J, Wilkinson M, McConkey D. Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression. Cancer Res. 2009;69:1836-43 pubmed publisher..Our data established that PIs down-regulated HIF-1alpha expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2alpha and inhibiting HIF-1alpha translation. ..
- Yang J, Ahmed A, Poon E, Perusinghe N, de Haven Brandon A, Box G, et al. Small-molecule activation of p53 blocks hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Mol Cell Biol. 2009;29:2243-53 pubmed publisher..RITA treatment of cells induced a p53-dependent increase in phosphorylation of the alpha subunit of eukaryotic initiation factor 2, requiring PKR-like endoplasmic reticulum kinase activity, and led to the subsequent downregulation of ..
- Karginov F, Conaco C, Xuan Z, Schmidt B, Parker J, Mandel G, et al. A biochemical approach to identifying microRNA targets. Proc Natl Acad Sci U S A. 2007;104:19291-6 pubmed..Reporter assays validated both classes, extending the spectrum of mRNA targets that can be experimentally linked to the miRNA pathway. ..
- Hutvagner G, Simard M. Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol. 2008;9:22-32 pubmed..With their functional domains, Argonaute proteins can bind small non-coding RNAs and control protein synthesis, affect messenger RNA stability and even participate in the production of a new class of small RNAs, Piwi-interacting RNAs. ..
- Silva A, Wang D, Komar A, Castilho B, Williams B. Salicylates trigger protein synthesis inhibition in a protein kinase R-like endoplasmic reticulum kinase-dependent manner. J Biol Chem. 2007;282:10164-71 pubmed..Thus, salicylates selectively trigger an endoplasmic reticulum stress-responsive signaling pathway initiated through activation of PERK to induce their cellular effects. ..
- Oyadomari S, Harding H, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 2008;7:520-32 pubmed publisher..These observations suggest that eIF2(alphaP)-mediated translation of key hepatic transcriptional regulators of intermediary metabolism contributes to the detrimental consequences of nutrient excess. ..
- Beitzinger M, Peters L, Zhu J, Kremmer E, Meister G. Identification of human microRNA targets from isolated argonaute protein complexes. RNA Biol. 2007;4:76-84 pubmed..Our data clearly indicate that miRNA targets can be experimentally identified from Ago complexes and therefore provide a new tool to directly analyze miRNA function. ..
- Baillat D, Shiekhattar R. Functional dissection of the human TNRC6 (GW182-related) family of proteins. Mol Cell Biol. 2009;29:4144-55 pubmed publisher..In contrast, the C-terminal domain containing the RNA recognition motif plays a critical role in the silencing mediated by the TNRC6B protein. ..
- Blenkiron C, Goldstein L, Thorne N, Spiteri I, Chin S, Dunning M, et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 2007;8:R214 pubmed..Furthermore, we demonstrate that bead-based flow cytometric miRNA expression profiling might be a suitable platform to classify breast cancer into prognostic molecular subtypes. ..
- Vasudevan S, Steitz J. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell. 2007;128:1105-18 pubmed..This novel cell-growth-dependent translation activation role for FXR1 and AGO2 allows new insights into ARE-mediated signaling and connects two important posttranscriptional regulatory systems in an unexpected way. ..
- Watanabe T, Totoki Y, Toyoda A, Kaneda M, Kuramochi Miyagawa S, Obata Y, et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature. 2008;453:539-43 pubmed publisher..Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs. ..