New frontiers in translational control of the cancer genome

The past several years have seen dramatic leaps in our understanding of how gene expression is rewired at the translation level during tumorigenesis to support the transformed phenotype. This work has been driven by an explosion in technological advances and is revealing previously unimagined regulatory mechanisms that dictate functional expression of the cancer genome. In this Review we discuss emerging trends and exciting new discoveries that reveal how this translational circuitry contributes to specific aspects of tumorigenesis and cancer cell function, with a particular focus on recent insights into the role of translational control in the adaptive response to oncogenic stress conditions.

[1]  Nicholas T. Ingolia,et al.  Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes , 2011, Cell.

[2]  D. Steinemann,et al.  Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis , 2014, Journal of Molecular Medicine.

[3]  Howard Y. Chang,et al.  RNA SHAPE analysis in living cells. , 2013, Nature chemical biology.

[4]  Howard Y. Chang,et al.  Genome-wide measurement of RNA secondary structure in yeast , 2010, Nature.

[5]  Nicholas T. Ingolia,et al.  Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling , 2009, Science.

[6]  P. Sarnow,et al.  Preferential Translation of Internal Ribosome Entry Site-containing mRNAs during the Mitotic Cycle in Mammalian Cells* , 2004, Journal of Biological Chemistry.

[7]  Alka A. Potdar,et al.  Programmed Translational Readthrough Generates Antiangiogenic VEGF-Ax , 2014, Cell.

[8]  Jiri Zavadil,et al.  DNA damage and eIF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs , 2012, Proceedings of the National Academy of Sciences.

[9]  Shifeng Xue,et al.  Specialized ribosomes: a new frontier in gene regulation and organismal biology , 2012, Nature Reviews Molecular Cell Biology.

[10]  R. Cencic,et al.  Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol , 2009, PloS one.

[11]  Guang Peng,et al.  Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. , 2010, Cancer research.

[12]  N. Sonenberg,et al.  The mRNA 5' cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts , 1992, Molecular and cellular biology.

[13]  J. Cate,et al.  eIF3 targets cell proliferation mRNAs for translational activation or repression , 2015, Nature.

[14]  Michael J. Sweredoski,et al.  The Xist lncRNA directly interacts with SHARP to silence transcription through HDAC3 , 2015, Nature.

[15]  D. Ruggero,et al.  Protein and Nucleotide Biosynthesis Are Coupled by a Single Rate-Limiting Enzyme, PRPS2, to Drive Cancer , 2014, Cell.

[16]  M. Ward,et al.  Activity and regulation by growth factors of calmodulin-dependent protein kinase III (elongation factor 2-kinase) in human breast cancer , 1999, British Journal of Cancer.

[17]  Stefano Fumagalli,et al.  S6K1−/−/S6K2−/− Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5′-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway , 2004, Molecular and Cellular Biology.

[18]  P. Carmeliet,et al.  Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism. , 2014, Cell reports.

[19]  G. Mize,et al.  The Two Upstream Open Reading Frames of Oncogene mdm2 Have Different Translational Regulatory Properties* , 2003, Journal of Biological Chemistry.

[20]  D. Haussler,et al.  FragSeq: transcriptome-wide RNA structure probing using high-throughput sequencing , 2010, Nature Methods.

[21]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[22]  N. Sonenberg,et al.  The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure. , 2001, RNA.

[23]  A. Willis,et al.  The biological and therapeutic relevance of mRNA translation in cancer , 2011, Nature Reviews Clinical Oncology.

[24]  Fatima Al-Shahrour,et al.  Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia , 2010, Nature Medicine.

[25]  A. Aguilera,et al.  Replication stress and cancer , 2015, Nature Reviews Cancer.

[26]  U. Pastorino,et al.  Identification and functional characterization of the candidate tumor suppressor gene TRIT1 in human lung cancer , 2005, Oncogene.

[27]  A. Gingras,et al.  A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development , 2012, Molecular and Cellular Biology.

[28]  Lars-Gunnar Larsson,et al.  c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription , 2005, Nature Cell Biology.

[29]  M. Kozak.  An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. , 1987, Nucleic acids research.

[30]  S. Formenti,et al.  Translational control in cancer , 2010, Nature Reviews Cancer.

[31]  S. Janga,et al.  Dissecting the expression landscape of RNA-binding proteins in human cancers , 2014, Genome Biology.

[32]  R. Rhoads,et al.  Immunological detection of the messenger RNA cap-binding protein. , 1985, The Journal of biological chemistry.

[33]  E. Hafen,et al.  Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. , 2004, Genes & development.

[34]  P. Pandolfi,et al.  eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression , 2010, Proceedings of the National Academy of Sciences.

[35]  M. Kupiec,et al.  Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq , 2012, Nature.

[36]  Tsung-Ming Chen,et al.  Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation , 2013, Nucleic acids research.

[37]  Stephen N. Jones,et al.  Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner. , 2014, Journal of molecular cell biology.

[38]  Richard Bonneau,et al.  The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. , 2012, Molecular cell.

[39]  H. Yee,et al.  A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. , 2007, Molecular cell.

[40]  Jernej Ule,et al.  hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1 , 2015, Nature.

[41]  Clement T Y Chan,et al.  Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival , 2010, Molecular and Cellular Biology.

[42]  Masahiro Morita,et al.  La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)* , 2015, The Journal of Biological Chemistry.

[43]  J. M. Izquierdo.  Hu Antigen R (HuR) Functions as an Alternative Pre-mRNA Splicing Regulator of Fas Apoptosis-promoting Receptor on Exon Definition* , 2008, Journal of Biological Chemistry.

[44]  R. Mukhopadhyay,et al.  The GAIT system: a gatekeeper of inflammatory gene expression. , 2009, Trends in biochemical sciences.

[45]  N. Sonenberg,et al.  mRNAs containing extensive secondary structure in their 5′ non‐coding region translate efficiently in cells overexpressing initiation factor eIF‐4E. , 1992, The EMBO journal.

[46]  R. Green,et al.  miRNA-Mediated Gene Silencing by Translational Repression Followed by mRNA Deadenylation and Decay , 2012, Science.

[47]  R. Hannan,et al.  An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. , 2001, Molecular cell.

[48]  B Lucks Julius,et al.  プライマー伸長塩基配列決定法(SHAPE‐Seq)を用いて分析した選択的2′‐ヒドロキシルアシル化による多重RNA構造の特徴化 , 2011 .

[49]  N. Socci,et al.  Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. , 2003, Molecular cell.

[50]  M. Gorospe,et al.  RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  F. Kirpekar,et al.  ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. , 2011, Nature communications.

[52]  A. Ryazanov,et al.  Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation , 1988, Nature.

[53]  D. A. Dixon,et al.  Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. , 2001, The Journal of clinical investigation.

[54]  S. Puget,et al.  A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy , 2015, Genes & development.

[55]  F. Kirpekar,et al.  Mammalian ALKBH8 Possesses tRNA Methyltransferase Activity Required for the Biogenesis of Multiple Wobble Uridine Modifications Implicated in Translational Decoding , 2010, Molecular and Cellular Biology.

[56]  Brendan J. Frey,et al.  A compendium of RNA-binding motifs for decoding gene regulation , 2013, Nature.

[57]  S. Gerstberger,et al.  A census of human RNA-binding proteins , 2014, Nature Reviews Genetics.

[58]  Yuichiro Mishima,et al.  MicroRNAs trigger dissociation of eIF4AI and eIF4AII from target mRNAs in humans. , 2014, Molecular cell.

[59]  K. Shokat,et al.  Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. , 2010, Cancer cell.

[60]  Shu-Bing Qian,et al.  Dynamic m6A mRNA methylation directs translational control of heat shock response , 2015, Nature.

[61]  S. Lowe,et al.  Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. , 2008, The Journal of clinical investigation.

[62]  P. Sharp,et al.  Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites , 2008, Science.

[63]  T. Marr,et al.  alternative polyadenylation in human , mouse , and rat Computational analysis of 3 '-ends of ESTs shows four classes of data , 2005 .

[64]  G. Thomas,et al.  Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[65]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[66]  Matthias W. Hentze,et al.  Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation , 2007, Nature.

[67]  Daehyun Baek,et al.  mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues. , 2014, Molecular cell.

[68]  E. Marcotte,et al.  Insights into the regulation of protein abundance from proteomic and transcriptomic analyses , 2012, Nature Reviews Genetics.

[69]  Yuval Dor,et al.  Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. , 2005, Genes & development.

[70]  A. Hinnebusch,et al.  Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. , 2000, Molecular cell.

[71]  G. Mize,et al.  Role of two upstream open reading frames in the translational control of oncogene mdm2 , 1999, Oncogene.

[72]  M. Halaby,et al.  The identification of an internal ribosomal entry site in the 5′-untranslated region of p53 mRNA provides a novel mechanism for the regulation of its translation following DNA damage , 2006, Oncogene.

[73]  Tao Pan,et al.  Tissue-Specific Differences in Human Transfer RNA Expression , 2006, PLoS genetics.

[74]  Olivier Elemento,et al.  5′ UTR m6A Promotes Cap-Independent Translation , 2015, Cell.

[75]  M. MacFarlane,et al.  Initiation of Apaf-1 translation by internal ribosome entry , 2000, Oncogene.

[76]  David Hogg,et al.  Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma , 1999, Nature Genetics.

[77]  O. Elemento,et al.  Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons , 2012, Cell.

[78]  T. Pan,et al.  tRNA over-expression in breast cancer and functional consequences , 2009, Nucleic acids research.

[79]  Jane-Jane Chen.  Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. , 2007, Blood.

[80]  Patrick B. F. O'Connor,et al.  Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression , 2015, eLife.

[81]  Javier Gallego,et al.  Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control , 2010, Nature Cell Biology.

[82]  Maurizio Guida,et al.  Small non-coding RNA deregulation in endometrial carcinogenesis , 2015, Oncotarget.

[83]  Takayuki Murata,et al.  MicroRNA Inhibition of Translation Initiation in Vitro by Targeting the Cap-Binding Complex eIF4F , 2007, Science.

[84]  Jonathan S. Weissman,et al.  Principles of ER cotranslational translocation revealed by proximity-specific ribosome profiling , 2014, Science.

[85]  D. Yee,et al.  eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells. , 2015, Cancer research.

[86]  K. Shokat,et al.  Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers , 2013, Proceedings of the National Academy of Sciences.

[87]  Michael N. Hall,et al.  mTORC1 mediated translational elongation limits intestinal tumour initiation and growth , 2014, Nature.

[88]  R. Grover,et al.  Two internal ribosome entry sites mediate the translation of p53 isoforms , 2006, EMBO reports.

[89]  I. Grummt,et al.  mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. , 2004, Genes & development.

[90]  S. Campaner,et al.  Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth. , 2011, Cancer cell.

[91]  T. Pan,et al.  Overexpression of initiator methionine tRNA leads to global reprogramming of tRNA expression and increased proliferation in human epithelial cells. , 2013, RNA.

[92]  C. Tsang,et al.  Mechanisms of regulation of RNA polymerase III‐dependent transcription by TORC1 , 2009, The EMBO journal.

[93]  N. Sonenberg,et al.  p53-dependent translational control of senescence and transformation via 4E-BPs. , 2009, Cancer cell.

[94]  W. Gilbert,et al.  Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells , 2014, Nature.

[95]  R. Hannan,et al.  Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. , 2011, Cancer research.

[96]  R. Eisenman,et al.  Direct activation of RNA polymerase III transcription by c-Myc , 2003, Nature.

[97]  N. Sonenberg,et al.  Insertion mutagenesis to increase secondary structure within the 5′ noncoding region of a eukaryotic mRNA reduces translational efficiency , 1985, Cell.

[98]  A. Rosenwald,et al.  A Phase I Pharmacologic Study of Necitumumab (imc-11f8), a Fully Human Igg1 Monoclonal Antibody Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High Myc Levels in Colorectal Cancer , 2022 .

[99]  P. Blackshear,et al.  Regulation of rat ornithine decarboxylase mRNA translation by its 5'-untranslated region. , 1990, The Journal of biological chemistry.

[100]  C. Stumpf,et al.  The cancerous translation apparatus. , 2011, Current opinion in genetics & development.

[101]  Klaus Wethmar,et al.  C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals. , 2010, Genes & development.

[102]  R. Abramson,et al.  ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors. , 1985, The Journal of biological chemistry.

[103]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[104]  P. Brown,et al.  Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[105]  I. Grummt,et al.  ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth. , 2003, Molecular cell.

[106]  N. Sonenberg,et al.  A New Paradigm for Translational Control: Inhibition via 5′-3′ mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP , 2005, Cell.

[107]  P. Howe,et al.  Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. , 2011, Molecular cell.

[108]  R. Perry,et al.  Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[109]  T. Pan,et al.  High levels of tRNA abundance and alteration of tRNA charging by bortezomib in multiple myeloma. , 2009, Biochemical and biophysical research communications.

[110]  T. Glisovic,et al.  RNA‐binding proteins and post‐transcriptional gene regulation , 2008, FEBS letters.

[111]  D. Durden,et al.  Regulation of XIAP translation and induction by MDM2 following irradiation. , 2009, Cancer cell.

[112]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[113]  N. Sonenberg,et al.  Repression of cap‐dependent translation by 4E‐binding protein 1: competition with p220 for binding to eukaryotic initiation factor‐4E. , 1995, The EMBO journal.

[114]  Qiangfeng Cliff Zhang,et al.  Systematic Discovery of Xist RNA Binding Proteins , 2015, Cell.

[115]  Howard Y. Chang,et al.  Structural imprints in vivo decode RNA regulatory mechanisms , 2015, Nature.

[116]  J. Saurin,et al.  p53 Acts as a Safeguard of Translational Control by Regulating Fibrillarin and rRNA Methylation in Cancer , 2013, Cancer Cell.

[117]  Nicholas T Ingolia,et al.  Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. , 2014, Cell reports.

[118]  S. Formenti,et al.  Vitronectin-αvβ3 integrin engagement directs hypoxia-resistant mTOR activity and sustained protein synthesis linked to invasion by breast cancer cells. , 2013, Cancer research.

[119]  N. Sonenberg,et al.  Phosphorylation of eIF4E Confers Resistance to Cellular Stress and DNA-Damaging Agents through an Interaction with 4E-T: A Rationale for Novel Therapeutic Approaches , 2015, PloS one.

[120]  T. Preiss,et al.  Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA , 2012, Nucleic acids research.

[121]  R. White,et al.  The mitogen‐activated protein (MAP) kinase ERK induces tRNA synthesis by phosphorylating TFIIIB , 2003, The EMBO journal.

[122]  D. Sabatini,et al.  An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1* , 2009, Journal of Biological Chemistry.

[123]  Clement T Y Chan,et al.  A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress , 2010, PLoS genetics.

[124]  W. Filipowicz,et al.  Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells , 2012, EMBO reports.

[125]  Wei Li,et al.  CFIm25 links Alternative Polyadenylation to Glioblastoma Tumor Suppression , 2014, Nature.

[126]  C. Fraser,et al.  Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity , 2013, Proceedings of the National Academy of Sciences.

[127]  C. Mayr,et al.  Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer Cells , 2009, Cell.

[128]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[129]  Thomas J. Begley,et al.  Trm9-catalyzed tRNA modifications link translation to the DNA damage response. , 2007, Molecular cell.

[130]  M. Holcik,et al.  Cap-independent regulation of gene expression in apoptosis. , 2007, Molecular bioSystems.

[131]  O. Meyuhas,et al.  Vertebrate mRNAs with a 5'-terminal pyrimidine tract are candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element , 1994, Molecular and cellular biology.

[132]  C. Galet,et al.  YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence , 2015, Oncotarget.

[133]  J. Hershey,et al.  Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F. , 1987, The Journal of biological chemistry.

[134]  T. Chow,et al.  A new internal-ribosome-entry-site motif potentiates XIAP- mediated cytoprotection , 1999, Nature Cell Biology.

[135]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[136]  C. Bellodi,et al.  Deregulation of oncogene‐induced senescence and p53 translational control in X‐linked dyskeratosis congenita , 2010, The EMBO journal.

[137]  N. Sonenberg,et al.  Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3 , 2014, Oncogene.

[138]  R. Spriggs,et al.  Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation , 2013, Science.

[139]  A. Gingras,et al.  Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases , 2004, The EMBO journal.

[140]  D. MacAlpine,et al.  Rare Codons Regulate KRas Oncogenesis , 2013, Current Biology.

[141]  Maxwell R. Mumbach,et al.  Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA , 2014, Cell.

[142]  Robert J. Schneider,et al.  Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells , 2006, Molecular and Cellular Biology.

[143]  Rhiju Das,et al.  RNA regulons in Hox 5′UTRs confer ribosome specificity to gene regulation , 2014, Nature.

[144]  J. Derisi,et al.  Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation , 2014, Genome Biology.

[145]  D. Vertommen,et al.  Eukaryotic Elongation Factor 2 Kinase Activity Is Controlled by Multiple Inputs from Oncogenic Signaling , 2014, Molecular and Cellular Biology.

[146]  A. Giraldez,et al.  Ribosome Profiling Shows That miR-430 Reduces Translation Before Causing mRNA Decay in Zebrafish , 2012, Science.

[147]  Sebastian M. Waszak,et al.  A Dual Program for Translation Regulation in Cellular Proliferation and Differentiation , 2014, Cell.

[148]  A. Burlingame,et al.  H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation. , 2013, Cell reports.

[149]  A. Czernik,et al.  Calmodulin-dependent protein kinases in rat glioblastoma. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[150]  M. Negrini,et al.  Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia , 2013, BMC Medical Genomics.

[151]  J. Ule,et al.  iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution , 2010, Nature Structural &Molecular Biology.

[152]  Bradley R. Cairns,et al.  Identification of direct targets and modified bases of RNA cytosine methyltransferases , 2013, Nature Biotechnology.

[153]  Takahiro Ito,et al.  Regulation of myeloid leukemia by the cell fate determinant Musashi , 2010, Nature.

[154]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[155]  M. Kozak.  Influences of mRNA secondary structure on initiation by eukaryotic ribosomes. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[156]  O. Meyuhas,et al.  Reassessment of the Role of TSC, mTORC1 and MicroRNAs in Amino Acids-Meditated Translational Control of TOP mRNAs , 2014, PloS one.

[157]  Robert J White,et al.  p53 is a general repressor of RNA polymerase III transcription , 1998, The EMBO journal.

[158]  A. Prats,et al.  Alternative Translation of the Proto-oncogene c-mycby an Internal Ribosome Entry Site* , 1997, The Journal of Biological Chemistry.

[159]  B. Williams,et al.  PKR; a sentinel kinase for cellular stress , 1999, Oncogene.

[160]  J. Flanagan,et al.  APC Is an RNA-Binding Protein, and Its Interactome Provides a Link to Neural Development and Microtubule Assembly , 2014, Cell.

[161]  Todd M. Lowe,et al.  ARM-Seq: AlkB-facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments , 2015, Nature Methods.

[162]  G. Hussey,et al.  Transforming Growth Factor-β (TGFβ)-mediated Phosphorylation of hnRNP E1 Induces EMT via Transcript Selective Translational Induction of Dab2 and ILEI , 2010, Nature cell biology.

[163]  B. Shen,et al.  Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution , 2012, Proceedings of the National Academy of Sciences.

[164]  Konstantinos J. Mavrakis,et al.  RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer , 2014, Nature.

[165]  Robbie Loewith,et al.  Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 , 2009, PLoS biology.

[166]  Jennifer S. Yu,et al.  A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival , 2013, Science.

[167]  Michele Pagano,et al.  S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth , 2006, Science.

[168]  David Tollervey,et al.  Cross-linking, ligation, and sequencing of hybrids reveals RNA–RNA interactions in yeast , 2011, Proceedings of the National Academy of Sciences.

[169]  M Schwab,et al.  N‐myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis , 2001, The EMBO journal.

[170]  P. Sorensen,et al.  Stress-mediated translational control in cancer cells. , 2015, Biochimica et biophysica acta.

[171]  N. Ilić,et al.  PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis , 2011, Proceedings of the National Academy of Sciences.

[172]  Y. Shi,et al.  Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress , 2015, Oncogene.

[173]  A. Eggermont,et al.  eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies , 2014, Nature.

[174]  B. Ramsbottom,et al.  mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1 , 2010, Proceedings of the National Academy of Sciences.

[175]  D. Spandidos,et al.  RNA polymerase III transcription factor TFIIIC2 is overexpressed in ovarian tumors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[176]  Wei Xu,et al.  Impaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita , 2006, Science.

[177]  N. Sonenberg,et al.  Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap , 1990, Nature.

[178]  F. Gebauer,et al.  RNA-binding proteins, multifaceted translational regulators in cancer. , 2015, Biochimica et biophysica acta.

[179]  R. Pearson,et al.  mTOR-Dependent Regulation of Ribosomal Gene Transcription Requires S6K1 and Is Mediated by Phosphorylation of the Carboxy-Terminal Activation Domain of the Nucleolar Transcription Factor UBF† , 2003, Molecular and Cellular Biology.

[180]  Scott B. Dewell,et al.  Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP , 2010, Cell.

[181]  P. Schumacker,et al.  Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? , 2014, Nature Reviews Cancer.

[182]  Thomas J. Begley,et al.  Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage , 2015, PloS one.

[183]  P. Pandolfi,et al.  The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis , 2004, Nature Medicine.

[184]  Shiqing Ma,et al.  Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. , 2015, Nature chemical biology.

[185]  P. Brown,et al.  Transcriptome-Wide Mapping of Pseudouridines: Pseudouridine Synthases Modify Specific mRNAs in S. cerevisiae , 2014, PloS one.

[186]  Clement T Y Chan,et al.  Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins , 2012, Nature Communications.

[187]  J. Avruch,et al.  The TSC-mTOR Pathway Mediates Translational Activation of TOP mRNAs by Insulin Largely in a Raptor- or Rictor-Independent Manner , 2008, Molecular and Cellular Biology.

[188]  I. Mills,et al.  ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. , 2012, The Journal of clinical investigation.

[189]  Arnold J Levine,et al.  Tissue-specific codon usage and the expression of human genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[190]  K. Isselbacher,et al.  Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[191]  N. Sonenberg,et al.  Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F , 1990, Molecular and cellular biology.

[192]  M. Polymenis,et al.  An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc , 1996, Molecular and cellular biology.

[193]  Davide Ruggero,et al.  Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency , 2008, Nature.

[194]  Francesco Piazza,et al.  Dyskeratosis Congenita and Cancer in Mice Deficient in Ribosomal RNA Modification , 2003, Science.

[195]  Christos G. Gkogkas,et al.  mRNA helicases: the tacticians of translational control , 2011, Nature Reviews Molecular Cell Biology.

[196]  A. Pause,et al.  An oxygen-regulated switch in the protein synthesis machinery , 2012, Nature.

[197]  E. Papadopoulos,et al.  Hypoxia-inducible Factor-1α (HIF-1α) Promotes Cap-dependent Translation of Selective mRNAs through Up-regulating Initiation Factor eIF4E1 in Breast Cancer Cells under Hypoxia Conditions* , 2013, The Journal of Biological Chemistry.

[198]  Chengqi Yi,et al.  Efficient and quantitative high-throughput transfer RNA sequencing , 2015, Nature Methods.

[199]  D. Sabatini,et al.  A unifying model for mTORC1-mediated regulation of mRNA translation , 2012, Nature.

[200]  A. De Benedetti,et al.  Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: Implications for tumor angiogenesis , 1996, International journal of cancer.

[201]  A E Willis,et al.  LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression , 2014, Oncogene.

[202]  L. Kay,et al.  Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch , 2014, Nature.

[203]  A. Hinnebusch,et al.  Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets , 2009, Cell.

[204]  E. Izaurralde,et al.  Towards a molecular understanding of microRNA-mediated gene silencing , 2015, Nature Reviews Genetics.

[205]  R. Guigó,et al.  Characterization of Mammalian Selenoproteomes , 2003, Science.

[206]  Bin Tian,et al.  A large-scale analysis of mRNA polyadenylation of human and mouse genes , 2005, Nucleic acids research.

[207]  C. Proud,et al.  Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase , 2001, The EMBO journal.

[208]  Anne E Willis,et al.  A perspective on mammalian upstream open reading frame function , 2013, The International Journal of Biochemistry & Cell Biology.

[209]  Roger R. Gomis,et al.  C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells , 2006 .

[210]  Shifeng Xue,et al.  Ribosome-Mediated Specificity in Hox mRNA Translation and Vertebrate Tissue Patterning , 2011, Cell.

[211]  Michael G. Kharas,et al.  Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. , 2015, The Journal of clinical investigation.

[212]  Pedro G. Ferreira,et al.  CPEB1 coordinates alternative 3′-UTR formation with translational regulation , 2013, Nature.

[213]  Y. Tomari,et al.  The Functions of MicroRNAs: mRNA Decay and Translational Repression. , 2015, Trends in cell biology.

[214]  Tyson A. Clark,et al.  HITS-CLIP yields genome-wide insights into brain alternative RNA processing , 2008, Nature.

[215]  J. Jia,et al.  Regulation and dysregulation of 3'UTR-mediated translational control. , 2013, Current opinion in genetics & development.

[216]  V. P. Collins,et al.  The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation , 2013, Cell.

[217]  Pankaj Pathak,et al.  Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs , 2015, International journal of cancer.

[218]  L. Hengst,et al.  ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR. , 2002, Genes & development.

[219]  Q. She,et al.  4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. , 2010, Cancer cell.

[220]  S. Temple,et al.  Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells , 2015, Nucleic acids research.

[221]  C. Kevil,et al.  Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation. , 1995, Oncogene.

[222]  M. V. van Eden,et al.  BCL-2 Translation Is Mediated via Internal Ribosome Entry during Cell Stress* , 2004, Journal of Biological Chemistry.

[223]  D. Bartel,et al.  Poly(A)-tail profiling reveals an embryonic switch in translational control , 2014, Nature.

[224]  E. Danen,et al.  The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest , 2015, Molecular and Cellular Biology.

[225]  Cole Trapnell,et al.  Multiplexed RNA structure characterization with selective 2′-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq) , 2011, Proceedings of the National Academy of Sciences.

[226]  N. Sonenberg,et al.  Targeting the translation machinery in cancer , 2015, Nature Reviews Drug Discovery.

[227]  R. Wek,et al.  Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[228]  Carleen Cullinane,et al.  Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. , 2012, Cancer cell.

[229]  T. Tokuyasu,et al.  Differential Requirements for eIF4E Dose in Normal Development and Cancer , 2015, Cell.

[230]  T. Mak,et al.  Modulation of oxidative stress as an anticancer strategy , 2013, Nature Reviews Drug Discovery.

[231]  Jeroen Krijgsveld,et al.  The RNA-binding protein repertoire of embryonic stem cells , 2013, Nature Structural &Molecular Biology.

[232]  Norman E. Davey,et al.  Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins , 2012, Cell.

[233]  Feng Jiang,et al.  Genome‐wide small nucleolar RNA expression analysis of lung cancer by next‐generation deep sequencing , 2015, International journal of cancer.

[234]  C. Proud,et al.  Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles. , 2014, Advances in biological regulation.

[235]  R. Elkon,et al.  Alternative cleavage and polyadenylation: extent, regulation and function , 2013, Nature Reviews Genetics.

[236]  P. Carroll,et al.  Cell type–specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors , 2015, Science Signaling.

[237]  S. Peltz,et al.  Derepression of the Her-2 uORF is mediated by a novel post-transcriptional control mechanism in cancer cells. , 2006, Genes & development.

[238]  A. Hopper,et al.  tRNA biology charges to the front. , 2010, Genes & development.

[239]  David M. Sabatini,et al.  The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1 , 2008, Science.

[240]  Jernej Ule,et al.  NSun2-Mediated Cytosine-5 Methylation of Vault Noncoding RNA Determines Its Processing into Regulatory Small RNAs , 2013, Cell reports.

[241]  Christopher G. Proud,et al.  A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin , 2004, Molecular and Cellular Biology.

[242]  Carla Grandori,et al.  c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I , 2005, Nature Cell Biology.

[243]  Edward L Huttlin,et al.  Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation , 2014, Genes & development.

[244]  T. Visakorpi,et al.  Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer , 2012, Oncogene.

[245]  V. Mootha,et al.  Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans , 2009, Proceedings of the National Academy of Sciences.

[246]  C. Dang,et al.  Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[247]  Tao Wang,et al.  Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. , 2007, The Journal of clinical investigation.

[248]  Lingling Hu,et al.  Analysis of human upstream open reading frames and impact on gene expression , 2015, Human Genetics.

[249]  Y. Tomari,et al.  MicroRNAs block assembly of eIF4F translation initiation complex in Drosophila. , 2014, Molecular cell.

[250]  Jonathan A. Cooper,et al.  Mitogen‐activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 , 1997, The EMBO journal.

[251]  G. Gerlitz,et al.  Phosphorylation of initiation factor-2 alpha is required for activation of internal translation initiation during cell differentiation. , 2002, European Journal of Biochemistry.

[252]  S. Jackson,et al.  Repression of RNA polymerase III transcription by the retinoblastoma protein , 1996, Nature.