Suppression of cap-dependent translation in mitosis.

Cap-dependent translation is mediated by eIF4F, a protein complex composed of three subunits as follows: eIF4E, which recognizes the mRNA 5' cap structure; eIF4A, an RNA-helicase; and eIF4G, a scaffolding protein that binds eIF4E, eIF4A, and the eIF4E-kinase Mnk1 simultaneously. eIF4E is hypophosphorylated and cap-dependent translation is reduced at mitosis. Here, we show that 4E-BP1, a suppressor of eIF4E function, is also hypophosphorylated in mitosis, resulting in disruption of the eIF4F complex. Consequently, eIF4E is sequestered from the eIF4G/Mnk1 complex. These results explain the specific inhibition of cap-dependent translation in mitosis and also explain how eIF4E is rendered hypophosphorylated during mitosis. Furthermore, eIF4E interaction with eIF4GII is strongly decreased coincident with hyperphosphorylation of eIF4GII. Thus, inhibition of cap-dependent translation in mitosis results from a combination of phosphorylation modifications leading to eIF4F complex disruption.

[1]  N. Sonenberg,et al.  Cell-cycle-dependent translational control. , 2001, Current opinion in genetics & development.

[2]  N. Sonenberg,et al.  A novel shuttling protein, 4E‐T, mediates the nuclear import of the mRNA 5′ cap‐binding protein, eIF4E , 2000, The EMBO journal.

[3]  A. Sachs.  Cell Cycle–Dependent Translation Initiation IRES Elements Prevail , 2000, Cell.

[4]  J. Darlix,et al.  An Internal Ribosome Entry Segment Promotes Translation of the Simian Immunodeficiency Virus Genomic RNA* , 2000, The Journal of Biological Chemistry.

[5]  S. Cornelis,et al.  Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. , 2000, Molecular cell.

[6]  N. Sonenberg,et al.  A cell cycle-dependent internal ribosome entry site. , 2000, Molecular cell.

[7]  S. Gygi,et al.  Serum‐stimulated, rapamycin‐sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI , 2000, The EMBO journal.

[8]  N. Sonenberg,et al.  Nuclear Eukaryotic Initiation Factor 4e (Eif4e) Colocalizes with Splicing Factors in Speckles , 2000, The Journal of cell biology.

[9]  J. Hershey,et al.  2 The Pathway and Mechanism of Initiation of Protein Synthesis , 2000 .

[10]  M. Honda,et al.  Cell cycle regulation of hepatitis C virus internal ribosomal entry site-directed translation. , 2000, Gastroenterology.

[11]  E. Krebs,et al.  Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Le,et al.  Differentiation-Induced Internal Translation of c-sis mRNA: Analysis of the cis Elements and Their Differentiation-Linked Binding to the hnRNP C Protein , 1999, Molecular and Cellular Biology.

[13]  A. Gingras,et al.  Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. , 1999, Molecular cell.

[14]  S. Schreiber,et al.  Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  N. Sonenberg,et al.  Eukaryotic Initiation Factor 4GII (eIF4GII), but Not eIF4GI, Cleavage Correlates with Inhibition of Host Cell Protein Synthesis after Human Rhinovirus Infection , 1999, Journal of Virology.

[16]  Jonathan A. Cooper,et al.  Phosphorylation of the Cap-Binding Protein Eukaryotic Translation Initiation Factor 4E by Protein Kinase Mnk1 In Vivo , 1999, Molecular and Cellular Biology.

[17]  A. Gingras,et al.  Human eukaryotic translation initiation factor 4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E , 1999, The EMBO journal.

[18]  A. Gingras,et al.  eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. , 1999, Annual review of biochemistry.

[19]  Jonathan A. Cooper,et al.  The Phosphorylation of Eukaryotic Initiation Factor eIF4E in Response to Phorbol Esters, Cell Stresses, and Cytokines Is Mediated by Distinct MAP Kinase Pathways* , 1998, The Journal of Biological Chemistry.

[20]  N. Sonenberg,et al.  A Novel Functional Human Eukaryotic Translation Initiation Factor 4G , 1998, Molecular and Cellular Biology.

[21]  M. Nowak,et al.  HIV-1 Vpr increases viral expression by manipulation of the cell cycle: A mechanism for selection of Vpr in vivo , 1998, Nature Medicine.

[22]  N. Sonenberg,et al.  Human eukaryotic translation initiation factor 4G (eIF4G) possesses two separate and independent binding sites for eIF4A , 1997, Molecular and cellular biology.

[23]  N. Sonenberg,et al.  eIF4G Dramatically Enhances the Binding of eIF4E to the mRNA 5′-Cap Structure* , 1997, The Journal of Biological Chemistry.

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

[25]  Tony Hunter,et al.  MNK1, a new MAP kinase‐activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates , 1997, The EMBO journal.

[26]  A. Gingras,et al.  Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[27]  V. M. Pain,et al.  The C‐terminal domain of eukaryotic protein synthesis initiation factor (eIF) 4G is sufficient to support cap‐independent translation in the absence of eIF4E. , 1996, The EMBO journal.

[28]  S. Kimball,et al.  Role of translation initiation factor eIF-2B in the regulation of protein synthesis in mammalian cells. , 1996, Progress in nucleic acid research and molecular biology.

[29]  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.

[30]  N. Sonenberg,et al.  The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins , 1995, Molecular and cellular biology.

[31]  R. Rhoads,et al.  Phosphorylation of Eukaryotic Protein Synthesis Initiation Factor 4E at Ser-209 (*) , 1995, The Journal of Biological Chemistry.

[32]  N. Sonenberg,et al.  PHAS-I as a link between mitogen-activated protein kinase and translation initiation. , 1994, Science.

[33]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[34]  R. Rhoads,et al.  Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF-4E: increased cap affinity of the phosphorylated form. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Dreyfuss,et al.  Cell cycle-regulated phosphorylation of the pre-mRNA-binding (heterogeneous nuclear ribonucleoprotein) C proteins. , 1993, Molecular and cellular biology.

[36]  C. Hagedorn,et al.  Novel phosphorylation sites of eukaryotic initiation factor-4F and evidence that phosphorylation stabilizes interactions of the p25 and p220 subunits. , 1993, The Journal of biological chemistry.

[37]  Brian A. Hemmings,et al.  The 55 kd regulatory subunit of Drosophila protein phosphatase 2A is required for anaphase , 1993, Cell.

[38]  Yazaki,et al.  Biphasic activation of two mitogen-activated protein kinases during the cell cycle in mammalian cells. , 1992, The Journal of biological chemistry.

[39]  T. Maniatis,et al.  Associations between distinct pre‐mRNA splicing components and the cell nucleus. , 1991, The EMBO journal.

[40]  G. Dreyfuss,et al.  Transcription-dependent and transcription-independent nuclear transport of hnRNP proteins. , 1991, Science.

[41]  N. Sonenberg,et al.  Phosphorylation of eukaryotic translation initiation factor 4E is increased in Src-transformed cell lines , 1991, Molecular and cellular biology.

[42]  R. Rhoads,et al.  Association of initiation factor eIF-4E in a cap binding protein complex (eIF-4F) is critical for and enhances phosphorylation by protein kinase C. , 1990, The Journal of biological chemistry.

[43]  N. Sonenberg,et al.  High-level synthesis in Escherichia coli of functional cap-binding eukaryotic initiation factor eIF-4E and affinity purification using a simplified cap-analog resin. , 1988, Gene.

[44]  E. Wimmer,et al.  A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation , 1988, Journal of virology.

[45]  N. Sonenberg,et al.  Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA , 1988, Nature.

[46]  N. Sonenberg,et al.  Involvement of the 24-kDa cap-binding protein in regulation of protein synthesis in mitosis. , 1987, The Journal of biological chemistry.

[47]  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.

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

[49]  N. Sonenberg,et al.  Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. , 1982, The Journal of biological chemistry.

[50]  H. Fan,et al.  Regulation of protein synthesis in mammalian cells. II. Inhibition of protein synthesis at the level of initiation during mitosis. , 1970, Journal of molecular biology.