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Nahum Sonenberg - One of the best experts on this subject based on the ideXlab platform.
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control of paip1 eukayrotic translation Initiation Factor 3 interaction by amino acids through s6 kinase
Molecular and Cellular Biology, 2014Co-Authors: Yvan Martineau, Tommy Alain, Xiaoshan Wang, Emmanuel Petroulakis, David Shahbazian, Bertrand Fabre, Mariepierre Bousquetdubouch, Bernard Monsarrat, Stephane Pyronnet, Nahum SonenbergAbstract:The simultaneous interaction of poly(A)-binding protein (PABP) with eukaryotic translation Initiation Factor 4G (eIF4G) and the mRNA 3' poly(A) tail promotes translation Initiation. We previously showed that the interaction of PABP-interacting protein 1 (Paip1) with PABP and eukaryotic translation Initiation Factor 3 (eIF3; via the eIF3g subunit) further stimulates translation. Here, we demonstrate that the interaction of eIF3 with Paip1 is regulated by amino acids through the mTORC1 signaling pathway. The Paip1-eIF3 interaction is impaired by the mTORC1 inhibitors, rapamycin and PP242. We show that ribosomal protein S6 kinases 1 and 2 (S6K1/2) promote the interaction of eIF3 with Paip1. The enhancement of Paip1-eIF3 interaction by amino acids is abrogated by an S6K inhibitor or shRNA against S6K1/2. S6K1 interacts with eIF3f and, in vitro, phosphorylates eIF3. Finally, we show that S6K inhibition leads to a reduction in translation by Paip1. We propose that S6K1/2 phosphorylate eIF3 to stimulate Paip1-eIF3 interaction and consequent translation Initiation. Taken together, these data demonstrate that eIF3 is a new translation target of the mTOR/S6K pathway.
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Control of cell survival and proliferation by mammalian eukaryotic Initiation Factor 4B.
Molecular and cellular biology, 2010Co-Authors: David Shahbazian, Yvan Martineau, Emmanuel Petroulakis, Armen Parsyan, Ivan Topisirovic, Bernard F. Gibbs, Yuri V. Svitkin, Nahum SonenbergAbstract:Translation Initiation plays an important role in cell growth, proliferation, and survival. The translation Initiation Factor eIF4B (eukaryotic Initiation Factor 4B) stimulates the RNA helicase activity of eIF4A in unwinding secondary structures in the 5′ untranslated region (5′UTR) of the mRNA in vitro. Here, we studied the effects of eIF4B depletion in cells using RNA interference (RNAi). In agreement with the role of eIF4B in translation Initiation, its depletion resulted in inhibition of this step. Selective reduction of translation was observed for mRNAs harboring strong to moderate secondary structures in their 5′UTRs. These mRNAs encode proteins, which function in cell proliferation (Cdc25C, c-myc, and ODC [ornithine decarboxylase]) and survival (Bcl-2 and XIAP [X-linked inhibitor of apoptosis]). Furthermore, eIF4B silencing led to decreased proliferation rates, promoted caspase-dependent apoptosis, and further sensitized cells to camptothecin-induced cell death. These results demonstrate that eIF4B is required for cell proliferation and survival by regulating the translation of proliferative and prosurvival mRNAs.
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a novel functional human eukaryotic translation Initiation Factor 4g
Molecular and Cellular Biology, 1998Co-Authors: Alessandra Gradi, Yuri V. Svitkin, Hiroaki Imataka, Eran Rom, Brian Raught, Shigenobu Morino, Nahum SonenbergAbstract:Mammalian eukaryotic translation Initiation Factor 4F (eIF4F) is a cap-binding protein complex consisting of three subunits: eIF4E, eIF4A, and eIF4G. In yeast and plants, two related eIF4G species are encoded by two different genes. To date, however, only one functional eIF4G polypeptide, referred to here as eIF4GI, has been identified in mammals. Here we describe the discovery and functional characterization of a closely related homolog, referred to as eIF4GII. eIF4GI and eIF4GII share 46% identity at the amino acid level and possess an overall similarity of 56%. The homology is particularly high in certain regions of the central and carboxy portions, while the amino-terminal regions are more divergent. Far-Western analysis and coimmunoprecipitation experiments were used to demonstrate that eIF4GII directly interacts with eIF4E, eIF4A, and eIF3. eIF4GII, like eIF4GI, is also cleaved upon picornavirus infection. eIF4GII restores cap-dependent translation in a reticulocyte lysate which had been pretreated with rhinovirus 2A to cleave endogenous eIF4G. Finally, eIF4GII exists as a complex with eIF4E in HeLa cells, because eIF4GII and eIF4E can be purified together by cap affinity chromatography. Taken together, our findings indicate that eIF4GII is a functional homolog of eIF4GI. These results may have important implications for the understanding of the mechanism of shutoff of host protein synthesis following picornavirus infection.
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elevated levels of cyclin d1 protein in response to increased expression of eukaryotic Initiation Factor 4e
Molecular and Cellular Biology, 1993Co-Authors: Igor B Rosenwald, A Lazariskaratzas, Nahum Sonenberg, Emmett V SchmidtAbstract:Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic Initiation Factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic Initiation Factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.
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A fraction of the mRNA 5' cap-binding protein, eukaryotic Initiation Factor 4E, localizes to the nucleus.
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Flavio Lejbkowicz, Charles Goyer, Andre Darveau, Sonia Neron, Real Lemieux, Nahum SonenbergAbstract:The 5' cap structure m7GpppN (where N is any nucleotide) is a ubiquitous feature of cellular eukaryotic mRNAs. The cap is multifunctional as it is involved in translation, nucleocytoplasmic transport, splicing, and stabilization of mRNA against 5' exonucleolytic degradation. The cap binding protein, eukaryotic Initiation Factor 4E (eIF-4E), is a translation Initiation Factor that binds to the cap structure and is part of a complex (eIF-4F) that promotes mRNA binding to ribosomes. Overexpression of eIF-4E in fibroblasts results in cell transformation. To test the hypothesis that some of the biological effects of eIF-4E might be effected by a nuclear function, we determined the cellular distribution of eIF-4E. By means of indirect immunofluorescence experiments using polyclonal and monoclonal antibodies against eIF-4E as well as transfected epitope-tagged eIF-4E, we demonstrate that a fraction of eIF-4E localizes to the nucleus. These results suggest that eIF-4E is also involved in a nuclear function.
Cecile Julier - One of the best experts on this subject based on the ideXlab platform.
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eif2ak3 encoding translation Initiation Factor 2 α kinase 3 is mutated in patients with wolcott rallison syndrome
Nature Genetics, 2000Co-Authors: Marc Delepine, Marc Nicolino, M Golamaully, Cecile Julier, G. Mark Lathrop, Timothy BarrettAbstract:EIF2AK3 , encoding translation Initiation Factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome
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eif2ak3 encoding translation Initiation Factor 2 α kinase 3 is mutated in patients with wolcott rallison syndrome
Nature Genetics, 2000Co-Authors: Marc Delepine, Marc Nicolino, M Golamaully, Cecile Julier, G. Mark Lathrop, Timothy BarrettAbstract:EIF2AK3 , encoding translation Initiation Factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome
Igor B Rosenwald - One of the best experts on this subject based on the ideXlab platform.
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upregulation of protein synthesis Initiation Factor eif 4e is an early event during colon carcinogenesis
Oncogene, 1999Co-Authors: Igor B Rosenwald, Janejane Chen, Louis Savas, Irving M London, Songtao Wang, James M PullmanAbstract:Upregulation of protein synthesis Initiation Factor eIF-4E is an early event during colon carcinogenesis
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elevated levels of cyclin d1 protein in response to increased expression of eukaryotic Initiation Factor 4e
Molecular and Cellular Biology, 1993Co-Authors: Igor B Rosenwald, A Lazariskaratzas, Nahum Sonenberg, Emmett V SchmidtAbstract:Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic Initiation Factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic Initiation Factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.
Augusto Ducati Luchessi - One of the best experts on this subject based on the ideXlab platform.
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Characterization of eukaryotic translation Initiation Factor 5A isoform A (752.13)
The FASEB Journal, 2014Co-Authors: Leticia Tamborlin, Karina Pereira, Isadora Almeida, Letícia Meneguello, Tavane D. Cambiaghi, Augusto Ducati LuchessiAbstract:The eukaryotic translation Initiation Factor 5A (EIF5A) protein is highly conserved in eukaryotes. Some studies shown that eIF5A has important roles in cell proliferation control and HIV-1 replicat...
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Inhibition of eukaryotic translation Initiation Factor 5A (eIF5A) hypusination impairs melanoma growth
Cell biochemistry and function, 2006Co-Authors: Miriam Galvonas Jasiulionis, Augusto Ducati Luchessi, Andreia G. Moreira, Pedro P. C. Souza, Ana Paula M. Suenaga, Mariangela Correa, Carlos Alberto De Souza Costa, Rui Curi, Claudio M. Costa-netoAbstract:The eukaryotic translation Initiation Factor 5A (eIF5A) undergoes a specific post-translational modification called hypusination. This modification is required for the functionality of this protein. The compound N1-guanyl-1,7-diaminoheptane (GC7) is a potent and selective inhibitor of deoxyhypusine synthase, which catalyses the first step of eIF5A hypusination process. In the present study, the effects of GC7 on cell death were investigated using two cell lines: melan-a murine melanocytes and Tm5 murine melanoma. In vitro treatment with GC7 increased by 3-fold the number of cells presenting DNA fragmentation in Tm5 cells. Exposure to GC7 also decreased viability to both cell lines. This study also describes, for the first time, the in vivo antitumour effect of GC7, as indicated by impaired melanoma growth in C57BL/6 mice.
J Averous - One of the best experts on this subject based on the ideXlab platform.
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regulation of cyclin d1 expression by mtorc1 signaling requires eukaryotic Initiation Factor 4e binding protein 1
Oncogene, 2008Co-Authors: J Averous, Bruno D Fonseca, Christopher G ProudAbstract:Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic Initiation Factor 4E-binding protein 1