Translation Initiation

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Cecile Julier - One of the best experts on this subject based on the ideXlab platform.

Nahum Sonenberg - One of the best experts on this subject based on the ideXlab platform.

  • control of paip1 eukayrotic Translation Initiation factor 3 interaction by amino acids through s6 kinase
    Molecular and Cellular Biology, 2014
    Co-Authors: Yvan Martineau, Tommy Alain, Xiaoshan Wang, Emmanuel Petroulakis, David Shahbazian, Bertrand Fabre, Mariepierre Bousquetdubouch, Bernard Monsarrat, Stephane Pyronnet, Nahum Sonenberg
    Abstract:

    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.

  • regulation of Translation Initiation in eukaryotes mechanisms and biological targets
    Cell, 2009
    Co-Authors: Nahum Sonenberg, Alan G. Hinnebusch
    Abstract:

    Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the Translation Initiation machinery and summarize key strategies that mediate general or gene-specific Translational control, particularly in mammalian systems.

  • metformin inhibits mammalian target of rapamycin dependent Translation Initiation in breast cancer cells
    Cancer Research, 2007
    Co-Authors: Ryan J O Dowling, Mahvash Zakikhani, George I Fantus, Michael Pollak, Nahum Sonenberg
    Abstract:

    Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits Translation Initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent Translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of Translation Initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in Translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on Translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of Translation. Furthermore, Translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2−/−) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in Translation Initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth. [Cancer Res 2007;67(22):10804–12]

  • mammalian poly a binding protein is a eukaryotic Translation Initiation factor which acts via multiple mechanisms
    Genes & Development, 2005
    Co-Authors: Avak Kahvejian, Yuri V Svitkin, Rami Sukarieh, Marienoel Mboutchou, Nahum Sonenberg
    Abstract:

    Translation Initiation is a multistep process involving several canonical Translation factors, which assemble at the 5'-end of the mRNA to promote the recruitment of the ribosome. Although the 3' poly(A) tail of eukaryotic mRNAs and its major bound protein, the poly(A)-binding protein (PABP), have been studied extensively, their mechanism of action in Translation is not well understood and is confounded by differences between in vivo and in vitro systems. Here, we provide direct evidence for the involvement of PABP in key steps of the Translation Initiation pathway. Using a new technique to deplete PABP from mammalian cell extracts, we show that extracts lacking PABP exhibit dramatically reduced rates of Translation, reduced efficiency of 48S and 80S ribosome Initiation complex formation, and impaired interaction of eIF4E with the mRNA cap structure. Supplementing PABP-depleted extracts with wild-type PABP completely rectified these deficiencies, whereas a mutant of PABP, M161A, which is incapable of interacting with eIF4G, failed to restore Translation. In addition, a stronger inhibition (approximately twofold) of 80S as compared to 48S ribosome complex formation (approximately 65% vs. approximately 35%, respectively) by PABP depletion suggests that PABP plays a direct role in 60S subunit joining. PABP can thus be considered a canonical Translation Initiation factor, integral to Initiation complex formation at the 5'-end of mRNA.

  • Eukaryotic Translation Initiation factors and regulators
    Current opinion in structural biology, 2003
    Co-Authors: Nahum Sonenberg, Thomas E. Dever
    Abstract:

    Significant progress has been made over the past several years on structural studies of the eukaryotic Translation Initiation factors that facilitate the assembly of a Translation-competent ribosome at the Initiation codon of an mRNA. These structural studies have revealed the repeated use of a set of common structural folds, highlighted the evolutionary conservation of the Translation apparatus, and provided insight into the mechanism and regulation of cellular and viral protein synthesis.

Marc Delepine - One of the best experts on this subject based on the ideXlab platform.

Marc Nicolino - One of the best experts on this subject based on the ideXlab platform.

Timothy Barrett - One of the best experts on this subject based on the ideXlab platform.

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