, 2009) A number of regulatory mechanisms modulate translation a

, 2009). A number of regulatory mechanisms modulate translation at the level

of translation initiation (Sonenberg Selleck GSK3 inhibitor and Hinnebusch, 2009). Two critical steps in translation initiation are the binding of the cap-binding protein complex with the 5′ end cap structure of mRNAs (m7GpppN), which is responsible for unwinding the secondary structure of mRNAs 5′UTR (untranslated region), and the formation of the ternary complex, which mediates the binding of Met-tRNAiMet to the 40S ribosomal subunit (Sonenberg and Hinnebusch, 2009). The eukaryotic initiation factors eIF4E and eIF2α are important components of the cap-binding protein complex and the ternary complex, respectively. Both of these initiation factors are tightly regulated through a host of molecular interactions in cells (Sonenberg and Hinnebusch, 2009). An important

level of regulation of cap-dependent translation is mediated by the target of rapamycin (TOR). This evolutionary conserved kinase plays a central role in linking many cellular and environmental cues to cell metabolism, growth, and proliferation in all eukaryotes (Ma and Blenis, 2009). Accumulating evidence suggests that TOR activity can also specifically influence synaptic growth, function, and plasticity CHIR-99021 datasheet in postmitotic neurons and during disease (Buckmaster et al., 2009, Ehninger et al., 2008, Hoeffer and Klann, 2010, Sharma et al., 2010, Swiech et al., 2008 and Tang et al., 2002). TOR activity promotes cap-dependent translation primarily through phosphorylation of 4E-BPs (eIF4E binding proteins) and p70 S6Ks (S6 ribosomal protein kinases) (Ma however and Blenis, 2009). Mammalian genomes encode three 4E-BP and two S6k genes, while Drosophila possess only one of each. Phosphorylation of 4E-BP suppresses its ability to bind to and inhibit eIF4E, thus enhancing the interaction of the cap-binding protein complex with the mRNA 5′ cap ( Sonenberg and Hinnebusch, 2009). In parallel, TOR phosphorylation

of S6K activates its ability to phosphorylate a number of downstream targets. S6K is best known for phosphorylation of ribosomal protein S6 and promoting the translation of a group of mRNAs that have an oligopyrimidine tract at their transcriptional start (5′TOP mRNAs), which encode important components of the translational machinery ( Jefferies et al., 1997 and Ma and Blenis, 2009). In addition, S6K activity promotes the helicase function of the cap-binding complex by enhancing the action of initiation factor eIF4A. S6K phosphorylates and inhibits PDCD4 (programmed cell death protein 4), a negative regulator of eIF4A, and directly phosphorylates eIF4B, a positive regulator of eIF4A ( Dorrello et al., 2006, Gingras et al., 2001, Holz et al., 2005 and Shahbazian et al., 2010).

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