The PI3K-AKT-mTOR pathway, which is stimulated by insulin, has been identified to be essential for many cellular processes (reviewed in [37]). mTORC1 is a protein complex containing mTOR (mammalian target of rapamycin) and raptor. mTORC1 activates S6K1, a kinase that promotes protein synthesis and cell growth by phosphorylation of multiple substrates including components of translation initiation or elongation such as ribosomal protein S6, eIF4B and eukaryotic elongation factor 2 kinase [38]. One target of this pathway is eIF4B (Figure 4) (reviewed in [39]). It was suggested that phosphorylation of eIF4B by S6 kinases, which are regulated by mTOR, stimulates its function. Indeed, this phosphorylation event favors recruitment of eIF4B into complexes with eIF3, which promotes the recruitment of ribosomes to the 5end of the message (reviewed in [40]). eIF4B, which was up-regulated in our study, stimulates the RNA helicase activity of eIF4A in unwinding secondary structures in the 5-untranslated regions (5-UTR) of mRNAs [41, 42]. By knock-down of eIF4B, selective reduction of translation was observed for mRNAs harboring strong to moderate secondary structures in their 5-UTRs. These mRNAs code for proteins that function in cell proliferation (e.g. CDC25C, c-MYC) or cell survival (e.g. BCL-2). Silencing of eIF4B also leads to decreased proliferation rates and caspase-dependent apoptosis: eIF4B is required for cell proliferation and survival by regulating the translation of proliferative and prosurvival mRNAs [43]. PPARγ expression is stimulated in response to mTORC1 [44]. PPARγ is a key adipogenic factor and exogenous expression is sufficient to induce adipogenesis. Zhang et al., 2009 discuss the possibility that AKT and mTORC1 facilitate adipogenesis by up-regulation of PPARγ via regulation of FOXO1 [44]. However, they do not discuss the activation of eIF4B upon mTORC1 activation with subsequent changes in the preference of ribosomes for certain mRNAs. We think that regulation of C/EBPα could possibly be explained by up-regulation of eIF4b activity, as members of the C/EBP family are regulated at the translational level (Figure 4).
free ifit activation code
2ff7e9595c
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