The Role of Translation Initiation Regulation in Haematopoiesis

Figure 2

Translation initiation control during growth factor stimulation, cellular stress, and cellular physiology. Growth factor addition activates the PI3K/PKB/mTOR pathway releasing the limiting translation initiation factor 4E (eIF4E) from a repression complex with 4EBP and activating S6K resulting in enhanced cap-dependent translation efficiency of structured mRNAs and ribogenesis. Interestingly, the tumour suppressor proteins PTEN, Tsc1/2, and Pp2a are involved in attenuating this pathway. Another limiting initiation factor, eIF2α, is involved in providing methionine-tRNA in a complex with the 60S ribosome subunit to start peptide synthesis once the proper AUG is recognised. eIF2 is phosphorylated by GCN2, PEK, HRI, or PRK in response to various stress conditions. Low levels of eIF4E and eIF2-GTP as a result of 4EBP repression or stress-induced eIF2 phosphorylation, respectively, repress cap-dependent translation. These conditions are optimal for translation initiation from Internal Ribosomal Entry Sites (IRESs). The levels of eIFs modulate translation initiation and this depends on the codes offered by the transcripts. Some transcripts are ideal to be translated under stress conditions having IRES structures in their 5′UTRs; others have secondary structures that are difficult to melt and hence hinder the scanning process. The presence of uORFs, attenuates translation initiation and also has a role in protein isoform formation. RNA-binding proteins modulate specific mRNAs by stabilising, silencing, or activating the transcripts. These RNA/protein complexes (RNPs) have an important role in cellular physiology. Some RNPs respond to oncogenic signals, while others are covalently modified and drive translation in response to terminal differentiation signals as in the case of the DICE elements (translation initiation factors in bold).