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. 2012:2012:576540.
doi: 10.1155/2012/576540. Epub 2012 May 9.

The role of translation initiation regulation in haematopoiesis

Godfrey Grech  1 , Marieke von Lindern
Affiliations

The role of translation initiation regulation in haematopoiesis

Godfrey Grech et al. Comp Funct Genomics. 2012.

Abstract

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

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Figures

Figure 1
Figure 1
The PI3K/PKB/mTOR pathway controls mRNA translation. SCF-receptor activation results in recruitment of PI3K to the receptor, which generates phosphorylates membrane lipids (PIP3) that form an anchor for the PH-domain containing kinases PDK1 and PKB. PIP3 is dephosphorylated by the tumour suppressor PTEN, which silences the PI3K-pathway. At the membrane PDK1 phosphorylates PKB, which phosphorylates the tuberous sclerosis tumour suppressor genes Tsc1 and Tsc2. Upon phosphorylation these genes release the GTPase Rheb to activate mTOR. Activation of mTOR results in phosphorylation of p70S6kinase (S6K) and eIF4E-binding protein (4E-BP). Upon phosphorylation, 4E-BP releases the cap-binding translation initiation factor 4E (eIF4E), which allows for association of eIF4E with the proteins that form the eIF4F scanning complex and with the 40S ribosomal subunit [4].
Figure 2
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).
Figure 3
Figure 3
Translation initiation control relays signals to erythroid and granulocytic differentiation. SCF binds c-kit, a Receptor Tyrosine Kinases (RTKs), activating PI3K/mTOR pathway in the same way as constitutive active mutant RTKs and kinase active fusion protein, BCR/ABL. mTOR downstream effector proteins are maintained active by attenuating the phosphatase Pp2a which is inhibited by SCF-driven alpha4 expression and enhanced expression of SET in response to BCR/ABL. High activity of translation initiation factors enhances polysome recruitment of structured mRNAs and delays erythroid terminal differentiation. During erythroid terminal differentiation the balance between globin synthesis and haeme biosynthesis is under the tight control of translation initiation. Iron Responsive Element (IRE) in the UTRs of ferritin and transferrin modulates iron uptake and storage in accordance to demand of haeme. Low cellular iron levels trigger phosphorylation of eIF2α to reduce the production of globin proteins. High eIFs levels also regulate commitment to the erythroid or megakaryocytic lineage by selective usage of AUGs in the SCL transcript driving different isoform production. The same mechanism is used to produce truncated isoforms of the transcription factor C/EBPα that acts as a dominant negative form of the full length and hence inhibits granulocytic terminal differentiation. Another form of translation control is involved in regulation of C/EBPα transcription activity. Full-length C/EBPα enhances transcription of micro RNA 223 (miRNA-223), an inhibitor of NFI-A translation. NFI-A is a competitor for binding C/EBPα DNA sites and hence its inhibition results in a positive feedback loop driving granulocytic differentiation. In addition to transcription inhibition of full-length C/EBPα driven by selective AUG usage or translation silencing of competitors, the role of RNA-binding proteins is important in modulating terminal differentiation. BCR/ABL enhances the expression of hnRNPE2 that binds the UTR of C/EBPα transcript and inhibits translation.
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