The Role of Translation Initiation Regulation in Haematopoiesis

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.