Targeting the translational machinery as a novel treatment strategy for hematologic malignancies

Abstract

IntroductionEukaryotic cells have various mechanisms and levels by which gene expression can be regulated including: transcription, export of mRNA messages, mRNA stability, and posttranslational modifications. Protein synthesis is essential for cell viability, and controlling mRNA translation is a critical step in regulation of gene expression. Translation can be divided between 3 stages: initiation, elongation, and termination. Translational control is principally exerted by regulating the formation of the cap-dependent translation initiation complex. Translation initiation comprises a mechanism in which the eIF4F ternary complex (eIF4E, eIF4A, and eIF4G) recruits a 43S preinitiation complex containing a Met-tRNAi and multiple initiation factors (eIFs 1, 1A, 2, 3, and 5) to the 5Ј methyl-7-GTP cap complex on mRNA (reviewed in Sonenberg and Hinnebusch). 1 Once the preinitiation complex scans the 5Ј untranslated region of the mRNA and reaches the AUG start codon, the large (60S) ribosomal subunit joins the small (40S) ribosomal subunit and begins to synthesize the protein. 1 Deregulated protein synthesis plays an important role in human cancer and deregulated translational control has been recognized as an integral part of the malignant state. 2,3 In the past several years it has become clear that the efficiency of expression of key proteins involved in cell-growth regulation, proliferation, and apoptosis may be controlled at the translational level by changes in the activity of components of the protein synthesis machinery. 4,5 Various classes of mRNAs differ considerably in their translational efficiency. Typically, mRNAs coding for proteins positively involved in regulating cell growth and survival have a high degree of secondary structure in the 5Ј untranslated region (UTR). The translation of such messages is particularly sensitive to the activity of the cap-dependent translation-initiation machinery. 6 In view of the fact that translation factors are closely regulated by conditions that affect cell growth, it is not surprising that, experimentally, aberrant expression of some of these factors has been shown to induce malignant transformation of cells.Translation initiation has recently been shown to be a common downstream target of signal transduction pathways deregulated in cancer and initiated by mutated/overexpressed oncogenes and tumor suppressors. 7 Several previous publications indicate that aberrant control of protein synthesis contributes to lymphomagenesis 3,8 opening up possibilities for innovative therapeutics, that is, targeting the translational machinery. Below, we present an overview of potentially targetable translational machinery components and regulatory signaling pathways that represent a novel approach for the treatment of hematologic malignancies. eIF4FA major regulatory step in control of protein synthesis is translation initiation. Translation initiation is modulated by the association of a ternary complex of proteins, eukaryotic translation initiation factor F (eIF4F), composed of e...

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