Targets and mechanisms for the regulation of translation in malignant transformation

Abstract

There is increasing evidence that deregulation of gene expression at the level of mRNA translation can contribute to cell transformation and the malignant phenotype. Two steps in the pathway of polypeptide chain initiation, viz. the assembly of the 43S initiation complex catalysed by polypeptide chain initiation factor eIF2 and the binding of eIF4E to eIF4G during the recruitment of mRNA to the ribosome, have been shown to be likely targets for changes associated with tumorigenesis. The activity of eIF2 is controlled by changes in phosphorylation of the a subunit of this factor. The availability of eIF4E for binding to eIF4G is regulated by the phosphorylation of a small family of eIF4E-binding proteins (the 4E-BPs). The activities of the protein kinases and/or phosphatases responsible for the (de)phosphorylation of these substrates may in turn be controlled by cellular and viral oncogenes and tumour-suppressor genes. This review will describe recent aspects of the mechanisms involved, with particular emphasis on the regulation of the eIF2a kinase PKR and the control of 4E-BP phosphorylation by viral gene products, growthinhibitory cytokines and the tumour-suppressor protein p53.

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

“…Elevated levels of eIF4E result in inhibition of apoptosis (Clemens, 2004;Mamane et al, 2004), whereas overexpression of 4E-BP1 is proapoptotic (Li et al, 2002;Proud, 2005). It is therefore of interest that calyculin A is also antiapoptotic (Song and Lavin, 1993).…”

“…Likewise, the inactivation or loss of 4E-BP1 releases active eIF4E, which stimulates post-transcriptionally the expression of antiapoptotic or oncogenic proteins (Rosenwald et al, 1995;Rousseau et al, 1996; Hoover et al, 1997; Carter Nimmanapalli et al, 2003;Othumpangat et al, 2005b). Since the overactivity or overexpression of either NF-kB or eIF4E inhibits apoptosis and promotes malignant transformation (Topisirovic et al, 2003;Clemens, 2004;Ren et al, 2006), the eIF4E/4E-BP1 system and its regulatory mechanisms can be viewed as a translational parallel to the NF-kB/IkB system.…”

“…The initiation factor also exerts important effects on the nucleo-cytoplasmic transport of a number of mRNAs (Strudwick and Borden, 2002). Overexpression of eIF4E is associated with malignant transformation (De Benedetti and Graff, 2004), probably because the factor promotes the synthesis of antiapoptotic proteins (Clemens, 2004;Mamane et al, 2004), and many naturally occurring tumours contain elevated levels of eIF4E. Conversely, enhanced expression of 4E-BP1 can reverse the transformed phenotype and increase the susceptibility of cells to apoptosis (Li et al, 2002;Proud, 2005).…”

Eukaryotic initiation factor 6 selectively regulates Wnt signaling and β-catenin protein synthesis

“…For example, changes in the level and/or activity of eukaryotic initiation factors 2 and 4 (eIF2 and eIF4) are often associated with transformation, and the Wnt/b-catenin target gene myc regulates the synthesis of ribosomal RNAs (Clemens, 2004;Arabi et al, 2005). Although eIF6 was named because of its homology to translational initiation factors, it does not play a direct role in the initiation of protein translation (Si and Maitra, 1999).…”

The role of 5′ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma

“…These 5 0 UTRs regulate the aberrant expression of growth-related genes such as mouse double minute 2 (MDM2), transforming growth factor-b (TGFb) and B-cell leukemia/lymphoma 2 (Bcl-2), which contribute significantly to cell transformation (Willis, 1999;Dua et al, 2001;Clemens, 2004;Pickering and Willis, 2005).…”