Abstract
Translation initiation plays a critical role in the regulation of gene expression for development and disease conditions. During the processes of development and disease, cells select specific mRNAs to be translated by controlling the use of diverse translation initiation mechanisms. Cells often switch translation initiation from a cap-dependent to a cap-independent mechanism during epithelial-to-mesenchymal transition (EMT), a process that plays an important role in both development and disease. EMT is involved in tumor metastasis because it leads to cancer cell migration and invasion, and is also associated with chemoresistance. In this review we will provide an overview of both the internal ribosome entry site (IRES)-dependent and N6-methyladenosine (m6A)-mediated translation initiation mechanisms and discuss how cap-independent translation enables cells from primary epithelial tumors to achieve a motile mesenchymal-like phenotype, which in turn drives tumor metastasis.
Highlights
Protein synthesis is a complex, energy consuming biosynthetic process that comprises three different steps: initiation, elongation and termination [1,2,3,4]
It is well-accepted that the cap-dependent translation initiation mechanism is the primary means of protein synthesis under normal growth condition for eukaryotes, and this has been extensively reviewed elsewhere [2,3,4]; cap-dependent translation is inhibited during cellular stress, angiogenesis, neurodegenerative disease, viral infection, and epithelial-to-mesenchymal transition (EMT) that occurs during development and metastasis [5,6,19,62]
We have found that in addition to inducing EMT, a reduction in eIF3e expression causes a repression in global cap-dependent translation while simultaneously favoring the cap-independent translation of mRNAs that rely on alternative translation initiation mechanisms, which are similar to the observations of Chiluiza et al for the effects of a mutant form of eIF3e [100]
Summary
Protein synthesis is a complex, energy consuming biosynthetic process that comprises three different steps: initiation, elongation and termination [1,2,3,4]. A group of transcription factors (Snail, Snail2/Slug, Twist, and Zeb1/2) that simultaneously induce the expression of genes required for mesenchymal properties and repress the expression of genes that are required for the epithelial phenotype are a key factor in the regulation of EMT [29] The expression of these EMT-regulating transcription factors can in turn be controlled at the transcriptional level by proteins such as NF-kB and both HIF-1α and HIF-2α [30,31], at the post-transcriptional level by microRNAs (miR-200 family; [32,33]), and at the post-translational level by proteasomal degradation [34]. We will briefly describe the different mechanisms of cap-independent translation initiation and discuss their role for the regulation of EMT in cancer
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