Remarkable progress has been made in defining a new understanding of the role of mRNA translation and protein synthesis in human cancer. Translational control is a crucial component of cancer development and progression, directing both global control of protein synthesis and selective translation of specific mRNAs that promote tumour cell survival, angiogenesis, transformation, invasion and metastasis. Translational control of cancer is multifaceted, involving alterations in translation factor levels and activities unique to different types of cancers, disease stages and the tumour microenvironment. Several clinical efforts are underway to target specific components of the translation apparatus or unique mRNA translation elements for cancer therapeutics.
Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential. In IBC, E-cadherin is overexpressed and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer.
As a step toward developing poliovirus as a vaccine vector, poliovirus recombinants were constructed by fusing exogenous peptides (up to 400 amino acids) and an artificial cleavage site for viral protease 3Cpro to the amino terminus of the viral polyprotein. Viral replication proceeded normally. An extended polyprotein was produced in infected cells and proteolytically processed into the complete array of viral proteins plus the foreign peptide, which was excluded from mature virions. The recombinants retained exogenous sequences through successive rounds of replication in culture and in vivo. Infection of animals with recombinants elicited a humoral immune response to the foreign peptides.
The poly(rC)-binding proteins (PCBP1 and PCBP2) are RNA-binding proteins whose RNA recognition motifs are composed of three K homology (KH) domains. These proteins are involved in both the stabilization and translational regulation of several cellular and viral RNAs. PCBP1 and PCBP2 specifically interact with both the 5-element known as the cloverleaf structure and the large stem-loop IV RNA of the poliovirus 5-untranslated region. We have found that the first KH domain of PCBP2 (KH1) specifically interacts with the viral RNAs, and together with viral protein 3CD, KH1 forms a high affinity ternary ribonucleoprotein complex with the cloverleaf RNA, resembling the full-length PCBP protein. Furthermore, KH1 acts as a dominant-negative mutant to inhibit translation from a poliovirus reporter gene in both Xenopus laevis oocytes and HeLa cell in vitro translation extracts.Translation in eukaryotic cells is a highly regulated process involving a complex protein machinery. There is increasing evidence that translation of several mRNAs is determined by the specific and regulated interaction of certain proteins with RNA elements in the 3Ј-and 5Ј-untranslated regions (for reviews, see Refs. 1 and 2). Although many of these cis-acting RNA elements have been defined, only a few trans-acting regulatory proteins are known, and the mechanisms by which they regulate translation are poorly understood.As with cellular messages, translation of viral RNA is also subjected to complex regulation. For example, for positive strand RNA viruses, the genomic RNA is utilized as a template for translation, RNA replication, and formation of new virions; hence, the usage of the RNA must be regulated. For poliovirus, this regulation seems to be dependent on signals within the 5Ј-UTR.1 Whereas the majority of cellular mRNAs depend on the 5Ј-cap structure to initiate translation, poliovirus initiates translation internally via a cap-independent mechanism from an RNA element termed the internal ribosomal entry site (IRES) located within the 5Ј-UTR. Computer modeling and biochemical analysis suggest that the secondary structure of the poliovirus 5Ј-UTR is composed of six distinct domains, stem-loops I-VI (see Fig. 1A). In addition to the canonical initiation factors, poliovirus translation initiation requires additional host cell factors, some of which appear to interact directly with the viral RNA (reviewed in Refs. 3 and 4). Among these essential factors are PCBP1 and PCBP2, two closely related poly(rC)-binding proteins, (also referred to as hnRNPs E1 and 2 or ␣CP1 and ␣CP2). These proteins facilitate viral translation through the interaction with both the first stemloop domain (which folds into a cloverleaf-like structure) and stem-loop IV of the poliovirus 5Ј-UTR (5-8). Both PCBP1 and PCBP2 form a low affinity complex with the cloverleaf RNA, but together with viral protein 3CD (the precursor of the viral polymerase 3D and the viral protease 3C), they are incorporated into a high affinity ternary ribonucleoprotein complex (9, 10). Ternary compl...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.