Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression

Abstract

Initiation of translation in eukaryotic cells can occur by two distinct mechanisms, cap-dependent scanning and internal ribosome entry. The latter mechanism requires the formation of a complex RNA structural element termed an internal ribosome entry segment (IRES). IRESs are located in the 5 0 untranslated region of the message, and in the presence of trans-acting factors allow the ribosome to be recruited to a site that is a considerable distance from the cap structure. Many cellular mRNAs have now been shown to contain IRESs and it is likely that up to 10% of all mRNAs have the capability to initiate translation by this mechanism. The majority of IRESs that have been identified thus far are found in mRNAs whose protein products are associated with the control of cell growth and cell death, including many growth factors, proto-oncogenes and proteins required for apoptosis. In this review, we discuss the cellular situations when IRESs are required, the trans-acting factors that are necessary for IRES function and deregulation of IRES-mediated translation in tumorigenesis.

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

“…In addition to the more commonly occurring cap-dependent translation initiation in eucaryotes it has also become increasingly evident that translation initiation can occur through alternative mechanisms that do not involve the cap structure. Cap-independent translation is mediated by internal ribosome entry sites (IRES) (Jackson, 2000;Schneider, 2001;Stoneley and Willis, 2004). These are usually comprised of structured regions in the 5 0 untranslated region (UTR) and were initially identified in viruses (Pelletier and Sonenberg, 1988) but have since been reported in eucaryotic mRNAs and are believed to constitute a major form of regulation of protein synthesis in mammalian cells (Johannes and Sarnow, 1998).…”

Structure-function relationships of the polypyrimidine tract binding protein

“…In other words, with the help of RRMs 3 and 4, PTB can bring pyrimidine tracts to close proximity that may be fairly far apart within the primary sequence of the RNA. This capacity might also explain many of the other functions of PTB, like its role in IRES-mediated translation initiation [43,44,46,47]. The structure of the complex also explains how several pyrimidine-rich pentaloops could create a PTB binding site in an IRES [50] or the 3'UTR of certain viral RNAs [95,96], since all four RRMs bind only three to five pyrimidines each.…”

“…IRESs help recruiting the translation machinery to initiate translation. This recruitment often requires cellular factors binding the IRES (initiation of translation accessory factors, ITAFs) for efficient translation initiation [43,44,46,47]. PTB is one of the most frequently encountered ITAFs and was found to be implicated in IRES-mediated translation of several Figure 1.…”

“…The second most studied function of PTB is its role in internal ribosomal entry site (IRES)-mediated translation initiation of both cellular and viral mRNAs. IRESs are large RNA structures present in the 5'-untranslated regions (UTR) of some cellular mRNAs [43,44] and of many viral mRNAs [45] (Fig. 2).…”

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

“…For instance, ERK1/2 activation affects multiple translation initiation components including S6K, p90 RSK, MNK and 4E-BP1, among others (Roux and Blenis, 2004). Also, in addition to eIF4E-mediated cap-dependent initiation, there are internal ribosome entry sites present in several mRNAs important in RCC such as MYC, VEGF and Cyclin D1 (Stoneley and Willis, 2004;Shi et al, 2005), which may allow translation initiation in a cap-independent manner.…”