Abstract
The 5' UTR of c -myc mRNA contains an internal ribo-some entry segment (IRES) and consequently, c -myc mRNAs can be translated by the alternative mechanism of internal ribosome entry. However, there is also some evidence suggesting that c -myc mRNA translation can occur via the conventional cap-dependent scanning mechanism. Using both bicistronic and monocistronic mRNAs containing the c- myc 5' UTR, we demonstrate that both mechanisms can contribute to c- myc protein synthesis. A wide range of cell types are capable of initiating translation of c- myc by internal ribosome entry, albeit with different efficiencies. Moreover, our data suggest that the spectrum of efficiencies observed in these cell types is likely to be due to variation in the cellular concentration of non-canonical translation factors. Interestingly, the c -myc IRES is 7-fold more active than the human rhinovirus 2 (HRV2) IRES and 5-fold more active than the encephalomyocarditis virus (EMCV) IRES. However, the protein requirements for the c -myc IRES must differ significantly from these viral IRESs, since an unidentified nuclear event appears to be a pre-requisite for efficient c -myc IRES-driven initiation.
Highlights
The proto-oncogene c-myc is required for both cell proliferation and programmed cell death, and de-regulated c-myc expression is associated with a wide range of cancers [1,2]
We demonstrate that the c-myc internal ribosome entry segment (IRES) is active in all cell lines of human origin tested, there is a wide variation in its efficiency, whereas the IRES is not active in cell lines of murine origin
We have investigated several features of the c-myc IRES and compared its activity in a range of cell lines and to IRESs of viral origin
Summary
The proto-oncogene c-myc is required for both cell proliferation and programmed cell death (apoptosis), and de-regulated c-myc expression is associated with a wide range of cancers [1,2]. It has been suggested that mRNAs with structured 5′ UTRs, such as c-myc, are poorly translated due to their reduced ability to associate with the cap-binding complex, the eukaryotic initiation factor 4F (eIF4F). Over-expression of the cap-binding protein eIF4E, which is believed to be a limiting component of this complex, causes an increase in the translation of mRNAs with structured 5′ UTRs such as c-myc [16,17,18]. Several eukaryotic mRNAs have the potential to initiate translation by an internal ribosome entry mechanism and interestingly many of the mammalian IRESs identified to date have been found in genes whose protein products are associated with the control of cell growth, e.g. c-myc, fibroblast growth factor –2 (FGF-2), platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). IRES depends on a prior nuclear event for efficient initiation of translation
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