Initiation Factor eIF2-independent Mode of c-Src mRNA Translation Occurs via an Internal Ribosome Entry Site

Allam, Hisham; Ali, Naushad

doi:10.1074/jbc.m109.029462

Cited by 28 publications

(44 citation statements)

References 63 publications

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“…Here, I consider the evidence that cellular IRESs rely on the formation of defined RNA structures that functionally substitute for one or more translation factors to recruit ribosomes. Mammalian c-src is a good candidate for a dedicated cellular IRES gene, as addition of an m 7 G-cap does not stimulate translation of mRNA containing the c-Src 5Ј-UTR (24). This observation is also consistent with the hypothesis that the c-Src 5Ј-UTR is extensively folded, as predicted in silico.…”

Section: Role Of Rna Tertiary Structure In Cellular Ires Activity: Issupporting

confidence: 76%

“…The 5Ј-UTR of mammalian c-src contains a potent IRES, having Ͼ80% of the activity of the poliovirus IRES in in vitro translation assays and Ͼ100% of the activity of the HCV IRES in in vivo RNA transfection experiments. In a bicistronic m 7 G-Renilla-IRES-firefly reporter mRNA, translation initiation by the c-src IRES produced a firefly/Renilla ratio of Ͼ1 (24).…”

Section: Cellular Iress Weak and Strongmentioning

confidence: 99%

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Alternative Ways to Think about Cellular Internal Ribosome Entry

Gilbert

2010

Journal of Biological Chemistry

108

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Internal ribosome entry sites (IRESs) are specialized mRNA elements that allow recruitment of eukaryotic ribosomes to naturally uncapped mRNAs or to capped mRNAs under conditions in which cap-dependent translation is inhibited. Putative cellular IRESs have been proposed to play crucial roles in stress responses, development, apoptosis, cell cycle control, and neuronal function. However, most of the evidence for cellular IRES activity rests on bicistronic reporter assays, the reliability of which has been questioned. Here, the mechanisms underlying cap-independent translation of cellular mRNAs and the contributions of such translation to cellular protein synthesis are discussed. I suggest that the division of cellular mRNAs into mutually exclusive categories of "cap-dependent" and "IRESdependent" should be reconsidered and that the implications of cellular IRES activity need to be incorporated into our models of cap-dependent initiation.Eukaryotic mRNAs are modified by the addition of an m 7 GpppN cap structure to their 5Ј-ends. The m 7 G cap is thought to stimulate translation of most mRNAs by enhancing binding of a 43 S preinitiation complex (containing 40 S ribosomal subunits, methionine initiator tRNA, and initiation factors eIF2 and eIF3) to 5Ј-UTRs of mRNAs through recognition of the m 7 G cap by a complex of the cap-binding protein, eIF4E; a large scaffold protein, eIF4G; and an ATP-dependent RNA helicase, eIF4A. Subsequent movement of the 43 S complex in a 5Ј-to 3Ј-direction (scanning) locates the initiating AUG through recognition by the anticodon of the initiator tRNA. The discovery that naturally uncapped picornaviral mRNAs can efficiently recruit the host cell translation machinery via internal ribosome entry sites (IRESs) 2 raised the possibility that certain cellular mRNAs might have a similar capability (1, 2).The cellular IRES hypothesis offered an attractive solution to two problems. First, a number of cellular stress responses involve inhibition of one or more general translation initiation factors, yet the adaptive responses to stress require new protein synthesis. Cellular IRES elements could allow mRNAs encoding key regulatory proteins to escape the general inhibition of translation. The observation that some cellular mRNAs continue to be translated in poliovirus-infected cells after the inhibition of cap-dependent initiation (through cleavage of eIF4G by a virally encoded protease) is consistent with this hypothesis (3). Second, the existence of cellular IRESs could explain how mRNAs with very long 5Ј-UTRs or containing numerous predicted stem-loop structures or upstream AUG codons within their 5Ј-UTRs could be translated with reasonable efficiency, despite evidence that such features can significantly reduce translation of model mRNAs (4 -6).Both arguments in favor of the cellular IRES hypothesis rest on certain assumptions about the predominant mechanism of cap-and scanning-dependent initiation that this minireview will re-examine in light of recent publications that (i) demonstrate that l...

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Section: Role Of Rna Tertiary Structure In Cellular Ires Activity: Issupporting

confidence: 76%

Section: Cellular Iress Weak and Strongmentioning

confidence: 99%

Alternative Ways to Think about Cellular Internal Ribosome Entry

Gilbert

2010

Journal of Biological Chemistry

108

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“…In some cases, an IRES is a special mRNA motif that can form a typical clover leaf-like structure with a length of 150-250 bp [4,31,32]. Therefore, we employed the bioinformatics tools RNAdraw and RNA fold (http://rna.…”

Section: Adar1-301-600 Exhibits Necessary Core Ires-like Activitymentioning

confidence: 99%

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Yang

Lin

et al. 2015

Cell. Mol. Life Sci.

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Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

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“…16,24,38 In addition to their of direct binding to 40S ribosomal subunits was reported for the c-Src kinase mRNA. 47 This feature of the c-Src kinase IRES element makes it similar to hepatitis C virus-like IRESs. 48 However, it is currently unclear how many other cellular elements utilize the same pathway.…”

Section: The Role Of Itafs In Cellular Ires-mediated Translationmentioning

confidence: 99%