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      IRES-mediated translation of cellular messenger RNA operates in eIF2α- independent manner during stress

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      1 , 1 , 2 , *
      Nucleic Acids Research
      Oxford University Press

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          Abstract

          Physiological and pathophysiological stress attenuates global translation via phosphorylation of eIF2α. This in turn leads to the reprogramming of gene expression that is required for adaptive stress response. One class of cellular messenger RNAs whose translation was reported to be insensitive to eIF2α phosphorylation-mediated repression of translation is that harboring an Internal Ribosome Entry Site (IRES). IRES-mediated translation of several apoptosis-regulating genes increases in response to hypoxia, serum deprivation or gamma irradiation and promotes tumor cell survival and chemoresistance. However, the molecular mechanism that allows IRES-mediated translation to continue in an eIF2α-independent manner is not known. Here we have used the X-chromosome linked Inhibitor of Apoptosis, XIAP, IRES to address this question. Using toeprinting assay, western blot analysis and polysomal profiling we show that the XIAP IRES supports cap-independent translation when eIF2α is phosphorylated both in vitro and in vivo. During normal growth condition eIF2α-dependent translation on the IRES is preferred. However, IRES-mediated translation switches to eIF5B-dependent mode when eIF2α is phosphorylated as a consequence of cellular stress.

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          Most cited references43

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          Translational control in cancer.

          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.
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            Molecular mechanisms of translational control

            Key Points Translational regulation can be global or mRNA specific, and most examples of translational regulation that have been described so far affect the rate-limiting initiation step. Global control of translation is frequently exerted by regulating the phosphorylation or availability of initiation factors. Two of the most well-known examples are the regulation of eukaryotic initiation factor (eIF)4E availability by 4E-binding proteins (4E-BPs), and the modulation of the levels of active ternary complex by eIF2α phosphorylation. mRNA-specific translational control is driven by RNA sequences and/or structures that are commonly located in the untranslated regions of the transcript. These features are usually recognized by regulatory proteins or micro RNAs (miRNAs). Quasi-circularization of mRNAs can be mediated by the cap structure and the poly(A) tail via the eIF4E–eIF4G–polyA-binding-protein (PABP) interaction. Such interactions between the 5′ and the 3′ ends of mRNAs could provide a spatial framework for the action of regulatory factors that bind to the 3′ untranslated region (UTR). However, other forms of 5′–3′-end interactions are likely to occur as well. Many regulatory proteins target the stable association of the small ribosomal subunit with the mRNA. These factors function by steric hindrance (for example, iron-regulatory protein; IRP), by interfering with the eIF4F complex (for example, Maskin, Bicoid, Cup) or by as-yet-unknown, distinct mechanisms to control translation initiation (sex-lethal; SXL). Other regulatory molecules modulate the joining of the large ribosomal subunit (hnRNP K and E1) or, potentially, post-initiation translation steps (miRNAs). General translation factors can regulate the expression of specific mRNAs. An illustrative example is the stimulation of translation of the mRNA that encodes the GCN4 transcriptional activator by eIF2α phosphorylation.
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              Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita.

              The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1(m) mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1(m) ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.
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                Author and article information

                Journal
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                January 2012
                January 2012
                14 September 2011
                14 September 2011
                : 40
                : 2
                : 541-552
                Affiliations
                1Apoptosis Research Centre, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, K1H 8L1 and 2Department of Pediatrics, University of Ottawa, 451 Smyth Rd, Ottawa, K1H 8M5, Canada
                Author notes
                *To whom correspondence should be addressed. Tel: 1 613 738 3207; Fax: 1 613 738 4833; Email: martin@ 123456arc.cheo.ca
                Article
                gkr701
                10.1093/nar/gkr701
                3258125
                21917851
                edeb6bd2-e712-4d7a-9cc8-b81dc6815f4d
                © The Author(s) 2011. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 April 2011
                : 11 August 2011
                : 12 August 2011
                Page count
                Pages: 12
                Categories
                Gene Regulation, Chromatin and Epigenetics

                Genetics
                Genetics

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