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  • Oncogenomics
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p53 and little brother p53/47: linking IRES activities with protein functions

Abstract

The tumor suppressor p53 represents a paradigm for gene regulation. Its rapid induction in response to DNA damage conditions has been attributed to both increased half-life of p53 protein and also increased translation of p53 mRNA. Recent advances in our understanding of the post-transcriptional regulation of p53 include the discovery of internal ribosome entry sites (IRESs) within the p53 mRNA. These IRES elements regulate the translation of the full length as well as the N-terminally truncated isoform, p53/47. The p53/47 isoform is generated by alternative initiation at an internal AUG codon present within the p53 ORF. The aim of this review is to summarize the role of translational control mechanisms in regulating p53 functions. We discuss here in detail how diverse cellular stress pathways trigger alterations in the cap-dependent and cap-independent translation of p53 mRNA and how changes in the relative expression levels of p53 isoforms result in more differentiated p53 activity.

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References

  • Anensen N, Skavland J, Stapnes C, Ryningen A, Borresen-Dale AL, Gjertsen BT et al. (2006). Acute myelogenous leukemia in a patient with Li-Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: a case report. Leukemia 20: 734–736.

    Article  CAS  Google Scholar 

  • Baird SD, Turcotte M, Korneluk RG, Holcik M . (2006). Searching for IRES. RNA 12: 1755–1785.

    Article  CAS  Google Scholar 

  • Barak Y, Juven T, Haffner R, Oren M . (1993). mdm2 expression is induced by wild type p53 activity. EMBO J 12: 461–468.

    Article  CAS  Google Scholar 

  • Boldrup L, Bourdon JC, Coates PJ, Sjostrom B, Nylander K . (2007). Expression of p53 isoforms in squamous cell carcinoma of the head and neck. Eur J Cancer 43: 617–623.

    Article  CAS  Google Scholar 

  • Bourdon JC . (2007). p53 and its isoforms in cancer. Br J Cancer 97: 277–282.

    Article  CAS  Google Scholar 

  • Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP et al. (2005). p53 isoforms can regulate p53 transcriptional activity. Genes Dev 19: 2122–2137.

    Article  CAS  Google Scholar 

  • Bushell M, Stoneley M, Kong YW, Hamilton TL, Spriggs KA, Dobbyn HC et al. (2006). Polypyrimidine tract binding protein regulates IRES-mediated gene expression during apoptosis. Mol Cell 23: 401–412.

    Article  CAS  Google Scholar 

  • Candeias MM, Powell DJ, Roubalova E, Apcher S, Bourougaa K, Vojtesek B et al. (2006). Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene 25: 6936–6947.

    Article  CAS  Google Scholar 

  • Candeias MM, Malbert-Colas L, Powell DJ, Daskalogianni C, Maslon MM, Naski N et al. (2008). p53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 10: 1098–1105.

    Article  CAS  Google Scholar 

  • Clemens MJ . (2001). Translational regulation in cell stress and apoptosis. Roles of the eIF4E binding proteins. J Cell Mol Med 5: 221–239.

    Article  CAS  Google Scholar 

  • Courtois S, Verhaegh G, North S, Luciani MG, Lassus P, Hibner U et al. (2002). DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 21: 6722–6728.

    Article  CAS  Google Scholar 

  • Courtois S, de Fromentel CC, Hainaut P . (2004). p53 protein variants: structural and functional similarities with p63 and p73 isoforms. Oncogene 23: 631–638.

    Article  CAS  Google Scholar 

  • Ewen ME, Miller SJ . (1996). p53 and translational control. Biochim Biophys Acta 1242: 181–184.

    PubMed  Google Scholar 

  • Fu L, Minden MD, Benchimol S . (1996). Translational regulation of human p53 gene expression. EMBO J 15: 4392–4401.

    Article  CAS  Google Scholar 

  • Gebauer F, Hentze MW . (2004). Molecular mechanisms of translational control. Nat Rev Mol Cell Biol 5: 827–835.

    Article  CAS  Google Scholar 

  • Ghosh A, Stewart D, Matlashewski G . (2004). Regulation of human p53 activity and cell localization by alternative splicing. Mol Cell Biol 24: 7987–7997.

    Article  CAS  Google Scholar 

  • Giaccia AJ, Kastan MB . (1998). The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12: 2973–2983.

    Article  CAS  Google Scholar 

  • Goldschneider D, Horvilleur E, Plassa LF, Guillaud-Bataille M, Million K, Wittmer-Dupret E et al. (2006). Expression of C-terminal deleted p53 isoforms in neuroblastoma. Nucleic Acids Res 34: 5603–5612.

    Article  CAS  Google Scholar 

  • Grover R, Ray PS, Das S . (2008). Polypyrimidine tract binding protein regulates IRES-mediated translation of p53 isoforms. Cell Cycle 7: 2189–2198.

    Article  CAS  Google Scholar 

  • Halaby MJ, Yang DQ . (2007). p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene 395: 1–7.

    Article  CAS  Google Scholar 

  • Harding HP, Zhang Y, Ron D . (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397: 271–274.

    Article  CAS  Google Scholar 

  • Haupt Y, Maya R, Kazaz A, Oren M . (1997). Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299.

    Article  CAS  Google Scholar 

  • Honda R, Tanaka H, Yasuda H . (1997). Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420: 25–27.

    Article  CAS  Google Scholar 

  • Hrstka R, Powell DJ, Kvardova V, Roubalova E, Bourougaa K, Candeias MM et al. (2008). The novel platinum(IV) complex LA-12 induces p53 and p53/47 responses that differ from the related drug, cisplatin. Anticancer Drugs 19: 369–379.

    Article  CAS  Google Scholar 

  • Kim JH, Paek KY, Choi K, Kim TD, Hahm B, Kim KT et al. (2003). Heterogeneous nuclear ribonucleoprotein C modulates translation of c-myc mRNA in a cell cycle phase-dependent manner. Mol Cell Biol 23: 708–720.

    Article  CAS  Google Scholar 

  • Kubbutat MH, Jones SN, Vousden KH . (1997). Regulation of p53 stability by Mdm2. Nature 387: 299–303.

    Article  CAS  Google Scholar 

  • Lane DP, Crawford LV . (1979). T antigen is bound to a host protein in SV40-transformed cells. Nature 278: 261–263.

    Article  CAS  Google Scholar 

  • Lev Bar-Or R, Maya R, Segel LA, Alon U, Levine AJ, Oren M . (2000). Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. Proc Natl Acad Sci USA 97: 11250–11255.

    Article  CAS  Google Scholar 

  • Linzer DI, Levine AJ . (1979). Characterization of a 54 k dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17: 43–52.

    Article  CAS  Google Scholar 

  • Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T et al. (2004). Modulation of mammalian life span by the short isoform of p53. Genes Dev 18: 306–319.

    Article  CAS  Google Scholar 

  • Mitchell SA, Brown EC, Coldwell MJ, Jackson RJ, Willis AE . (2001). Protein factor requirements of the Apaf-1 internal ribosome entry segment: roles of polypyrimidine tract binding protein and upstream of N-ras. Mol Cell Biol 21: 3364–3374.

    Article  CAS  Google Scholar 

  • Mitchell SA, Spriggs KA, Coldwell MJ, Jackson RJ, Willis AE . (2003). The Apaf-1 internal ribosome entry segment attains the correct structural conformation for function via interactions with PTB and unr. Mol Cell 11: 757–771.

    Article  CAS  Google Scholar 

  • Morley SJ, Coldwell MJ, Clemens MJ . (2005). Initiation factor modifications in the preapoptotic phase. Cell Death Differ 12: 571–584.

    Article  CAS  Google Scholar 

  • Mosner J, Mummenbrauer T, Bauer C, Sczakiel G, Grosse F, Deppert W . (1995). Negative feedback regulation of wild-type p53 biosynthesis. EMBO J 14: 4442–4449.

    Article  CAS  Google Scholar 

  • Ofir-Rosenfeld Y, Boggs K, Michael D, Kastan MB, Oren M . (2008). Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Mol Cell 32: 180–189.

    Article  CAS  Google Scholar 

  • Ohki R, Kawase T, Ohta T, Ichikawa H, Taya Y . (2007). Dissecting functional roles of p53 N-terminal transactivation domains by microarray expression analysis. Cancer Sci 98: 189–200.

    Article  CAS  Google Scholar 

  • Ossipow V, Descombes P, Schibler U . (1993). CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc Natl Acad Sci USA 90: 8219–8223.

    Article  CAS  Google Scholar 

  • Perry ME . (2004). Mdm2 in the response to radiation. Mol Cancer Res 2: 9–19.

    CAS  PubMed  Google Scholar 

  • Pfingsten JS, Costantino DA, Kieft JS . (2007). Conservation and diversity among the three-dimensional folds of the Dicistroviridae intergenic region IRESes. J Mol Biol 370: 856–869.

    Article  CAS  Google Scholar 

  • Pickering BM, Mitchell SA, Evans JR, Willis AE . (2003). Polypyrimidine tract binding protein and poly r(C) binding protein 1 interact with the BAG-1 IRES and stimulate its activity in vitro and in vivo. Nucleic Acids Res 31: 639–646.

    Article  CAS  Google Scholar 

  • Pickering BM, Mitchell SA, Spriggs KA, Stoneley M, Willis AE . (2004). Bag-1 internal ribosome entry segment activity is promoted by structural changes mediated by poly(rC) binding protein 1 and recruitment of polypyrimidine tract binding protein 1. Mol Cell Biol 24: 5595–5605.

    Article  CAS  Google Scholar 

  • Powell DJ, Hrstka R, Candeias M, Bourougaa K, Vojtesek B, Fahraeus R . (2008). Stress-dependent changes in the properties of p53 complexes by the alternative translation product p53/47. Cell Cycle 7: 950–959.

    Article  CAS  Google Scholar 

  • Ray PS, Grover R, Das S . (2006). Two internal ribosome entry sites mediate the translation of p53 isoforms. EMBO Rep 7: 404–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Samuels-Lev Y, O’Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S et al. (2001). ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 8: 781–794.

    Article  CAS  Google Scholar 

  • Scrable H, Sasaki T, Maier B . (2005). DeltaNp53 or p44: priming the p53 pump. Int J Biochem Cell Biol 37: 913–919.

    Article  CAS  Google Scholar 

  • Spriggs KA, Bushell M, Mitchell SA, Willis AE . (2005). Internal ribosome entry segment-mediated translation during apoptosis: the role of IRES-trans-acting factors. Cell Death Differ 12: 585–591.

    Article  CAS  Google Scholar 

  • Takagi M, Absalon MJ, McLure KG, Kastan MB . (2005). Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123: 49–63.

    Article  CAS  Google Scholar 

  • Taupin JL, Tian Q, Kedersha N, Robertson M, Anderson P . (1995). The RNA-binding protein TIAR is translocated from the nucleus to the cytoplasm during Fas-mediated apoptotic cell death. Proc Natl Acad Sci USA 92: 1629–1633.

    Article  CAS  Google Scholar 

  • Wagner EJ, Garcia-Blanco MA . (2001). Polypyrimidine tract binding protein antagonizes exon definition. Mol Cell Biol 21: 3281–3288.

    Article  CAS  Google Scholar 

  • Wek RC, Jiang HY, Anthony TG . (2006). Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34: 7–11.

    Article  CAS  Google Scholar 

  • Wu X, Bayle JH, Olson D, Levine AJ . (1993). The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7: 1126–1132.

    Article  CAS  Google Scholar 

  • Yang DQ, Halaby MJ, Zhang Y . (2006). The identification of an internal ribosomal entry site in the 5′-untranslated region of p53 mRNA provides a novel mechanism for the regulation of its translation following DNA damage. Oncogene 25: 4613–4619.

    Article  CAS  Google Scholar 

  • Yin Y, Stephen CW, Luciani MG, Fahraeus R . (2002). p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. Nat Cell Biol 4: 462–467.

    Article  CAS  Google Scholar 

  • Zhu J, Zhou W, Jiang J, Chen X . (1998). Identification of a novel p53 functional domain that is necessary for mediating apoptosis. J Biol Chem 273: 13030–13036.

    Article  CAS  Google Scholar 

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Acknowledgements

This study is supported by a research grant from the Indo-French (IFCPAR) to SD and RF. RG is supported by pre-doctoral fellowship from Council of Scientific and Industrial Research, India.

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Correspondence to S Das.

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Grover, R., Candeias, M., Fåhraeus, R. et al. p53 and little brother p53/47: linking IRES activities with protein functions. Oncogene 28, 2766–2772 (2009). https://doi.org/10.1038/onc.2009.138

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