Abstract
p53 protein levels have been shown to increase in a number of cells after treatment with genotoxic agents through a post-transcriptional mechanism. In gamma-irradiated human cells, the accumulation of p53 protein is accompanied by an increase in the association of p53 mRNA with large polysomes without any change in the level of p53 mRNA. This redistribution of p53 mRNA on polysomes in response to irradiation is consistent with enhanced translational activity of p53 mRNA. We demonstrate that a region of the p53 3'-untranslated region (3'UTR) inhibits translation of a chimeric reporter mRNA in vivo. Induced elevation of reporter activity after gamma-irradiation was seen in cells expressing chimeric reporter-p53 3'UTR transcripts. These data taken together demonstrate translational control of p53 gene expression after gamma-irradiation and denote a previously unsuspected and novel role for the p53 3'UTR in controlling translation.
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- Adamou J., Bag J. Alteration of translation and stability of mRNA for the poly(A)-binding protein during myogenesis. Eur J Biochem. 1992 Nov 1;209(3):803–812. doi: 10.1111/j.1432-1033.1992.tb17351.x. [DOI] [PubMed] [Google Scholar]
- Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
- Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
- Dover R., Jayaram Y., Patel K., Chinery R. p53 expression in cultured cells following radioisotope labelling. J Cell Sci. 1994 May;107(Pt 5):1181–1184. doi: 10.1242/jcs.107.5.1181. [DOI] [PubMed] [Google Scholar]
- Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fritsche M., Haessler C., Brandner G. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene. 1993 Feb;8(2):307–318. [PubMed] [Google Scholar]
- Fu L., Minden M. D., Benchimol S. Translational regulation of human p53 gene expression. EMBO J. 1996 Aug 15;15(16):4392–4401. [PMC free article] [PubMed] [Google Scholar]
- Gavis E. R., Lehmann R. Translational regulation of nanos by RNA localization. Nature. 1994 May 26;369(6478):315–318. doi: 10.1038/369315a0. [DOI] [PubMed] [Google Scholar]
- Herzog H., Höfferer L., Schneider R., Schweiger M. cDNA encoding the human homologue of rat ribosomal protein L35a. Nucleic Acids Res. 1990 Aug 11;18(15):4600–4600. doi: 10.1093/nar/18.15.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huarte J., Stutz A., O'Connell M. L., Gubler P., Belin D., Darrow A. L., Strickland S., Vassalli J. D. Transient translational silencing by reversible mRNA deadenylation. Cell. 1992 Jun 12;69(6):1021–1030. doi: 10.1016/0092-8674(92)90620-r. [DOI] [PubMed] [Google Scholar]
- Hupp T. R., Meek D. W., Midgley C. A., Lane D. P. Regulation of the specific DNA binding function of p53. Cell. 1992 Nov 27;71(5):875–886. doi: 10.1016/0092-8674(92)90562-q. [DOI] [PubMed] [Google Scholar]
- Hupp T. R., Sparks A., Lane D. P. Small peptides activate the latent sequence-specific DNA binding function of p53. Cell. 1995 Oct 20;83(2):237–245. doi: 10.1016/0092-8674(95)90165-5. [DOI] [PubMed] [Google Scholar]
- Jackson R. J. Cytoplasmic regulation of mRNA function: the importance of the 3' untranslated region. Cell. 1993 Jul 16;74(1):9–14. doi: 10.1016/0092-8674(93)90290-7. [DOI] [PubMed] [Google Scholar]
- Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
- Kuerbitz S. J., Plunkett B. S., Walsh W. V., Kastan M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7491–7495. doi: 10.1073/pnas.89.16.7491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kwon Y. K., Hecht N. B. Binding of a phosphoprotein to the 3' untranslated region of the mouse protamine 2 mRNA temporally represses its translation. Mol Cell Biol. 1993 Oct;13(10):6547–6557. doi: 10.1128/mcb.13.10.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kwon Y. K., Murray M. T., Hecht N. B. Proteins homologous to the Xenopus germ cell-specific RNA-binding proteins p54/p56 are temporally expressed in mouse male germ cells. Dev Biol. 1993 Jul;158(1):99–100. doi: 10.1006/dbio.1993.1170. [DOI] [PubMed] [Google Scholar]
- Kyrpides N., Tavernarakis N., Papamatheakis J., Thireos G. A transient GCN4 mRNA destabilization follows GCN4 translational derepression. J Biol Chem. 1995 Jul 21;270(29):17317–17320. doi: 10.1074/jbc.270.29.17317. [DOI] [PubMed] [Google Scholar]
- Lowe S. W., Ruley H. E., Jacks T., Housman D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993 Sep 24;74(6):957–967. doi: 10.1016/0092-8674(93)90719-7. [DOI] [PubMed] [Google Scholar]
- Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
- Lu X., Lane D. P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell. 1993 Nov 19;75(4):765–778. doi: 10.1016/0092-8674(93)90496-d. [DOI] [PubMed] [Google Scholar]
- Matlashewski G., Lamb P., Pim D., Peacock J., Crawford L., Benchimol S. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J. 1984 Dec 20;3(13):3257–3262. doi: 10.1002/j.1460-2075.1984.tb02287.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Minich W. B., Maidebura I. P., Ovchinnikov L. P. Purification and characterization of the major 50-kDa repressor protein from cytoplasmic mRNP of rabbit reticulocytes. Eur J Biochem. 1993 Mar 15;212(3):633–638. doi: 10.1111/j.1432-1033.1993.tb17701.x. [DOI] [PubMed] [Google Scholar]
- Mosner J., Mummenbrauer T., Bauer C., Sczakiel G., Grosse F., Deppert W. Negative feedback regulation of wild-type p53 biosynthesis. EMBO J. 1995 Sep 15;14(18):4442–4449. doi: 10.1002/j.1460-2075.1995.tb00123.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nelson W. G., Kastan M. B. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol. 1994 Mar;14(3):1815–1823. doi: 10.1128/mcb.14.3.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ostareck-Lederer A., Ostareck D. H., Standart N., Thiele B. J. Translation of 15-lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3' untranslated region. EMBO J. 1994 Mar 15;13(6):1476–1481. doi: 10.1002/j.1460-2075.1994.tb06402.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Papayannopoulou T., Nakamoto B., Kurachi S., Tweeddale M., Messner H. Surface antigenic profile and globin phenotype of two new human erythroleukemia lines: characterization and interpretations. Blood. 1988 Sep;72(3):1029–1038. [PubMed] [Google Scholar]
- Peltz S. W., Jacobson A. mRNA stability: in trans-it. Curr Opin Cell Biol. 1992 Dec;4(6):979–983. doi: 10.1016/0955-0674(92)90129-z. [DOI] [PubMed] [Google Scholar]
- Sheets M. D., Fox C. A., Hunt T., Vande Woude G., Wickens M. The 3'-untranslated regions of c-mos and cyclin mRNAs stimulate translation by regulating cytoplasmic polyadenylation. Genes Dev. 1994 Apr 15;8(8):926–938. doi: 10.1101/gad.8.8.926. [DOI] [PubMed] [Google Scholar]
- Slingerland J. M., Minden M. D., Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991 Apr 1;77(7):1500–1507. [PubMed] [Google Scholar]
- Standart N., Jackson R. J. Regulation of translation by specific protein/mRNA interactions. Biochimie. 1994;76(9):867–879. doi: 10.1016/0300-9084(94)90189-9. [DOI] [PubMed] [Google Scholar]
- Sun X., Shimizu H., Yamamoto K. Identification of a novel p53 promoter element involved in genotoxic stress-inducible p53 gene expression. Mol Cell Biol. 1995 Aug;15(8):4489–4496. doi: 10.1128/mcb.15.8.4489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tuck S. P., Crawford L. Characterization of the human p53 gene promoter. Mol Cell Biol. 1989 May;9(5):2163–2172. doi: 10.1128/mcb.9.5.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang C., Curtis J. E., Minden M. D., McCulloch E. A. Expression of a retinoic acid receptor gene in myeloid leukemia cells. Leukemia. 1989 Apr;3(4):264–269. [PubMed] [Google Scholar]
- Weiss I. M., Liebhaber S. A. Erythroid cell-specific mRNA stability elements in the alpha 2-globin 3' nontranslated region. Mol Cell Biol. 1995 May;15(5):2457–2465. doi: 10.1128/mcb.15.5.2457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wickens M. Messenger RNA. Springtime in the desert. Nature. 1993 May 27;363(6427):305–306. doi: 10.1038/363305a0. [DOI] [PubMed] [Google Scholar]
- Wolffe A. P. Structural and functional properties of the evolutionarily ancient Y-box family of nucleic acid binding proteins. Bioessays. 1994 Apr;16(4):245–251. doi: 10.1002/bies.950160407. [DOI] [PubMed] [Google Scholar]
- Yeargin J., Haas M. Elevated levels of wild-type p53 induced by radiolabeling of cells leads to apoptosis or sustained growth arrest. Curr Biol. 1995 Apr 1;5(4):423–431. doi: 10.1016/s0960-9822(95)00083-2. [DOI] [PubMed] [Google Scholar]
- el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]