Abstract
Transient expression of some proto-oncogenes, cytokines, and transcription factors occurs as a cellular response to growth factors, 12-O-tetradecanoylphorbol-13-acetate, antigen stimulation, or inflammation. Expression of these genes is mediated in part by the rapid turnover of their mRNAs. A + U-rich elements in the 3' untranslated regions of these mRNAs serve as one recognition signal targeting the mRNAs for rapid degradation. I report the identification of a cytosolic factor that both binds to the proto-oncogene c-myc A + U-rich element and specifically destabilizes c-myc mRNA in a cell-free mRNA decay system which reconstitutes mRNA decay processes found in cells. Proteinase K treatment of the factor abolishes its c-myc mRNA degradation activity without affecting its RNA-binding capacity. Thus, RNA substrate binding and degradation appear to be separable functions. These findings should aid in understanding how the cell selectively targets mRNAs for rapid turnover.
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- Akhayat O., Infante A. A., Infante D., Martins de SA C., Grossi de SA M. F., Scherrer K. A new type of prosome-like particle, composed of small cytoplasmic RNA and multimers of a 21-kDa protein, inhibits protein synthesis in vitro. Eur J Biochem. 1987 Dec 30;170(1-2):23–33. doi: 10.1111/j.1432-1033.1987.tb13663.x. [DOI] [PubMed] [Google Scholar]
- Altus M. S., Pearson D., Horiuchi A., Nagamine Y. Inhibition of protein synthesis in LLC-PK1 cells increases calcitonin-induced plasminogen-activator gene transcription and mRNA stability. Biochem J. 1987 Mar 1;242(2):387–392. doi: 10.1042/bj2420387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arrigo A. P., Tanaka K., Goldberg A. L., Welch W. J. Identity of the 19S 'prosome' particle with the large multifunctional protease complex of mammalian cells (the proteasome). Nature. 1988 Jan 14;331(6152):192–194. doi: 10.1038/331192a0. [DOI] [PubMed] [Google Scholar]
- Bandyopadhyay R., Coutts M., Krowczynska A., Brawerman G. Nuclease activity associated with mammalian mRNA in its native state: possible basis for selectivity in mRNA decay. Mol Cell Biol. 1990 May;10(5):2060–2069. doi: 10.1128/mcb.10.5.2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Battey J., Moulding C., Taub R., Murphy W., Stewart T., Potter H., Lenoir G., Leder P. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983 Oct;34(3):779–787. doi: 10.1016/0092-8674(83)90534-2. [DOI] [PubMed] [Google Scholar]
- Blanchard J. M., Piechaczyk M., Dani C., Chambard J. C., Franchi A., Pouyssegur J., Jeanteur P. c-myc gene is transcribed at high rate in G0-arrested fibroblasts and is post-transcriptionally regulated in response to growth factors. Nature. 1985 Oct 3;317(6036):443–445. doi: 10.1038/317443a0. [DOI] [PubMed] [Google Scholar]
- Bonnieu A., Piechaczyk M., Marty L., Cuny M., Blanchard J. M., Fort P., Jeanteur P. Sequence determinants of c-myc mRNA turn-over: influence of 3' and 5' non-coding regions. Oncogene Res. 1988 Sep;3(2):155–166. [PubMed] [Google Scholar]
- Brawerman G. Determinants of messenger RNA stability. Cell. 1987 Jan 16;48(1):5–6. doi: 10.1016/0092-8674(87)90346-1. [DOI] [PubMed] [Google Scholar]
- Brawerman G. mRNA decay: finding the right targets. Cell. 1989 Apr 7;57(1):9–10. doi: 10.1016/0092-8674(89)90166-9. [DOI] [PubMed] [Google Scholar]
- Brewer G., Ross J. Messenger RNA turnover in cell-free extracts. Methods Enzymol. 1990;181:202–209. doi: 10.1016/0076-6879(90)81122-b. [DOI] [PubMed] [Google Scholar]
- Brewer G., Ross J. Poly(A) shortening and degradation of the 3' A+U-rich sequences of human c-myc mRNA in a cell-free system. Mol Cell Biol. 1988 Apr;8(4):1697–1708. doi: 10.1128/mcb.8.4.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brewer G., Ross J. Regulation of c-myc mRNA stability in vitro by a labile destabilizer with an essential nucleic acid component. Mol Cell Biol. 1989 May;9(5):1996–2006. doi: 10.1128/mcb.9.5.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caput D., Beutler B., Hartog K., Thayer R., Brown-Shimer S., Cerami A. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670–1674. doi: 10.1073/pnas.83.6.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dani C., Blanchard J. M., Piechaczyk M., El Sabouty S., Marty L., Jeanteur P. Extreme instability of myc mRNA in normal and transformed human cells. Proc Natl Acad Sci U S A. 1984 Nov;81(22):7046–7050. doi: 10.1073/pnas.81.22.7046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hennessy S. W., Frazier B. A., Kim D. D., Deckwerth T. L., Baumgartel D. M., Rotwein P., Frazier W. A. Complete thrombospondin mRNA sequence includes potential regulatory sites in the 3' untranslated region. J Cell Biol. 1989 Feb;108(2):729–736. doi: 10.1083/jcb.108.2.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones T. R., Cole M. D. Rapid cytoplasmic turnover of c-myc mRNA: requirement of the 3' untranslated sequences. Mol Cell Biol. 1987 Dec;7(12):4513–4521. doi: 10.1128/mcb.7.12.4513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kabnick K. S., Housman D. E. Determinants that contribute to cytoplasmic stability of human c-fos and beta-globin mRNAs are located at several sites in each mRNA. Mol Cell Biol. 1988 Aug;8(8):3244–3250. doi: 10.1128/mcb.8.8.3244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koeller D. M., Casey J. L., Hentze M. W., Gerhardt E. M., Chan L. N., Klausner R. D., Harford J. B. A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA. Proc Natl Acad Sci U S A. 1989 May;86(10):3574–3578. doi: 10.1073/pnas.86.10.3574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Konarska M. M., Sharp P. A. Electrophoretic separation of complexes involved in the splicing of precursors to mRNAs. Cell. 1986 Sep 12;46(6):845–855. doi: 10.1016/0092-8674(86)90066-8. [DOI] [PubMed] [Google Scholar]
- Kruys V., Marinx O., Shaw G., Deschamps J., Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989 Aug 25;245(4920):852–855. doi: 10.1126/science.2672333. [DOI] [PubMed] [Google Scholar]
- Lamph W. W., Wamsley P., Sassone-Corsi P., Verma I. M. Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988 Aug 18;334(6183):629–631. doi: 10.1038/334629a0. [DOI] [PubMed] [Google Scholar]
- Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
- Majesky M. W., Benditt E. P., Schwartz S. M. Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1524–1528. doi: 10.1073/pnas.85.5.1524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malim M. H., Tiley L. S., McCarn D. F., Rusche J. R., Hauber J., Cullen B. R. HIV-1 structural gene expression requires binding of the Rev trans-activator to its RNA target sequence. Cell. 1990 Feb 23;60(4):675–683. doi: 10.1016/0092-8674(90)90670-a. [DOI] [PubMed] [Google Scholar]
- Malter J. S. Identification of an AUUUA-specific messenger RNA binding protein. Science. 1989 Nov 3;246(4930):664–666. doi: 10.1126/science.2814487. [DOI] [PubMed] [Google Scholar]
- Martins de Sa C., Grossi de Sa M. F., Akhayat O., Broders F., Scherrer K., Horsch A., Schmid H. P. Prosomes. Ubiquity and inter-species structural variation. J Mol Biol. 1986 Feb 20;187(4):479–493. doi: 10.1016/0022-2836(86)90328-1. [DOI] [PubMed] [Google Scholar]
- Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mitchell R. L., Zokas L., Schreiber R. D., Verma I. M. Rapid induction of the expression of proto-oncogene fos during human monocytic differentiation. Cell. 1985 Jan;40(1):209–217. doi: 10.1016/0092-8674(85)90324-1. [DOI] [PubMed] [Google Scholar]
- Müllner E. W., Neupert B., Kühn L. C. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA. Cell. 1989 Jul 28;58(2):373–382. doi: 10.1016/0092-8674(89)90851-9. [DOI] [PubMed] [Google Scholar]
- Pei R., Calame K. Differential stability of c-myc mRNAS in a cell-free system. Mol Cell Biol. 1988 Jul;8(7):2860–2868. doi: 10.1128/mcb.8.7.2860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Piechaczyk M., Yang J. Q., Blanchard J. M., Jeanteur P., Marcu K. B. Posttranscriptional mechanisms are responsible for accumulation of truncated c-myc RNAs in murine plasma cell tumors. Cell. 1985 Sep;42(2):589–597. doi: 10.1016/0092-8674(85)90116-3. [DOI] [PubMed] [Google Scholar]
- Rabbitts P. H., Forster A., Stinson M. A., Rabbitts T. H. Truncation of exon 1 from the c-myc gene results in prolonged c-myc mRNa stability. EMBO J. 1985 Dec 30;4(13B):3727–3733. doi: 10.1002/j.1460-2075.1985.tb04141.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ross J., Kobs G. H4 histone messenger RNA decay in cell-free extracts initiates at or near the 3' terminus and proceeds 3' to 5'. J Mol Biol. 1986 Apr 20;188(4):579–593. doi: 10.1016/s0022-2836(86)80008-0. [DOI] [PubMed] [Google Scholar]
- Ross J., Peltz S. W., Kobs G., Brewer G. Histone mRNA degradation in vivo: the first detectable step occurs at or near the 3' terminus. Mol Cell Biol. 1986 Dec;6(12):4362–4371. doi: 10.1128/mcb.6.12.4362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryseck R. P., Hirai S. I., Yaniv M., Bravo R. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature. 1988 Aug 11;334(6182):535–537. doi: 10.1038/334535a0. [DOI] [PubMed] [Google Scholar]
- Schuler G. D., Cole M. D. GM-CSF and oncogene mRNA stabilities are independently regulated in trans in a mouse monocytic tumor. Cell. 1988 Dec 23;55(6):1115–1122. doi: 10.1016/0092-8674(88)90256-5. [DOI] [PubMed] [Google Scholar]
- Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
- Shyu A. B., Greenberg M. E., Belasco J. G. The c-fos transcript is targeted for rapid decay by two distinct mRNA degradation pathways. Genes Dev. 1989 Jan;3(1):60–72. doi: 10.1101/gad.3.1.60. [DOI] [PubMed] [Google Scholar]
- Sunitha I., Slobin L. I. An in vitro system derived from Friend erythroleukemia cells to study messenger RNA stability. Biochem Biophys Res Commun. 1987 Apr 29;144(2):560–568. doi: 10.1016/s0006-291x(87)80003-7. [DOI] [PubMed] [Google Scholar]
- Swartwout S. G., Kinniburgh A. J. c-myc RNA degradation in growing and differentiating cells: possible alternate pathways. Mol Cell Biol. 1989 Jan;9(1):288–295. doi: 10.1128/mcb.9.1.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Theodorakis N. G., Morimoto R. I. Posttranscriptional regulation of hsp70 expression in human cells: effects of heat shock, inhibition of protein synthesis, and adenovirus infection on translation and mRNA stability. Mol Cell Biol. 1987 Dec;7(12):4357–4368. doi: 10.1128/mcb.7.12.4357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson C. B., Challoner P. B., Neiman P. E., Groudine M. Expression of the c-myb proto-oncogene during cellular proliferation. 1986 Jan 30-Feb 5Nature. 319(6052):374–380. doi: 10.1038/319374a0. [DOI] [PubMed] [Google Scholar]
- Thorens B., Mermod J. J., Vassalli P. Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation. Cell. 1987 Feb 27;48(4):671–679. doi: 10.1016/0092-8674(87)90245-5. [DOI] [PubMed] [Google Scholar]
- Wilson T., Treisman R. Removal of poly(A) and consequent degradation of c-fos mRNA facilitated by 3' AU-rich sequences. Nature. 1988 Nov 24;336(6197):396–399. doi: 10.1038/336396a0. [DOI] [PubMed] [Google Scholar]
- Young H. A., Varesio L., Hwu P. Posttranscriptional control of human gamma interferon gene expression in transfected mouse fibroblasts. Mol Cell Biol. 1986 Jun;6(6):2253–2256. doi: 10.1128/mcb.6.6.2253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zambetti G., Stein J., Stein G. Targeting of a chimeric human histone fusion mRNA to membrane-bound polysomes in HeLa cells. Proc Natl Acad Sci U S A. 1987 May;84(9):2683–2687. doi: 10.1073/pnas.84.9.2683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zapp M. L., Green M. R. Sequence-specific RNA binding by the HIV-1 Rev protein. Nature. 1989 Dec 7;342(6250):714–716. doi: 10.1038/342714a0. [DOI] [PubMed] [Google Scholar]