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. 1992 Oct;12(10):4796–4805. doi: 10.1128/mcb.12.10.4796

cis-acting elements involved in the alternative translation initiation process of human basic fibroblast growth factor mRNA.

A C Prats 1, S Vagner 1, H Prats 1, F Amalric 1
PMCID: PMC360406  PMID: 1406661

Abstract

Four forms of basic fibroblast growth factor (bFGF) are synthesized from the same mRNA, resulting from alternative initiations of translation at three CUG start codons and one AUG start codon. The CUG- and AUG-initiated forms have distinct intracellular localizations and can modify cell phenotypes differently, indicating that control of the alternative expression of the different forms of bFGF has an important impact on the cell. In this study, we investigated the roles of the mRNA 5' untranslated region and the alternatively translated region located between the CUG and AUG codons in the regulation of alternative translation of the different forms of bFGF. Deletions and site-directed mutagenesis were carried out in bFGF mRNA leader, and translation was studied in vitro and in vivo. The results enabled us to identify five cis-acting RNA elements (two in the 5' untranslated region and three in the alternatively translated region) involved in the regulation of either global or alternative initiation of translation. Each of these elements had a specific effect on the level of synthesis of the different forms of bFGF. Furthermore, we showed that the 5' untranslated region regulatory elements had different effects on bFGF translation, depending on the translation system used. These results suggest that bFGF translation is modulated by cis-acting elements corresponding to secondary or tertiary RNA structures, which could be the targets of cell-specific trans-acting factors.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acland P., Dixon M., Peters G., Dickson C. Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon. Nature. 1990 Feb 15;343(6259):662–665. doi: 10.1038/343662a0. [DOI] [PubMed] [Google Scholar]
  2. Arrick B. A., Lee A. L., Grendell R. L., Derynck R. Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5' untranslated region. Mol Cell Biol. 1991 Sep;11(9):4306–4313. doi: 10.1128/mcb.11.9.4306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Banerji J., Olson L., Schaffner W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell. 1983 Jul;33(3):729–740. doi: 10.1016/0092-8674(83)90015-6. [DOI] [PubMed] [Google Scholar]
  4. Bates B., Hardin J., Zhan X., Drickamer K., Goldfarb M. Biosynthesis of human fibroblast growth factor-5. Mol Cell Biol. 1991 Apr;11(4):1840–1845. doi: 10.1128/mcb.11.4.1840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bensaid M., Malecaze F., Prats H., Bayard F., Tauber J. P. Autocrine regulation of bovine retinal capillary endothelial cell (BREC) proliferation by BREC-derived basic fibroblast growth factor. Exp Eye Res. 1989 Jun;48(6):801–813. doi: 10.1016/0014-4835(89)90065-1. [DOI] [PubMed] [Google Scholar]
  6. Bouche G., Gas N., Prats H., Baldin V., Tauber J. P., Teissié J., Amalric F. Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing G0----G1 transition. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6770–6774. doi: 10.1073/pnas.84.19.6770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bugler B., Amalric F., Prats H. Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor. Mol Cell Biol. 1991 Jan;11(1):573–577. doi: 10.1128/mcb.11.1.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Couderc B., Prats H., Bayard F., Amalric F. Potential oncogenic effects of basic fibroblast growth factor requires cooperation between CUG and AUG-initiated forms. Cell Regul. 1991 Sep;2(9):709–718. doi: 10.1091/mbc.2.9.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curran J., Kolakofsky D. Ribosomal initiation from an ACG codon in the Sendai virus P/C mRNA. EMBO J. 1988 Jan;7(1):245–251. doi: 10.1002/j.1460-2075.1988.tb02806.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Falcone D., Andrews D. W. Both the 5' untranslated region and the sequences surrounding the start site contribute to efficient initiation of translation in vitro. Mol Cell Biol. 1991 May;11(5):2656–2664. doi: 10.1128/mcb.11.5.2656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Florkiewicz R. Z., Baird A., Gonzalez A. M. Multiple forms of bFGF: differential nuclear and cell surface localization. Growth Factors. 1991;4(4):265–275. doi: 10.3109/08977199109043912. [DOI] [PubMed] [Google Scholar]
  12. Florkiewicz R. Z., Sommer A. Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. Proc Natl Acad Sci U S A. 1989 Jun;86(11):3978–3981. doi: 10.1073/pnas.86.11.3978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gospodarowicz D., Neufeld G., Schweigerer L. Fibroblast growth factor. Mol Cell Endocrinol. 1986 Aug;46(3):187–204. doi: 10.1016/0303-7207(86)90001-8. [DOI] [PubMed] [Google Scholar]
  14. Grens A., Scheffler I. E. The 5'- and 3'-untranslated regions of ornithine decarboxylase mRNA affect the translational efficiency. J Biol Chem. 1990 Jul 15;265(20):11810–11816. [PubMed] [Google Scholar]
  15. Hann S. R., King M. W., Bentley D. L., Anderson C. W., Eisenman R. N. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas. Cell. 1988 Jan 29;52(2):185–195. doi: 10.1016/0092-8674(88)90507-7. [DOI] [PubMed] [Google Scholar]
  16. Hinnebusch A. G. Novel mechanisms of translational control in Saccharomyces cerevisiae. Trends Genet. 1988 Jun;4(6):169–174. doi: 10.1016/0168-9525(88)90023-6. [DOI] [PubMed] [Google Scholar]
  17. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kozak M. An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol. 1991 Nov;115(4):887–903. doi: 10.1083/jcb.115.4.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kozak M. Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8301–8305. doi: 10.1073/pnas.87.21.8301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kruys V., Kemmer K., Shakhov A., Jongeneel V., Beutler B. Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):673–677. doi: 10.1073/pnas.89.2.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Manzella J. M., Blackshear P. J. Regulation of rat ornithine decarboxylase mRNA translation by its 5'-untranslated region. J Biol Chem. 1990 Jul 15;265(20):11817–11822. [PubMed] [Google Scholar]
  24. Moscatelli D., Joseph-Silverstein J., Manejias R., Rifkin D. B. Mr 25,000 heparin-binding protein from guinea pig brain is a high molecular weight form of basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5778–5782. doi: 10.1073/pnas.84.16.5778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Parkin N., Darveau A., Nicholson R., Sonenberg N. cis-acting translational effects of the 5' noncoding region of c-myc mRNA. Mol Cell Biol. 1988 Jul;8(7):2875–2883. doi: 10.1128/mcb.8.7.2875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Prats A. C., De Billy G., Wang P., Darlix J. L. CUG initiation codon used for the synthesis of a cell surface antigen coded by the murine leukemia virus. J Mol Biol. 1989 Jan 20;205(2):363–372. doi: 10.1016/0022-2836(89)90347-1. [DOI] [PubMed] [Google Scholar]
  27. Prats H., Kaghad M., Prats A. C., Klagsbrun M., Lélias J. M., Liauzun P., Chalon P., Tauber J. P., Amalric F., Smith J. A. High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1836–1840. doi: 10.1073/pnas.86.6.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rao C. D., Pech M., Robbins K. C., Aaronson S. A. The 5' untranslated sequence of the c-sis/platelet-derived growth factor 2 transcript is a potent translational inhibitor. Mol Cell Biol. 1988 Jan;8(1):284–292. doi: 10.1128/mcb.8.1.284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rifkin D. B., Moscatelli D. Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol. 1989 Jul;109(1):1–6. doi: 10.1083/jcb.109.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rusconi S., Severne Y., Georgiev O., Galli I., Wieland S. A novel expression assay to study transcriptional activators. Gene. 1990 May 14;89(2):211–221. doi: 10.1016/0378-1119(90)90008-f. [DOI] [PubMed] [Google Scholar]
  31. Schweigerer L., Neufeld G., Friedman J., Abraham J. A., Fiddes J. C., Gospodarowicz D. Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth. Nature. 1987 Jan 15;325(6101):257–259. doi: 10.1038/325257a0. [DOI] [PubMed] [Google Scholar]
  32. Shibata F., Baird A., Florkiewicz R. Z. Functional characterization of the human basic fibroblast growth factor gene promoter. Growth Factors. 1991;4(4):277–287. doi: 10.3109/08977199109043913. [DOI] [PubMed] [Google Scholar]
  33. Weich H. A., Iberg N., Klagsbrun M., Folkman J. Expression of acidic and basic fibroblast growth factors in human and bovine vascular smooth muscle cells. Growth Factors. 1990;2(4):313–320. doi: 10.3109/08977199009167026. [DOI] [PubMed] [Google Scholar]
  34. Yayon A., Klagsbrun M., Esko J. D., Leder P., Ornitz D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991 Feb 22;64(4):841–848. doi: 10.1016/0092-8674(91)90512-w. [DOI] [PubMed] [Google Scholar]

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