Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1990 Dec;9(12):4127–4133. doi: 10.1002/j.1460-2075.1990.tb07635.x

Translational repression by a complex between the iron-responsive element of ferritin mRNA and its specific cytoplasmic binding protein is position-dependent in vivo.

B Goossen 1, S W Caughman 1, J B Harford 1, R D Klausner 1, M W Hentze 1
PMCID: PMC552186  PMID: 1701143

Abstract

The interaction of ferritin mRNA is regulated by iron via the interaction of a cytoplasmic binding protein (IRE-BP) with a specific stem-loop structure in the 5' untranslated region (UTR), referred to as the iron-responsive element (IRE). A high affinity RNA-protein complex between the IRE and the IRE-BP functions as a repressor of translation in vivo. Translational repression appears to depend upon the position of the IRE in the 5' UTR of the mRNA. IREs located in the 5' untranslated region 67 nucleotides or more downstream of the 5' terminus of the mRNA fail to mediate iron-dependent translational regulation and give rise to constitutively derepressed transcripts. A model is proposed in which translational regulation of protein biosynthesis involves a position-dependent interference of the IRE/IRE-BP complex with one of the initial steps in translation initiation.

Full text

PDF

Images in this article

4129Fig. 2.
on p.4129
4129Fig. 3.
on p.4129
4130Fig. 4.
on p.4130
4130Fig. 5.
on p.4130

Selected References

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

  1. Abramson R. D., Dever T. E., Lawson T. G., Ray B. K., Thach R. E., Merrick W. C. The ATP-dependent interaction of eukaryotic initiation factors with mRNA. J Biol Chem. 1987 Mar 15;262(8):3826–3832. [PubMed] [Google Scholar]
  2. Aziz N., Munro H. N. Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8478–8482. doi: 10.1073/pnas.84.23.8478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Banerjee A. K. 5'-terminal cap structure in eucaryotic messenger ribonucleic acids. Microbiol Rev. 1980 Jun;44(2):175–205. doi: 10.1128/mr.44.2.175-205.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birnstiel M. L., Busslinger M., Strub K. Transcription termination and 3' processing: the end is in site! Cell. 1985 Jun;41(2):349–359. doi: 10.1016/s0092-8674(85)80007-6. [DOI] [PubMed] [Google Scholar]
  5. Casey J. L., Hentze M. W., Koeller D. M., Caughman S. W., Rouault T. A., Klausner R. D., Harford J. B. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988 May 13;240(4854):924–928. doi: 10.1126/science.2452485. [DOI] [PubMed] [Google Scholar]
  6. Casey J. L., Koeller D. M., Ramin V. C., Klausner R. D., Harford J. B. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA. EMBO J. 1989 Dec 1;8(12):3693–3699. doi: 10.1002/j.1460-2075.1989.tb08544.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Caughman S. W., Hentze M. W., Rouault T. A., Harford J. B., Klausner R. D. The iron-responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis. Evidence for function as the binding site for a translational repressor. J Biol Chem. 1988 Dec 15;263(35):19048–19052. [PubMed] [Google Scholar]
  8. Costanzo F., Colombo M., Staempfli S., Santoro C., Marone M., Frank R., Delius H., Cortese R. Structure of gene and pseudogenes of human apoferritin H. Nucleic Acids Res. 1986 Jan 24;14(2):721–736. doi: 10.1093/nar/14.2.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dynan W. S. Modularity in promoters and enhancers. Cell. 1989 Jul 14;58(1):1–4. doi: 10.1016/0092-8674(89)90393-0. [DOI] [PubMed] [Google Scholar]
  10. Haile D. J., Hentze M. W., Rouault T. A., Harford J. B., Klausner R. D. Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements. Mol Cell Biol. 1989 Nov;9(11):5055–5061. doi: 10.1128/mcb.9.11.5055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hentze M. W., Caughman S. W., Casey J. L., Koeller D. M., Rouault T. A., Harford J. B., Klausner R. D. A model for the structure and functions of iron-responsive elements. Gene. 1988 Dec 10;72(1-2):201–208. doi: 10.1016/0378-1119(88)90145-x. [DOI] [PubMed] [Google Scholar]
  12. Hentze M. W., Caughman S. W., Rouault T. A., Barriocanal J. G., Dancis A., Harford J. B., Klausner R. D. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science. 1987 Dec 11;238(4833):1570–1573. doi: 10.1126/science.3685996. [DOI] [PubMed] [Google Scholar]
  13. Hentze M. W., Keim S., Papadopoulos P., O'Brien S., Modi W., Drysdale J., Leonard W. J., Harford J. B., Klausner R. D. Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7226–7230. doi: 10.1073/pnas.83.19.7226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hentze M. W., Rouault T. A., Caughman S. W., Dancis A., Harford J. B., Klausner R. D. A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6730–6734. doi: 10.1073/pnas.84.19.6730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hentze M. W., Rouault T. A., Harford J. B., Klausner R. D. Oxidation-reduction and the molecular mechanism of a regulatory RNA-protein interaction. Science. 1989 Apr 21;244(4902):357–359. doi: 10.1126/science.2711187. [DOI] [PubMed] [Google Scholar]
  16. Hentze M. W., Seuanez H. N., O'Brien S. J., Harford J. B., Klausner R. D. Chromosomal localization of nucleic acid-binding proteins by affinity mapping: assignment of the IRE-binding protein gene to human chromosome 9. Nucleic Acids Res. 1989 Aug 11;17(15):6103–6108. doi: 10.1093/nar/17.15.6103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hochschild A., Ptashne M. Cooperative binding of lambda repressors to sites separated by integral turns of the DNA helix. Cell. 1986 Mar 14;44(5):681–687. doi: 10.1016/0092-8674(86)90833-0. [DOI] [PubMed] [Google Scholar]
  18. Hultmark D., Klemenz R., Gehring W. J. Translational and transcriptional control elements in the untranslated leader of the heat-shock gene hsp22. Cell. 1986 Feb 14;44(3):429–438. doi: 10.1016/0092-8674(86)90464-2. [DOI] [PubMed] [Google Scholar]
  19. Keller W. The RNA lariat: a new ring to the splicing of mRNA precursors. Cell. 1984 Dec;39(3 Pt 2):423–425. doi: 10.1016/0092-8674(84)90449-5. [DOI] [PubMed] [Google Scholar]
  20. Klausner R. D., Harford J. B. cis-trans models for post-transcriptional gene regulation. Science. 1989 Nov 17;246(4932):870–872. doi: 10.1126/science.2683086. [DOI] [PubMed] [Google Scholar]
  21. Kozak M. Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol Cell Biol. 1989 Nov;9(11):5134–5142. doi: 10.1128/mcb.9.11.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kozak M. Influences of mRNA secondary structure on initiation by eukaryotic ribosomes. Proc Natl Acad Sci U S A. 1986 May;83(9):2850–2854. doi: 10.1073/pnas.83.9.2850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kozak M. Leader length and secondary structure modulate mRNA function under conditions of stress. Mol Cell Biol. 1988 Jul;8(7):2737–2744. doi: 10.1128/mcb.8.7.2737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Leibold E. A., Munro H. N. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2171–2175. doi: 10.1073/pnas.85.7.2171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maitra U., Stringer E. A., Chaudhuri A. Initiation factors in protein biosynthesis. Annu Rev Biochem. 1982;51:869–900. doi: 10.1146/annurev.bi.51.070182.004253. [DOI] [PubMed] [Google Scholar]
  27. McGarry T. J., Lindquist S. The preferential translation of Drosophila hsp70 mRNA requires sequences in the untranslated leader. Cell. 1985 Oct;42(3):903–911. doi: 10.1016/0092-8674(85)90286-7. [DOI] [PubMed] [Google Scholar]
  28. McGrew L. L., Dworkin-Rastl E., Dworkin M. B., Richter J. D. Poly(A) elongation during Xenopus oocyte maturation is required for translational recruitment and is mediated by a short sequence element. Genes Dev. 1989 Jun;3(6):803–815. doi: 10.1101/gad.3.6.803. [DOI] [PubMed] [Google Scholar]
  29. Miller P. F., Hinnebusch A. G. Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control. Genes Dev. 1989 Aug;3(8):1217–1225. doi: 10.1101/gad.3.8.1217. [DOI] [PubMed] [Google Scholar]
  30. Moldave K. Eukaryotic protein synthesis. Annu Rev Biochem. 1985;54:1109–1149. doi: 10.1146/annurev.bi.54.070185.005333. [DOI] [PubMed] [Google Scholar]
  31. Moskaitis J. E., Pastori R. L., Schoenberg D. R. Sequence of Xenopus laevis ferritin mRNA. Nucleic Acids Res. 1990 Apr 25;18(8):2184–2184. doi: 10.1093/nar/18.8.2184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Müllner E. W., Kühn L. C. A stem-loop in the 3' untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell. 1988 Jun 3;53(5):815–825. doi: 10.1016/0092-8674(88)90098-0. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Pelletier J., Sonenberg N. Insertion mutagenesis to increase secondary structure within the 5' noncoding region of a eukaryotic mRNA reduces translational efficiency. Cell. 1985 Mar;40(3):515–526. doi: 10.1016/0092-8674(85)90200-4. [DOI] [PubMed] [Google Scholar]
  35. Pelletier J., Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988 Jul 28;334(6180):320–325. doi: 10.1038/334320a0. [DOI] [PubMed] [Google Scholar]
  36. Pelletier J., Sonenberg N. Photochemical cross-linking of cap binding proteins to eucaryotic mRNAs: effect of mRNA 5' secondary structure. Mol Cell Biol. 1985 Nov;5(11):3222–3230. doi: 10.1128/mcb.5.11.3222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Platt T. Transcription termination and the regulation of gene expression. Annu Rev Biochem. 1986;55:339–372. doi: 10.1146/annurev.bi.55.070186.002011. [DOI] [PubMed] [Google Scholar]
  38. Ray B. K., Lawson T. G., Kramer J. C., Cladaras M. H., Grifo J. A., Abramson R. D., Merrick W. C., Thach R. E. ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors. J Biol Chem. 1985 Jun 25;260(12):7651–7658. [PubMed] [Google Scholar]
  39. Rouault T. A., Hentze M. W., Caughman S. W., Harford J. B., Klausner R. D. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science. 1988 Sep 2;241(4870):1207–1210. doi: 10.1126/science.3413484. [DOI] [PubMed] [Google Scholar]
  40. Sarkar G., Edery I., Sonenberg N. Photoaffinity labeling of the cap-binding protein complex with ATP/dATP. Differential labeling of free eukaryotic initiation factor 4A and the eukaryotic initiation factor 4A component of the cap-binding protein complex with [alpha-32P]ATP/dATP. J Biol Chem. 1985 Nov 5;260(25):13831–13837. [PubMed] [Google Scholar]
  41. Schneider C., Owen M. J., Banville D., Williams J. G. Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature. 1984 Oct 18;311(5987):675–678. doi: 10.1038/311675b0. [DOI] [PubMed] [Google Scholar]
  42. Shatkin A. J. mRNA cap binding proteins: essential factors for initiating translation. Cell. 1985 Feb;40(2):223–224. doi: 10.1016/0092-8674(85)90132-1. [DOI] [PubMed] [Google Scholar]
  43. Sonenberg N. Cap-binding proteins of eukaryotic messenger RNA: functions in initiation and control of translation. Prog Nucleic Acid Res Mol Biol. 1988;35:173–207. doi: 10.1016/s0079-6603(08)60614-5. [DOI] [PubMed] [Google Scholar]
  44. Sonenberg N. Regulation of translation by poliovirus. Adv Virus Res. 1987;33:175–204. doi: 10.1016/s0065-3527(08)60318-8. [DOI] [PubMed] [Google Scholar]
  45. Strickland S., Huarte J., Belin D., Vassalli A., Rickles R. J., Vassalli J. D. Antisense RNA directed against the 3' noncoding region prevents dormant mRNA activation in mouse oocytes. Science. 1988 Aug 5;241(4866):680–684. doi: 10.1126/science.2456615. [DOI] [PubMed] [Google Scholar]
  46. Theil E. C. Regulation of ferritin and transferrin receptor mRNAs. J Biol Chem. 1990 Mar 25;265(9):4771–4774. [PubMed] [Google Scholar]
  47. Tzamarias D., Roussou I., Thireos G. Coupling of GCN4 mRNA translational activation with decreased rates of polypeptide chain initiation. Cell. 1989 Jun 16;57(6):947–954. doi: 10.1016/0092-8674(89)90333-4. [DOI] [PubMed] [Google Scholar]
  48. Walden W. E., Daniels-McQueen S., Brown P. H., Gaffield L., Russell D. A., Bielser D., Bailey L. C., Thach R. E. Translational repression in eukaryotes: partial purification and characterization of a repressor of ferritin mRNA translation. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9503–9507. doi: 10.1073/pnas.85.24.9503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zähringer J., Baliga B. S., Munro H. N. Novel mechanism for translational control in regulation of ferritin synthesis by iron. Proc Natl Acad Sci U S A. 1976 Mar;73(3):857–861. doi: 10.1073/pnas.73.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES