Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Apr 15;16(8):2130–2139. doi: 10.1093/emboj/16.8.2130

Identification of HuR as a protein implicated in AUUUA-mediated mRNA decay.

V E Myer 1, X C Fan 1, J A Steitz 1
PMCID: PMC1169815  PMID: 9155038

Abstract

Expression of many proto-oncogenes, cytokines and lymphokines is regulated by targeting their messenger RNAs for rapid degradation. Essential signals for this control are AU-rich elements (AREs) in the 3' untranslated region (UTR) of these messages. The ARE is loosely defined as the five-nucleotide sequence AUUUA embedded in a uracil-rich region. A transacting factor, presumably a protein, binds the ARE and initiates recognition by the destabilization machinery. Numerous candidate ARE-binding proteins have been proposed. We show that a 32 kDa protein in HeLa nuclear extracts characterized previously has RNA-binding specificity that correlates with the activity of an ARE in directing mRNA decay. Purification and subsequent analyses demonstrate that this 32 kDa protein is identical to a recently identified member of the Elav-like gene family (ELG) called HuR. The in vitro binding selectivity of HuR is indicative of an ARE sequence's ability to destabilize a mRNA in vivo, suggesting a critical role for HuR in the regulation of mRNA degradation.

Full Text

The Full Text of this article is available as a PDF (359.3 KB).

Selected References

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

  1. Aharon T., Schneider R. J. Selective destabilization of short-lived mRNAs with the granulocyte-macrophage colony-stimulating factor AU-rich 3' noncoding region is mediated by a cotranslational mechanism. Mol Cell Biol. 1993 Mar;13(3):1971–1980. doi: 10.1128/mcb.13.3.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bohjanen P. R., Petryniak B., June C. H., Thompson C. B., Lindsten T. AU RNA-binding factors differ in their binding specificities and affinities. J Biol Chem. 1992 Mar 25;267(9):6302–6309. [PubMed] [Google Scholar]
  3. Bohjanen P. R., Petryniak B., June C. H., Thompson C. B., Lindsten T. An inducible cytoplasmic factor (AU-B) binds selectively to AUUUA multimers in the 3' untranslated region of lymphokine mRNA. Mol Cell Biol. 1991 Jun;11(6):3288–3295. doi: 10.1128/mcb.11.6.3288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brewer G. An A + U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol Cell Biol. 1991 May;11(5):2460–2466. doi: 10.1128/mcb.11.5.2460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Campos A. R., Grossman D., White K. Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects. A developmental-genetic analysis. J Neurogenet. 1985 Jun;2(3):197–218. doi: 10.3109/01677068509100150. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Chen C. Y., Chen T. M., Shyu A. B. Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNA-destabilizing function. Mol Cell Biol. 1994 Jan;14(1):416–426. doi: 10.1128/mcb.14.1.416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen C. Y., Shyu A. B. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci. 1995 Nov;20(11):465–470. doi: 10.1016/s0968-0004(00)89102-1. [DOI] [PubMed] [Google Scholar]
  9. Chen C. Y., Shyu A. B. Selective degradation of early-response-gene mRNAs: functional analyses of sequence features of the AU-rich elements. Mol Cell Biol. 1994 Dec;14(12):8471–8482. doi: 10.1128/mcb.14.12.8471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dalmau J., Furneaux H. M., Gralla R. J., Kris M. G., Posner J. B. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis. Ann Neurol. 1990 May;27(5):544–552. doi: 10.1002/ana.410270515. [DOI] [PubMed] [Google Scholar]
  11. Gao F. B., Carson C. C., Levine T., Keene J. D. Selection of a subset of mRNAs from combinatorial 3' untranslated region libraries using neuronal RNA-binding protein Hel-N1. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11207–11211. doi: 10.1073/pnas.91.23.11207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Graus F., Cordon-Cardo C., Posner J. B. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985 Apr;35(4):538–543. doi: 10.1212/wnl.35.4.538. [DOI] [PubMed] [Google Scholar]
  13. Koeller D. M., Horowitz J. A., Casey J. L., Klausner R. D., Harford J. B. Translation and the stability of mRNAs encoding the transferrin receptor and c-fos. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7778–7782. doi: 10.1073/pnas.88.17.7778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lee S. I., Murthy S. C., Trimble J. J., Desrosiers R. C., Steitz J. A. Four novel U RNAs are encoded by a herpesvirus. Cell. 1988 Aug 26;54(5):599–607. doi: 10.1016/s0092-8674(88)80004-7. [DOI] [PubMed] [Google Scholar]
  15. Levine T. D., Gao F., King P. H., Andrews L. G., Keene J. D. Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs. Mol Cell Biol. 1993 Jun;13(6):3494–3504. doi: 10.1128/mcb.13.6.3494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Ma W. J., Cheng S., Campbell C., Wright A., Furneaux H. Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem. 1996 Apr 5;271(14):8144–8151. doi: 10.1074/jbc.271.14.8144. [DOI] [PubMed] [Google Scholar]
  18. Malter J. S., Hong Y. A redox switch and phosphorylation are involved in the post-translational up-regulation of the adenosine-uridine binding factor by phorbol ester and ionophore. J Biol Chem. 1991 Feb 15;266(5):3167–3171. [PubMed] [Google Scholar]
  19. Meijlink F., Curran T., Miller A. D., Verma I. M. Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4987–4991. doi: 10.1073/pnas.82.15.4987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Myer V. E., Steitz J. A. Isolation and characterization of a novel, low abundance hnRNP protein: A0. RNA. 1995 Apr;1(2):171–182. [PMC free article] [PubMed] [Google Scholar]
  21. Nakamaki T., Imamura J., Brewer G., Tsuruoka N., Koeffler H. P. Characterization of adenosine-uridine-rich RNA binding factors. J Cell Physiol. 1995 Dec;165(3):484–492. doi: 10.1002/jcp.1041650306. [DOI] [PubMed] [Google Scholar]
  22. Robinow S., Campos A. R., Yao K. M., White K. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs. Science. 1988 Dec 16;242(4885):1570–1572. doi: 10.1126/science.3144044. [DOI] [PubMed] [Google Scholar]
  23. Savant-Bhonsale S., Cleveland D. W. Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a > 20S degradation complex. Genes Dev. 1992 Oct;6(10):1927–1939. doi: 10.1101/gad.6.10.1927. [DOI] [PubMed] [Google Scholar]
  24. Shyu A. B., Belasco J. G., Greenberg M. E. Two distinct destabilizing elements in the c-fos message trigger deadenylation as a first step in rapid mRNA decay. Genes Dev. 1991 Feb;5(2):221–231. doi: 10.1101/gad.5.2.221. [DOI] [PubMed] [Google Scholar]
  25. You Y., Chen C. Y., Shyu A. B. U-rich sequence-binding proteins (URBPs) interacting with a 20-nucleotide U-rich sequence in the 3' untranslated region of c-fos mRNA may be involved in the first step of c-fos mRNA degradation. Mol Cell Biol. 1992 Jul;12(7):2931–2940. doi: 10.1128/mcb.12.7.2931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zhang W., Wagner B. J., Ehrenman K., Schaefer A. W., DeMaria C. T., Crater D., DeHaven K., Long L., Brewer G. Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Mol Cell Biol. 1993 Dec;13(12):7652–7665. doi: 10.1128/mcb.13.12.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zubiaga A. M., Belasco J. G., Greenberg M. E. The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation. Mol Cell Biol. 1995 Apr;15(4):2219–2230. doi: 10.1128/mcb.15.4.2219. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES