• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Jun 1993; 13(6): 3494–3504.
PMCID: PMC359819

Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs.

Abstract

We have investigated the RNA binding specificity of Hel-N1, a human neuron-specific RNA-binding protein, which contains three RNA recognition motifs. Hel-N1 is a human homolog of Drosophila melanogaster elav, which plays a vital role in the development of neurons. A random RNA selection procedure revealed that Hel-N1 prefers to bind RNAs containing short stretches of uridylates similar to those found in the 3' untranslated regions (3' UTRs) of oncoprotein and cytokine mRNAs such as c-myc, c-fos, and granulocyte macrophage colony-stimulating factor. Direct binding studies demonstrated that Hel-N1 bound and formed multimers with c-myc 3' UTR mRNA and required, as a minimum, a specific 29-nucleotide stretch containing AUUUG, AUUUA, and GUUUUU. Deletion analysis demonstrated that a fragment of Hel-N1 containing 87 amino acids, encompassing the third RNA recognition motif, forms an RNA binding domain for the c-myc 3' UTR. In addition, Hel-N1 was shown to be reactive with autoantibodies from patients with paraneoplastic encephalomyelitis both before and after binding to c-myc mRNA.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adam SA, Nakagawa T, Swanson MS, Woodruff TK, Dreyfuss G. mRNA polyadenylate-binding protein: gene isolation and sequencing and identification of a ribonucleoprotein consensus sequence. Mol Cell Biol. 1986 Aug;6(8):2932–2943. [PMC free article] [PubMed]
  • Alitalo K, Schwab M, Lin CC, Varmus HE, Bishop JM. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1707–1711. [PMC free article] [PubMed]
  • Ayane M, Preuss U, Köhler G, Nielsen PJ. A differentially expressed murine RNA encoding a protein with similarities to two types of nucleic acid binding motifs. Nucleic Acids Res. 1991 Mar 25;19(6):1273–1278. [PMC free article] [PubMed]
  • Bandziulis RJ, Swanson MS, Dreyfuss G. RNA-binding proteins as developmental regulators. Genes Dev. 1989 Apr;3(4):431–437. [PubMed]
  • Bartel DP, Zapp ML, Green MR, Szostak JW. HIV-1 Rev regulation involves recognition of non-Watson-Crick base pairs in viral RNA. Cell. 1991 Nov 1;67(3):529–536. [PubMed]
  • Bentley RC, Keene JD. Recognition of U1 and U2 small nuclear RNAs can be altered by a 5-amino-acid segment in the U2 small nuclear ribonucleoprotein particle (snRNP) B" protein and through interactions with U2 snRNP-A' protein. Mol Cell Biol. 1991 Apr;11(4):1829–1839. [PMC free article] [PubMed]
  • Bepler G, Bading H, Heimann B, Kiefer P, Havemann K, Moelling K. Expression of p64c-myc and neuroendocrine properties define three subclasses of small cell lung cancer. Oncogene. 1989 Jan;4(1):45–50. [PubMed]
  • Bernstein PL, Herrick DJ, Prokipcak RD, Ross J. Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev. 1992 Apr;6(4):642–654. [PubMed]
  • Bigner SH, Friedman HS, Vogelstein B, Oakes WJ, Bigner DD. Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res. 1990 Apr 15;50(8):2347–2350. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Burd CG, Matunis EL, Dreyfuss G. The multiple RNA-binding domains of the mRNA poly(A)-binding protein have different RNA-binding activities. Mol Cell Biol. 1991 Jul;11(7):3419–3424. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Chamberlain JS, Jaynes JB, Hauschka SD. Regulation of creatine kinase induction in differentiating mouse myoblasts. Mol Cell Biol. 1985 Mar;5(3):484–492. [PMC free article] [PubMed]
  • Cole MD. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. [PubMed]
  • Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner JB. 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. [PubMed]
  • DePinho RA, Legouy E, Feldman LB, Kohl NE, Yancopoulos GD, Alt FW. Structure and expression of the murine N-myc gene. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1827–1831. [PMC free article] [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [PMC free article] [PubMed]
  • Dropcho EJ, Chen YT, Posner JB, Old LJ. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4552–4556. [PMC free article] [PubMed]
  • Hammerling U, Bjelfman C, Påhlman S. Different regulation of N- and c-myc expression during phorbol ester-induced maturation of human SH-SY5Y neuroblastoma cells. Oncogene. 1987;2(1):73–77. [PubMed]
  • Hoffman DW, Query CC, Golden BL, White SW, Keene JD. RNA-binding domain of the A protein component of the U1 small nuclear ribonucleoprotein analyzed by NMR spectroscopy is structurally similar to ribosomal proteins. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2495–2499. [PMC free article] [PubMed]
  • Jalava AM, Heikkilä JE, Akerman KE. Decline in c-myc mRNA expression but not the induction of c-fos mRNA expression is associated with differentiation of SH-SY5Y human neuroblastoma cells. Exp Cell Res. 1988 Nov;179(1):10–17. [PubMed]
  • Jiménez F, Campos-Ortega JA. A region of the Drosophila genome necessary for CNS development. Nature. 1979 Nov 15;282(5736):310–312. [PubMed]
  • Johnson BE, Makuch RW, Simmons AD, Gazdar AF, Burch D, Cashell AW. myc family DNA amplification in small cell lung cancer patients' tumors and corresponding cell lines. Cancer Res. 1988 Sep 15;48(18):5163–5166. [PubMed]
  • Jones TR, Cole MD. Rapid cytoplasmic turnover of c-myc mRNA: requirement of the 3' untranslated sequences. Mol Cell Biol. 1987 Dec;7(12):4513–4521. [PMC free article] [PubMed]
  • Keene JD, Query CC. Nuclear RNA-binding proteins. Prog Nucleic Acid Res Mol Biol. 1991;41:179–202. [PubMed]
  • Kim YJ, Baker BS. The Drosophila gene rbp9 encodes a protein that is a member of a conserved group of putative RNA binding proteins that are nervous system-specific in both flies and humans. J Neurosci. 1993 Mar;13(3):1045–1056. [PubMed]
  • Kim YJ, Baker BS. Isolation of RRM-type RNA-binding protein genes and the analysis of their relatedness by using a numerical approach. Mol Cell Biol. 1993 Jan;13(1):174–183. [PMC free article] [PubMed]
  • Laird-Offringa IA, Elfferich P, van der Eb AJ. Rapid c-myc mRNA degradation does not require (A + U)-rich sequences or complete translation of the mRNA. Nucleic Acids Res. 1991 May 11;19(9):2387–2394. [PMC free article] [PubMed]
  • Lerner MR, Steitz JA. Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5495–5499. [PMC free article] [PubMed]
  • Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature. 1983 Nov 10;306(5939):194–196. [PubMed]
  • Lutz-Freyermuth C, Query CC, Keene JD. Quantitative determination that one of two potential RNA-binding domains of the A protein component of the U1 small nuclear ribonucleoprotein complex binds with high affinity to stem-loop II of U1 RNA. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6393–6397. [PMC free article] [PubMed]
  • Malter JS. Identification of an AUUUA-specific messenger RNA binding protein. Science. 1989 Nov 3;246(4930):664–666. [PubMed]
  • Myer VE, Lee SI, Steitz JA. Viral small nuclear ribonucleoproteins bind a protein implicated in messenger RNA destabilization. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1296–1300. [PMC free article] [PubMed]
  • Nagai K, Oubridge C, Jessen TH, Li J, Evans PR. Crystal structure of the RNA-binding domain of the U1 small nuclear ribonucleoprotein A. Nature. 1990 Dec 6;348(6301):515–520. [PubMed]
  • Nietfeld W, Mentzel H, Pieler T. The Xenopus laevis poly(A) binding protein is composed of multiple functionally independent RNA binding domains. EMBO J. 1990 Nov;9(11):3699–3705. [PMC free article] [PubMed]
  • Piñol-Roma S, Dreyfuss G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992 Feb 20;355(6362):730–732. [PubMed]
  • Query CC, Bentley RC, Keene JD. A common RNA recognition motif identified within a defined U1 RNA binding domain of the 70K U1 snRNP protein. Cell. 1989 Apr 7;57(1):89–101. [PubMed]
  • Query CC, Bentley RC, Keene JD. A specific 31-nucleotide domain of U1 RNA directly interacts with the 70K small nuclear ribonucleoprotein component. Mol Cell Biol. 1989 Nov;9(11):4872–4881. [PMC free article] [PubMed]
  • Query CC, Keene JD. A human autoimmune protein associated with U1 RNA contains a region of homology that is cross-reactive with retroviral p30gag antigen. Cell. 1987 Oct 23;51(2):211–220. [PubMed]
  • Rabbitts PH, Forster A, Stinson MA, Rabbitts TH. 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. [PMC free article] [PubMed]
  • Robinow S, Campos AR, Yao KM, White K. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs. Science. 1988 Dec 16;242(4885):1570–1572. [PubMed]
  • Robinow S, White K. The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages. Dev Biol. 1988 Apr;126(2):294–303. [PubMed]
  • Rosenberg AH, Lade BN, Chui DS, Lin SW, Dunn JJ, Studier FW. Vectors for selective expression of cloned DNAs by T7 RNA polymerase. Gene. 1987;56(1):125–135. [PubMed]
  • Sachs AB, Bond MW, Kornberg RD. A single gene from yeast for both nuclear and cytoplasmic polyadenylate-binding proteins: domain structure and expression. Cell. 1986 Jun 20;45(6):827–835. [PubMed]
  • Scherly D, Dathan NA, Boelens W, van Venrooij WJ, Mattaj IW. The U2B'' RNP motif as a site of protein-protein interaction. EMBO J. 1990 Nov;9(11):3675–3681. [PMC free article] [PubMed]
  • Schuler GD, Cole MD. GM-CSF and oncogene mRNA stabilities are independently regulated in trans in a mouse monocytic tumor. Cell. 1988 Dec 23;55(6):1115–1122. [PubMed]
  • 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. [PubMed]
  • Shyu AB, Greenberg ME, Belasco JG. The c-fos transcript is targeted for rapid decay by two distinct mRNA degradation pathways. Genes Dev. 1989 Jan;3(1):60–72. [PubMed]
  • Sorrentino V, Pepperkok R, Davis RL, Ansorge W, Philipson L. Cell proliferation inhibited by MyoD1 independently of myogenic differentiation. Nature. 1990 Jun 28;345(6278):813–815. [PubMed]
  • Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J, Posner JB, Furneaux HM. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell. 1991 Oct 18;67(2):325–333. [PubMed]
  • Tian Q, Streuli M, Saito H, Schlossman SF, Anderson P. A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell. 1991 Nov 1;67(3):629–639. [PubMed]
  • Tsai DE, Harper DS, Keene JD. U1-snRNP-A protein selects a ten nucleotide consensus sequence from a degenerate RNA pool presented in various structural contexts. Nucleic Acids Res. 1991 Sep 25;19(18):4931–4936. [PMC free article] [PubMed]
  • Tsai DE, Keene JD. In vitro selection of RNA epitopes using autoimmune patient serum. J Immunol. 1993 Feb 1;150(3):1137–1145. [PubMed]
  • Tsai DE, Kenan DJ, Keene JD. In vitro selection of an RNA epitope immunologically cross-reactive with a peptide. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8864–8868. [PMC free article] [PubMed]
  • Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science. 1990 Aug 3;249(4968):505–510. [PubMed]
  • Vakalopoulou E, Schaack J, Shenk T. A 32-kilodalton protein binds to AU-rich domains in the 3' untranslated regions of rapidly degraded mRNAs. Mol Cell Biol. 1991 Jun;11(6):3355–3364. [PMC free article] [PubMed]
  • Villares R, Cabrera CV. The achaete-scute gene complex of D. melanogaster: conserved domains in a subset of genes required for neurogenesis and their homology to myc. Cell. 1987 Jul 31;50(3):415–424. [PubMed]
  • von Besser H, Schnabel P, Wieland C, Fritz E, Stanewsky R, Saumweber H. The puff-specific Drosophila protein Bj6, encoded by the gene no-on transient A, shows homology to RNA-binding proteins. Chromosoma. 1990 Dec;100(1):37–47. [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...