Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1998 Jul 15;26(14):3418–3423. doi: 10.1093/nar/26.14.3418

hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA.

L E Rajagopalan 1, C J Westmark 1, J A Jarzembowski 1, J S Malter 1
PMCID: PMC147701  PMID: 9649628

Abstract

We have previously shown that heterogeneous nuclear ribonucleoprotein C (hnRNP C) and nucleolin bound specifically to a 29 nt sequence in the 3'-untranslated region of amyloid precursor protein (APP) mRNA. Upon activation of peripheral blood mononuclear cells, hnRNP C and nucleolin acquired APP mRNA binding activity, concurrent with APP mRNA stabilization. These data suggested that the regulated interaction of hnRNP C and nucleolin with APP mRNA controlled its stability. Here we have directly examined the role of the cis element and trans factors in the turnover and translation of APP mRNA in vitro . In a rabbit reticulocyte lysate (RRL) translation system, a mutant APP mRNA lacking the 29 nt element was 3-4-fold more stable and synthesized 2-4-fold more APP as wild-type APP mRNA. Therefore, the 29 nt element functioned as an APP mRNA destabilizer. RNA gel mobility shift assays with the RRL suggested the presence of endogenous nucleolin, but failed to show hnRNP C binding activity. However, wild-type APP mRNA was stabilized and coded for 6-fold more APP when translated in an RRL system supplemented with exogenous active hnRNP C. Control mRNAs lacking the 29 nt element were unaffected by hnRNP C supplementation. Therefore, occupancy of the 29 nt element by hnRNP C stabilized APP mRNA and enhanced its translation.

Full Text

The Full Text of this article is available as a PDF (141.1 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. Altus M. S., Nagamine Y. Protein synthesis inhibition stabilizes urokinase-type plasminogen activator mRNA. Studies in vivo and in cell-free decay reactions. J Biol Chem. 1991 Nov 5;266(31):21190–21196. [PubMed] [Google Scholar]
  3. Bickel M., Cohen R. B., Pluznik D. H. Post-transcriptional regulation of granulocyte-macrophage colony-stimulating factor synthesis in murine T cells. J Immunol. 1990 Aug 1;145(3):840–845. [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. Cai X. D., Golde T. E., Younkin S. G. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514–516. doi: 10.1126/science.8424174. [DOI] [PubMed] [Google Scholar]
  7. Chen C. Y., Xu N., Shyu A. B. mRNA decay mediated by two distinct AU-rich elements from c-fos and granulocyte-macrophage colony-stimulating factor transcripts: different deadenylation kinetics and uncoupling from translation. Mol Cell Biol. 1995 Oct;15(10):5777–5788. doi: 10.1128/mcb.15.10.5777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chung S., Eckrich M., Perrone-Bizzozero N., Kohn D. T., Furneaux H. The Elav-like proteins bind to a conserved regulatory element in the 3'-untranslated region of GAP-43 mRNA. J Biol Chem. 1997 Mar 7;272(10):6593–6598. doi: 10.1074/jbc.272.10.6593. [DOI] [PubMed] [Google Scholar]
  9. Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., Vigo-Pelfrey C., Lieberburg I., Selkoe D. J. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672–674. doi: 10.1038/360672a0. [DOI] [PubMed] [Google Scholar]
  10. Fukuchi K., Kamino K., Deeb S. S., Smith A. C., Dang T., Martin G. M. Overexpression of amyloid precursor protein alters its normal processing and is associated with neurotoxicity. Biochem Biophys Res Commun. 1992 Jan 15;182(1):165–173. doi: 10.1016/s0006-291x(05)80126-3. [DOI] [PubMed] [Google Scholar]
  11. Ghisolfi-Nieto L., Joseph G., Puvion-Dutilleul F., Amalric F., Bouvet P. Nucleolin is a sequence-specific RNA-binding protein: characterization of targets on pre-ribosomal RNA. J Mol Biol. 1996 Jul 5;260(1):34–53. doi: 10.1006/jmbi.1996.0380. [DOI] [PubMed] [Google Scholar]
  12. Gillis P., Malter J. S. The adenosine-uridine binding factor recognizes the AU-rich elements of cytokine, lymphokine, and oncogene mRNAs. J Biol Chem. 1991 Feb 15;266(5):3172–3177. [PubMed] [Google Scholar]
  13. Goldberg M. A., Gaut C. C., Bunn H. F. Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. Blood. 1991 Jan 15;77(2):271–277. [PubMed] [Google Scholar]
  14. Gorospe M., Baglioni C. Degradation of unstable interleukin-1 alpha mRNA in a rabbit reticulocyte cell-free system. Localization of an instability determinant to a cluster of AUUUA motifs. J Biol Chem. 1994 Apr 22;269(16):11845–11851. [PubMed] [Google Scholar]
  15. Görlach M., Burd C. G., Dreyfuss G. The determinants of RNA-binding specificity of the heterogeneous nuclear ribonucleoprotein C proteins. J Biol Chem. 1994 Sep 16;269(37):23074–23078. [PubMed] [Google Scholar]
  16. Hepler J. E., Van Wyk J. J., Lund P. K. Different half-lives of insulin-like growth factor I mRNAs that differ in length of 3' untranslated sequence. Endocrinology. 1990 Sep;127(3):1550–1552. doi: 10.1210/endo-127-3-1550. [DOI] [PubMed] [Google Scholar]
  17. Higgins L. S., Rodems J. M., Catalano R., Quon D., Cordell B. Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4402–4406. doi: 10.1073/pnas.92.10.4402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Holtzman D. M., Bayney R. M., Li Y. W., Khosrovi H., Berger C. N., Epstein C. J., Mobley W. C. Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J. 1992 Feb;11(2):619–627. doi: 10.1002/j.1460-2075.1992.tb05094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hsiao K. K., Borchelt D. R., Olson K., Johannsdottir R., Kitt C., Yunis W., Xu S., Eckman C., Younkin S., Price D. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron. 1995 Nov;15(5):1203–1218. doi: 10.1016/0896-6273(95)90107-8. [DOI] [PubMed] [Google Scholar]
  20. Iwai Y., Akahane K., Pluznik D. H., Cohen R. B. Ca2+ ionophore A23187-dependent stabilization of granulocyte-macrophage colony-stimulating factor messenger RNA in murine thymoma EL-4 cells is mediated through two distinct regions in the 3'-untranslated region. J Immunol. 1993 May 15;150(10):4386–4394. [PubMed] [Google Scholar]
  21. Iwai Y., Bickel M., Pluznik D. H., Cohen R. B. Identification of sequences within the murine granulocyte-macrophage colony-stimulating factor mRNA 3'-untranslated region that mediate mRNA stabilization induced by mitogen treatment of EL-4 thymoma cells. J Biol Chem. 1991 Sep 25;266(27):17959–17965. [PubMed] [Google Scholar]
  22. Johnson S. A., McNeill T., Cordell B., Finch C. E. Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease. Science. 1990 May 18;248(4957):854–857. doi: 10.1126/science.2111579. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Levy N. S., Chung S., Furneaux H., Levy A. P. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem. 1998 Mar 13;273(11):6417–6423. doi: 10.1074/jbc.273.11.6417. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Moran P. M., Higgins L. S., Cordell B., Moser P. C. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5341–5345. doi: 10.1073/pnas.92.12.5341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nakagawa T. Y., Swanson M. S., Wold B. J., Dreyfuss G. Molecular cloning of cDNA for the nuclear ribonucleoprotein particle C proteins: a conserved gene family. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2007–2011. doi: 10.1073/pnas.83.7.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Rajagopalan L. E., Burkholder J. K., Turner J., Culp J., Yang N. S., Malter J. S. Granulocyte-macrophage colony-stimulating factor mRNA stabilization enhances transgenic expression in normal cells and tissues. Blood. 1995 Oct 1;86(7):2551–2558. [PubMed] [Google Scholar]
  33. Rajagopalan L. E., Malter J. S. Modulation of granulocyte-macrophage colony-stimulating factor mRNA stability in vitro by the adenosine-uridine binding factor. J Biol Chem. 1994 Sep 30;269(39):23882–23888. [PubMed] [Google Scholar]
  34. Rajagopalan L. E., Malter J. S. Regulation of eukaryotic messenger RNA turnover. Prog Nucleic Acid Res Mol Biol. 1997;56:257–286. doi: 10.1016/s0079-6603(08)61007-7. [DOI] [PubMed] [Google Scholar]
  35. Rajagopalan L. E., Malter J. S. Turnover and translation of in vitro synthesized messenger RNAs in transfected, normal cells. J Biol Chem. 1996 Aug 16;271(33):19871–19876. doi: 10.1074/jbc.271.33.19871. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Ross J. mRNA stability in mammalian cells. Microbiol Rev. 1995 Sep;59(3):423–450. doi: 10.1128/mr.59.3.423-450.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rumble B., Retallack R., Hilbich C., Simms G., Multhaup G., Martins R., Hockey A., Montgomery P., Beyreuther K., Masters C. L. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989 Jun 1;320(22):1446–1452. doi: 10.1056/NEJM198906013202203. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Seiser C., Posch M., Thompson N., Kühn L. C. Effect of transcription inhibitors on the iron-dependent degradation of transferrin receptor mRNA. J Biol Chem. 1995 Dec 8;270(49):29400–29406. doi: 10.1074/jbc.270.49.29400. [DOI] [PubMed] [Google Scholar]
  41. Selkoe D. J. Physiological production of the beta-amyloid protein and the mechanism of Alzheimer's disease. Trends Neurosci. 1993 Oct;16(10):403–409. doi: 10.1016/0166-2236(93)90008-a. [DOI] [PubMed] [Google Scholar]
  42. Serin G., Joseph G., Faucher C., Ghisolfi L., Bouche G., Amalric F., Bouvet P. Localization of nucleolin binding sites on human and mouse pre-ribosomal RNA. Biochimie. 1996;78(6):530–538. doi: 10.1016/0300-9084(96)84759-6. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. Wisdom R., Lee W. The protein-coding region of c-myc mRNA contains a sequence that specifies rapid mRNA turnover and induction by protein synthesis inhibitors. Genes Dev. 1991 Feb;5(2):232–243. doi: 10.1101/gad.5.2.232. [DOI] [PubMed] [Google Scholar]
  46. Wisdom R., Lee W. The protein-coding region of c-myc mRNA contains a sequence that specifies rapid mRNA turnover and induction by protein synthesis inhibitors. Genes Dev. 1991 Feb;5(2):232–243. doi: 10.1101/gad.5.2.232. [DOI] [PubMed] [Google Scholar]
  47. Wodnar-Filipowicz A., Moroni C. Regulation of interleukin 3 mRNA expression in mast cells occurs at the posttranscriptional level and is mediated by calcium ions. Proc Natl Acad Sci U S A. 1990 Jan;87(2):777–781. doi: 10.1073/pnas.87.2.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wreschner D. H., Rechavi G. Differential mRNA stability to reticulocyte ribonucleases correlates with 3' non-coding (U)nA sequences. Eur J Biochem. 1988 Mar 1;172(2):333–340. doi: 10.1111/j.1432-1033.1988.tb13891.x. [DOI] [PubMed] [Google Scholar]
  49. Yoshikawa K., Aizawa T., Hayashi Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature. 1992 Sep 3;359(6390):64–67. doi: 10.1038/359064a0. [DOI] [PubMed] [Google Scholar]
  50. Yoshikawa K., Aizawa T., Hayashi Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature. 1992 Sep 3;359(6390):64–67. doi: 10.1038/359064a0. [DOI] [PubMed] [Google Scholar]
  51. Zaidi S. H., Denman R., Malter J. S. Multiple proteins interact at a unique cis-element in the 3'-untranslated region of amyloid precursor protein mRNA. J Biol Chem. 1994 Sep 30;269(39):24000–24006. [PubMed] [Google Scholar]
  52. Zaidi S. H., Malter J. S. Amyloid precursor protein mRNA stability is controlled by a 29-base element in the 3'-untranslated region. J Biol Chem. 1994 Sep 30;269(39):24007–24013. [PubMed] [Google Scholar]
  53. Zaidi S. H., Malter J. S. Nucleolin and heterogeneous nuclear ribonucleoprotein C proteins specifically interact with the 3'-untranslated region of amyloid protein precursor mRNA. J Biol Chem. 1995 Jul 21;270(29):17292–17298. doi: 10.1074/jbc.270.29.17292. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES