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. 1988 Sep;7(9):2807–2813. doi: 10.1002/j.1460-2075.1988.tb03136.x

The promoter of Alzheimer's disease amyloid A4 precursor gene.

J M Salbaum 1, A Weidemann 1, H G Lemaire 1, C L Masters 1, K Beyreuther 1
PMCID: PMC457072  PMID: 3053167

Abstract

The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.

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Selected References

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  1. Bahmanyar S., Higgins G. A., Goldgaber D., Lewis D. A., Morrison J. H., Wilson M. C., Shankar S. K., Gajdusek D. C. Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science. 1987 Jul 3;237(4810):77–80. doi: 10.1126/science.3299701. [DOI] [PubMed] [Google Scholar]
  2. Basler K., Oesch B., Scott M., Westaway D., Wälchli M., Groth D. F., McKinley M. P., Prusiner S. B., Weissmann C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell. 1986 Aug 1;46(3):417–428. doi: 10.1016/0092-8674(86)90662-8. [DOI] [PubMed] [Google Scholar]
  3. Benditt E. P., Eriksen N. Chemical classes of amyloid substance. Am J Pathol. 1971 Oct;65(1):231–252. [PMC free article] [PubMed] [Google Scholar]
  4. Bendotti C., Forloni G. L., Morgan R. A., O'Hara B. F., Oster-Granite M. L., Reeves R. H., Gearhart J. D., Coyle J. T. Neuroanatomical localization and quantification of amyloid precursor protein mRNA by in situ hybridization in the brains of normal, aneuploid, and lesioned mice. Proc Natl Acad Sci U S A. 1988 May;85(10):3628–3632. doi: 10.1073/pnas.85.10.3628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Biedler J. L., Helson L., Spengler B. A. Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973 Nov;33(11):2643–2652. [PubMed] [Google Scholar]
  6. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  7. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  8. Cohen M. L., Golde T. E., Usiak M. F., Younkin L. H., Younkin S. G. In situ hybridization of nucleus basalis neurons shows increased beta-amyloid mRNA in Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1227–1231. doi: 10.1073/pnas.85.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dignam J. D., Lebovitz R. M., Roeder R. G. 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. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doerfler W. DNA methylation and gene activity. Annu Rev Biochem. 1983;52:93–124. doi: 10.1146/annurev.bi.52.070183.000521. [DOI] [PubMed] [Google Scholar]
  11. Dynan W. S., Tjian R. Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II. Cell. 1983 Mar;32(3):669–680. doi: 10.1016/0092-8674(83)90053-3. [DOI] [PubMed] [Google Scholar]
  12. Dyrks T., Weidemann A., Multhaup G., Salbaum J. M., Lemaire H. G., Kang J., Müller-Hill B., Masters C. L., Beyreuther K. Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J. 1988 Apr;7(4):949–957. doi: 10.1002/j.1460-2075.1988.tb02900.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  14. Giguére V., Isobe K., Grosveld F. Structure of the murine Thy-1 gene. EMBO J. 1985 Aug;4(8):2017–2024. doi: 10.1002/j.1460-2075.1985.tb03886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Glenner G. G., Wong C. W. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984 Aug 16;122(3):1131–1135. doi: 10.1016/0006-291x(84)91209-9. [DOI] [PubMed] [Google Scholar]
  16. Goedert M. Neuronal localization of amyloid beta protein precursor mRNA in normal human brain and in Alzheimer's disease. EMBO J. 1987 Dec 1;6(12):3627–3632. doi: 10.1002/j.1460-2075.1987.tb02694.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
  18. Higgins G. A., Lewis D. A., Bahmanyar S., Goldgaber D., Gajdusek D. C., Young W. G., Morrison J. H., Wilson M. C. Differential regulation of amyloid-beta-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1297–1301. doi: 10.1073/pnas.85.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Karin M., Haslinger A., Holtgreve H., Richards R. I., Krauter P., Westphal H. M., Beato M. Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene. Nature. 1984 Apr 5;308(5959):513–519. doi: 10.1038/308513a0. [DOI] [PubMed] [Google Scholar]
  21. Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H. Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature. 1988 Feb 11;331(6156):530–532. doi: 10.1038/331530a0. [DOI] [PubMed] [Google Scholar]
  22. Lee W., Haslinger A., Karin M., Tjian R. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40. Nature. 1987 Jan 22;325(6102):368–372. doi: 10.1038/325368a0. [DOI] [PubMed] [Google Scholar]
  23. Lewis D. A., Higgins G. A., Young W. G., Goldgaber D., Gajdusek D. C., Wilson M. C., Morrison J. H. Distribution of precursor amyloid-beta-protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1691–1695. doi: 10.1073/pnas.85.5.1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lindquist S. The heat-shock response. Annu Rev Biochem. 1986;55:1151–1191. doi: 10.1146/annurev.bi.55.070186.005443. [DOI] [PubMed] [Google Scholar]
  25. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Masters C. L., Multhaup G., Simms G., Pottgiesser J., Martins R. N., Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985 Nov;4(11):2757–2763. doi: 10.1002/j.1460-2075.1985.tb04000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ponte P., Gonzalez-DeWhitt P., Schilling J., Miller J., Hsu D., Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F. A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature. 1988 Feb 11;331(6156):525–527. doi: 10.1038/331525a0. [DOI] [PubMed] [Google Scholar]
  29. Rauscher F. J., 3rd, Sambucetti L. C., Curran T., Distel R. J., Spiegelman B. M. Common DNA binding site for Fos protein complexes and transcription factor AP-1. Cell. 1988 Feb 12;52(3):471–480. doi: 10.1016/s0092-8674(88)80039-4. [DOI] [PubMed] [Google Scholar]
  30. Razin A., Riggs A. D. DNA methylation and gene function. Science. 1980 Nov 7;210(4470):604–610. doi: 10.1126/science.6254144. [DOI] [PubMed] [Google Scholar]
  31. Robakis N. K., Ramakrishna N., Wolfe G., Wisniewski H. M. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4190–4194. doi: 10.1073/pnas.84.12.4190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ruppert C., Goldowitz D., Wille W. Proto-oncogene c-myc is expressed in cerebellar neurons at different developmental stages. EMBO J. 1986 Aug;5(8):1897–1901. doi: 10.1002/j.1460-2075.1986.tb04442.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schöler H. R., Gruss P. Specific interaction between enhancer-containing molecules and cellular components. Cell. 1984 Feb;36(2):403–411. doi: 10.1016/0092-8674(84)90233-2. [DOI] [PubMed] [Google Scholar]
  35. Shivers B. D., Hilbich C., Multhaup G., Salbaum M., Beyreuther K., Seeburg P. H. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. EMBO J. 1988 May;7(5):1365–1370. doi: 10.1002/j.1460-2075.1988.tb02952.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Staudt L. M., Singh H., Sen R., Wirth T., Sharp P. A., Baltimore D. A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes. Nature. 1986 Oct 16;323(6089):640–643. doi: 10.1038/323640a0. [DOI] [PubMed] [Google Scholar]
  37. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
  38. Tanzi R. E., McClatchey A. I., Lamperti E. D., Villa-Komaroff L., Gusella J. F., Neve R. L. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 1988 Feb 11;331(6156):528–530. doi: 10.1038/331528a0. [DOI] [PubMed] [Google Scholar]
  39. Valerio D., Duyvesteyn M. G., Dekker B. M., Weeda G., Berkvens T. M., van der Voorn L., van Ormondt H., van der Eb A. J. Adenosine deaminase: characterization and expression of a gene with a remarkable promoter. EMBO J. 1985 Feb;4(2):437–443. doi: 10.1002/j.1460-2075.1985.tb03648.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Van Broeckhoven C., Genthe A. M., Vandenberghe A., Horsthemke B., Backhovens H., Raeymaekers P., Van Hul W., Wehnert A., Gheuens J., Cras P. Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature. 1987 Sep 10;329(6135):153–155. doi: 10.1038/329153a0. [DOI] [PubMed] [Google Scholar]
  41. Wu C., Wilson S., Walker B., Dawid I., Paisley T., Zimarino V., Ueda H. Purification and properties of Drosophila heat shock activator protein. Science. 1987 Nov 27;238(4831):1247–1253. doi: 10.1126/science.3685975. [DOI] [PubMed] [Google Scholar]
  42. Zimmermann K., Herget T., Salbaum J. M., Schubert W., Hilbich C., Cramer M., Masters C. L., Multhaup G., Kang J., Lemaire H. G. Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle. EMBO J. 1988 Feb;7(2):367–372. doi: 10.1002/j.1460-2075.1988.tb02822.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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