Search tips
Search criteria 


Logo of narLink to Publisher's site
Nucleic Acids Res. 1992 January 11; 20(1): 63–68.
PMCID: PMC310326

The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter.


The structure of the promoter of the human APP gene resembles that of housekeeping genes, with the presence of a GC-rich region and the lack of a canonical TATA box. Since analysis of the expression of the APP gene, especially at the transcriptional level, might reveal factors or elements, which influence amyloid formation in Alzheimer's disease, a 5' deletion analysis of the APP promoter was performed, leading to the identification of an activating DNA fragment (Ac), acting also on a heterologous promoter. DNaseI-footprint analysis revealed three protected regions on the Ac fragment. Further gene transfer experiments showed, that at least two elements, designated A and C, confer transcriptional activity in HeLa cells. Whereas the proximal element A is a 19bp long GC-rich DNA sequence, the distal element C is a GC-palindrome with the sequence 5'GCGGCGCCGC.

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 (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Müller-Hill B, Beyreuther K. Molecular biology of Alzheimer's disease. Annu Rev Biochem. 1989;58:287–307. [PubMed]
  • Selkoe DJ. Biochemistry of altered brain proteins in Alzheimer's disease. Annu Rev Neurosci. 1989;12:463–490. [PubMed]
  • Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, 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. [PubMed]
  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, 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. [PubMed]
  • Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. [PubMed]
  • Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. [PubMed]
  • Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 1988 Feb 11;331(6156):528–530. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Weidemann A, König G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989 Apr 7;57(1):115–126. [PubMed]
  • de Sauvage F, Octave JN. A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein. Science. 1989 Aug 11;245(4918):651–653. [PubMed]
  • Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG. Expression of beta amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron. 1990 Feb;4(2):253–267. [PubMed]
  • Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL. Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing. Science. 1990 Apr 27;248(4954):492–495. [PubMed]
  • Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144–147. [PubMed]
  • Van Nostrand WE, Wagner SL, Suzuki M, Choi BH, Farrow JS, Geddes JW, Cotman CW, Cunningham DD. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature. 1989 Oct 12;341(6242):546–549. [PubMed]
  • Buxbaum JD, Gandy SE, Cicchetti P, Ehrlich ME, Czernik AJ, Fracasso RP, Ramabhadran TV, Unterbeck AJ, Greengard P. Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):6003–6006. [PubMed]
  • Quon D, Wang Y, Catalano R, Scardina JM, Murakami K, Cordell B. Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature. 1991 Jul 18;352(6332):239–241. [PubMed]
  • Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, Vitek MP, Gajdusek DC. Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7606–7610. [PubMed]
  • Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y. Genomic organization of the human amyloid beta-protein precursor gene. Gene. 1990 Mar 15;87(2):257–263. [PubMed]
  • Mobley WC, Neve RL, Prusiner SB, McKinley MP. Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9811–9815. [PubMed]
  • Quon D, Catalano R, Cordell B. Fibroblast growth factor induces beta-amyloid precursor mRNA in glial but not neuronal cultured cells. Biochem Biophys Res Commun. 1990 Feb 28;167(1):96–102. [PubMed]
  • König G, Masters CL, Beyreuther K. Retinoic acid induced differentiated neuroblastoma cells show increased expression of the beta A4 amyloid gene of Alzheimer's disease and an altered splicing pattern. FEBS Lett. 1990 Sep 3;269(2):305–310. [PubMed]
  • Mönning U, König G, Prior R, Mechler H, Schreiter-Gasser U, Masters CL, Beyreuther K. Synthesis and secretion of Alzheimer amyloid beta A4 precursor protein by stimulated human peripheral blood leucocytes. FEBS Lett. 1990 Dec 17;277(1-2):261–266. [PubMed]
  • Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL. 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. [PubMed]
  • Neve RL, Rogers J, Higgins GA. The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain. Neuron. 1990 Sep;5(3):329–338. [PubMed]
  • Salbaum JM, Weidemann A, Lemaire HG, Masters CL, Beyreuther K. The promoter of Alzheimer's disease amyloid A4 precursor gene. EMBO J. 1988 Sep;7(9):2807–2813. [PubMed]
  • Wirak DO, Bayney R, Kundel CA, Lee A, Scangos GA, Trapp BD, Unterbeck AJ. Regulatory region of human amyloid precursor protein (APP) gene promotes neuron-specific gene expression in the CNS of transgenic mice. EMBO J. 1991 Feb;10(2):289–296. [PubMed]
  • Henikoff S. Unidirectional digestion with exonuclease III creates targeted breakpoints for DNA sequencing. Gene. 1984 Jun;28(3):351–359. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed]
  • Kadonaga JT, Tjian R. Affinity purification of sequence-specific DNA binding proteins. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5889–5893. [PubMed]
  • van der Eb AJ, Graham FL. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. [PubMed]
  • Hall CV, Jacob PE, Ringold GM, Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed]
  • Williams TM, Burlein JE, Ogden S, Kricka LJ, Kant JA. Advantages of firefly luciferase as a reporter gene: application to the interleukin-2 gene promoter. Anal Biochem. 1989 Jan;176(1):28–32. [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]
  • Lee KA, Bindereif A, Green MR. A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Anal Tech. 1988 Mar-Apr;5(2):22–31. [PubMed]
  • Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. [PubMed]
  • Lahiri DK, Robakis NK. The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences. Brain Res Mol Brain Res. 1991 Feb;9(3):253–257. [PubMed]
  • McKnight S, Tjian R. Transcriptional selectivity of viral genes in mammalian cells. Cell. 1986 Sep 12;46(6):795–805. [PubMed]
  • Johnson PF, McKnight SL. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. [PubMed]
  • Galas DJ, Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res. 1978 Sep;5(9):3157–3170. [PMC free article] [PubMed]
  • Lee W, Mitchell P, Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987 Jun 19;49(6):741–752. [PubMed]
  • Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. [PubMed]
  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704–706. [PubMed]
  • Tazi J, Bird A. Alternative chromatin structure at CpG islands. Cell. 1990 Mar 23;60(6):909–920. [PubMed]
  • Pugh BF, Tjian R. Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell. 1990 Jun 29;61(7):1187–1197. [PubMed]
  • Iguchi-Ariga SM, Schaffner W. CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Dev. 1989 May;3(5):612–619. [PubMed]
  • Watt F, Molloy PL. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 1988 Sep;2(9):1136–1143. [PubMed]
  • Höller M, Westin G, Jiricny J, Schaffner W. Sp1 transcription factor binds DNA and activates transcription even when the binding site is CpG methylated. Genes Dev. 1988 Sep;2(9):1127–1135. [PubMed]
  • Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, 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. [PubMed]
  • Crosby SD, Puetz JJ, Simburger KS, Fahrner TJ, Milbrandt J. The early response gene NGFI-C encodes a zinc finger transcriptional activator and is a member of the GCGGGGGCG (GSG) element-binding protein family. Mol Cell Biol. 1991 Aug;11(8):3835–3841. [PMC free article] [PubMed]
  • Christy B, Nathans D. DNA binding site of the growth factor-inducible protein Zif268. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8737–8741. [PubMed]
  • Sukhatme VP, Cao XM, Chang LC, Tsai-Morris CH, Stamenkovich D, Ferreira PC, Cohen DR, Edwards SA, Shows TB, Curran T, et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988 Apr 8;53(1):37–43. [PubMed]
  • Hazel TG, Misra R, Davis IJ, Greenberg ME, Lau LF. Nur77 is differentially modified in PC12 cells upon membrane depolarization and growth factor treatment. Mol Cell Biol. 1991 Jun;11(6):3239–3246. [PMC free article] [PubMed]
  • Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron. 1988 May;1(3):183–188. [PubMed]
  • Sheng M, Greenberg ME. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990 Apr;4(4):477–485. [PubMed]
  • Scott JN, Parhad IM, Clark AW. Beta-amyloid precursor protein gene is differentially expressed in axotomized sensory and motor systems. Brain Res Mol Brain Res. 1991 Jul;10(4):315–325. [PubMed]

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