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Functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells

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Abstract

The β-amyloid (Aβ) protein present in the neuritic plaques of Alzheimer's disease is cleaved, from Aβ precursor protein (APP) by β-and γ-secretases. Following identification of β-APP cleaving enzyme (BACE1) as the β-secretase, a homologous β-secretase 2 (BACE2) was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATA and CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1, sequence contains more repetitive elements than does BACE2 (no elements). Regulatory domains do not overlapstrongly between the two promoter regions. The BACE1 upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2 sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2-driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion.

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References

  • Acquati F., Accarino M., Nucci C., Fumagalli P., Jovine L., Ottolenghi S., and Taramelli R. (2000) The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett. 468, 59–64.

    Article  PubMed  CAS  Google Scholar 

  • Basi G., Frigon N., Barbour R., Doan T., Gordon G., McConlogue L., et al. (2003) Antagonistic effects of β-site amyloid precursor protein-cleaving enzymes 1 and 2 on β-amyloid peptide production in cells. J. Biol Chem. 278, 31,512–31,520.

    CAS  Google Scholar 

  • Bennett B. D., Babu-Khan S., Loeloff R., Louis J. C., Curran E., Citron M., and Vassar R. (2000) Expression analysis of BACE2 in brain and peripheral tissues. J. Biol. Chem. 275, 20,647–20,651

    CAS  Google Scholar 

  • Benson D. A., Karsch-Mizrachi I., Lipman D. J., Ostell J., and Wheeler D. L. (2005) GenBank. Nucleic Acids Res. 33, D34–38.

    Article  Google Scholar 

  • Bradford M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254.

    Article  PubMed  CAS  Google Scholar 

  • Cady C., Evans M. S., and Brewer G. J. (2001) Age-related differences in NMDA responses in cultured rat hippocampal neurons. Brain Res. 921, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Carrodeguas J. A., Rodolosse A., Garza M. V., Sanz-Clemente A., Perez-Pe R., Lacosta A. M. et al. (2005) The chick embryo appears as a natural model for research in β-amyloid precursor protein processing. Neuroscience 134, 1285–1300.

    Article  PubMed  CAS  Google Scholar 

  • Chen Q. Y. and Jackson N. (2004) Human CD1D gene has TATA boxless dual promoters: an SP1-binding element determines the function of the proximal promoter. J. Immunol. 172, 5512–5521.

    PubMed  CAS  Google Scholar 

  • Christensen M. A., Zhou W., Qing H., Lehman A., Philipsen S., and Song W. (2004) Transcriptional regulation of BACE1 the β-amyloid precursor protein β-secretase, by Sp1. Mol. Cell. Biol. 24, 865–874.

    Article  PubMed  CAS  Google Scholar 

  • Corpet F. (1988) Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 16, 10,881–10,890.

    Article  CAS  Google Scholar 

  • Farzan M., Schnitzler C. E., Vasilieva N., Leung D., and Choe H. (2000) BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl. Acad. Sci. U.S.A. 97, 9712–9717.

    Article  PubMed  CAS  Google Scholar 

  • Ge Y. W., Maloney B., Sambamurti K., and Lahiri D. K. (2004) Functional characterization of the 5′ flanking region of the BACE gene: identification of a 91 b p fragment involved in basallevel of BACE promoter expression. FASEB J. 18, 1037–1039.

    PubMed  CAS  Google Scholar 

  • Ghosh C., Song W., and Lahiri D. K. (2000) Efficient DNA transfection in neuronal and astrocytic cell lines. Mol. Biol. Rep. 27, 113–121.

    Article  PubMed  CAS  Google Scholar 

  • Girish V. and Vijayalakshmi A. (2004) Affordableimage analysis using NIH Image/ImageJ. Indian J. Cancer. 41, 47.

    PubMed  CAS  Google Scholar 

  • Hardy J. and Selkoe D. J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356.

    Article  PubMed  CAS  Google Scholar 

  • Hussain I., Powell D., Howlett D. R., Tew D. G., Meek T. D., Chapman C., et al. (1999) Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 14, 419–427.

    Article  PubMed  CAS  Google Scholar 

  • Ikeo K., Takahashi K., and Gojobori T. (1992) Evolutionary origin of a Kunitz-type trypsin inhibitor domain inserted in the amyloid β precursor protein of Alzheimer's disease. J. Mol. Evol. 34, 536–543.

    Article  PubMed  CAS  Google Scholar 

  • Jurka J., Klonowski P., Dagman V., and Pelton P. (1996). CENSOR—a program for identification and elimination of repetitive elements from DNA sequences. Comput. Chem. 20, 119–121.

    Article  PubMed  CAS  Google Scholar 

  • Kim C. S., Hwang C. K., Choi H. S., Song K. Y., Law P. Y., Wei L. N., and Loh H. H. (2004) Neuron-restrictive silencer factor (NRSF) functions as a repressor in neuronal cells to regulate the mu opioid receptor gene. J. Biol. Chem. 279, 46,464–46,473.

    CAS  Google Scholar 

  • Kitami Y., Fukuoka T., Okura T., Takata Y., Maguchi M., Igase M. et al. (1998) Molecular structure and function of rat platelet-derived growth factor β-receptor gene promoter. J. Hypertens 16, 437–445.

    Article  PubMed  CAS  Google Scholar 

  • Kitami Y., Maguchi M., Nishida W., Okura T., Kohara K., and Hiwada K. (1999) The unique 5′-flanking region of the human basic calponin gene. Hypertens. Res. 22, 187–193.

    Article  PubMed  CAS  Google Scholar 

  • Klein S. L., Strausberg R. L., Wagner L., Pontius J., Clifton S. W., and Richardson P. (2002) Genetic and genomic tools for Xenopus research: The NIH Xenopus initiative. Dev. Dyn. 225, 384–391.

    Article  PubMed  CAS  Google Scholar 

  • Kong A., Gudbjartsson D. F., Sainz J., Jonsdottir G. M., Gudjonsson S. A., Richardsson B., et al. (2002) A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247.

    PubMed  CAS  Google Scholar 

  • Lahiri D. K., Alley G. M., Ge Y. W., and Du Y. (2002) Functional characterization of the 5′-regulatory region of the murine apolipoprotein gene. Ann. N. Y. Acad. Sci. 973, 340–344.

    Article  PubMed  CAS  Google Scholar 

  • Lahiri D. K. and Ge Y. (2000) Electrophoretic mobility shift assay for the detection of specific DNA-protein complex in nuclear extracts from the cultured cells and frozen autopsy human brain tissue. Brain Res. Brain Res. Protoc. 5, 257–265.

    Article  PubMed  CAS  Google Scholar 

  • Lahiri D. K., Farlow M. R., Sambamurti K., Greig N. H., Giacobini E., and Schneider L. S. (2003) A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease. Curr. Drug Targets 4, 97–112.

    Article  PubMed  CAS  Google Scholar 

  • Lahiri D. K., Ge Y.-W., and Maloney B. (2005a) Characterization of the APP proximal promoter and 5′-untranslated regions: identification of cell-type specific domains and implications in APP gene expression and Alzheimer's disease. FASEB J. 19, 653–655.

    PubMed  CAS  Google Scholar 

  • Lahiri D. K., Maloney B., and Ge Y.-W. (2006) BACE1 gene promoter is differentially regulated: detection of a novel promoter region for its cell type-specific regulation. J. Mol. Neurosci., in press.

  • Lahiri D. K., Nall C., and Ge Y. W. (1999) Promoter activity of the β-amyloid precursor protein gene is negatively modulated by an upstream regulatory element. Brain Res. Mol. Brain Res. 71, 32–41.

    Article  PubMed  CAS  Google Scholar 

  • Lahiri D. K., Sambamurti K., and Bennett D. A. (2004) Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer's disease. Neurobiol. Aging 25, 651–660.

    Article  PubMed  CAS  Google Scholar 

  • Lahiri D. K., Wavrant De-Vrieze F., Ge Y.-W., Maloney B., and Hardy J. (2005b) Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease. Neurobiol. Aging 26, 1329–1341.

    Article  PubMed  CAS  Google Scholar 

  • Li Y. P. and Chen W. (1999) Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression. J. Bone Miner. Res. 14, 487–499.

    Article  PubMed  CAS  Google Scholar 

  • Lin X., Koelsch G., Wu S., Downs D., Dashti A., and Tang J. (2000) Human aspartic protease memapsin 2 cleaves the β-secretasesite of β-amyloid precursor protein. Proc. Natl. Acad. Sci. U. S. A. 97, 1456–1460.

    Article  PubMed  CAS  Google Scholar 

  • Long J. A. and Gordon M. S. (2004) The greatest step in vertebrate history: a paleobiological review of the fish-tetrapod transition. Physiol. Biochem. Zool. 77, 700–719.

    Article  PubMed  Google Scholar 

  • Maloney B., Ge Y.-W., and Lahiri D. K. (2006) Structural and functional characterization of the human β-secretase 2 (BACE2) 5′-flanking region: identification of a 268-kb region as the basal BACE2 promoter. J. Mol. Neurosci., this issue.

  • Maloney B., Ge Y.-W., Greig N., and Lahiri D. K. (2004) Presence of a “CAGA box” in the APP gene unique to amyloid plaque-forming species and absent in all APLP-1/2 genes: implications in Alzheimer's disease. FASEB J. 18, 1288–1290.

    Article  PubMed  CAS  Google Scholar 

  • Neve R. L., McPhie D. L., and Chen Y. (2001) Alzheimer's disease: dysfunction of a signalling pathway mediated by the amyloid precursor protein? Biochem. Soc. Symp. 37–50.

  • Pruitt K. D., Tatusova T., and Maglott D. R. (2005) NCBl Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 33, D501-D504.

    Article  PubMed  CAS  Google Scholar 

  • Sambamurti K., Kinsey R., Maloney B., Ge Y.-W., and Lahiri D. K. (2004) Gene structure and organization of the human β-secretase (BACE) promoter. FASEB J. 18, 1034–1036.

    PubMed  CAS  Google Scholar 

  • Schoenherr C. J. and Anderson D. J. (1995) The neuronrestrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363.

    Article  PubMed  CAS  Google Scholar 

  • Solans A., Estivill X., and de la Luna S. (2000) A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein β-secretase. Cytogenet. Cell Genet. 89, 177–184.

    Article  PubMed  CAS  Google Scholar 

  • Song W. and Lahiri D. K. (1998) Molecular cloning of the promoter of the gene encoding the Rhesus monkey β-amyloid precursor protein: structural characterization and a comparative study with other species. Gene 217, 151–164.

    Article  PubMed  CAS  Google Scholar 

  • Stamatoyannopoulos J. A. (2004) The genomics of gene expression. Genomics 84, 449–457.

    Article  PubMed  CAS  Google Scholar 

  • Sun X., Wang Y., Qing H., Christensen M. A., Liu Y., Zhou W., et al. (2005) Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J. 19, 739–749.

    Article  PubMed  CAS  Google Scholar 

  • Vassar R., Bennett B. D., Babu-Khan S., Kahn S., Mendiaz E. A., Denis P., et al. (1999) β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741.

    Article  PubMed  CAS  Google Scholar 

  • Waisman A., Aloni Y., and Laub O. (1990) In vitro regulation of human hepatitis B virus core gene transcription. Virology 177, 737–744.

    Article  PubMed  CAS  Google Scholar 

  • Xie J., Roddy P., Rife T. K., Murad F., and Young A. P. (1995) Two closely linked but separable promoters for human neuronal nitric oxide synthase gene transcription. Proc. Natl. Acad. Sci. U. S. A. 92, 1242–1246.

    Article  PubMed  CAS  Google Scholar 

  • Yan R., Bienkowski M. J., Shuck M. E., Miao H., Tory M. C., Pauley A. M. et al. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537.

    Article  PubMed  CAS  Google Scholar 

  • Yan R., Munzner J. B., Shuck M. E., and Bienkowski M. J. (2001) BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. 276, 34,019–34,027.

    CAS  Google Scholar 

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Correspondence to Debomoy K. Lahiri.

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Lahiri, D.K., Maloney, B. & Ge, YW. Functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells. J Mol Neurosci 29, 65–80 (2006). https://doi.org/10.1385/JMN:29:1:65

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