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. 2004 Aug;18(11):1288-90. doi: 10.1096/fj.03-1703fje. Epub 2004 Jun 18.

Abstract

Potentially toxic amyloid beta-peptide (Abeta) in Alzheimer's disease (AD) is generated from a family of Abeta-containing precursor proteins (APP), which is regulated via the 5'-untranslated region (5'-UTR) of its mRNA. We analyzed 5'-UTRs of the APP superfamily, including amyloid plaque-forming and non-amyloid plaque-forming species, and of prions (27 different DNA sequences). A "CAGA" sequence proximal to the "ATG" start codon was present in a location unique to APP genes of amyloid plaque-forming species and absent in all other genes surveyed. This CAGA box is immediately upstream of an interleukin-1-responsive element (acute box). In addition, the proximal CAGA box is predicted to appear on a stem-loop structure in both human and guinea pig APP mRNA. This stem-loop is part of a predicted bulge-loop that encompasses a known iron regulatory element (IRE). Electrophoretic mobility shift with segments of the APP 5'-UTR showed that a region with the proximal CAGA sequence binds nuclear proteins, and this UTR fragment is active in a reporter gene functional assay. Thus, the 5'-UTR in the human APP but not those of APP-like proteins contains a specific region that may participate in APP regulation and may determine a more general model for amyloid generation as seen in AD. The 5'-UTR of human APP contains several interesting control elements, such as an acute box element, a CAGA box, an IRE, and a transforming growth factor-beta-responsive element, that could control APP expression and provide suitable and specific drug targets for AD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Alzheimer Disease / genetics*
  • Amino Acid Sequence
  • Amyloid / chemistry
  • Amyloid / genetics*
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Base Sequence
  • Caenorhabditis elegans / genetics
  • Cattle
  • Cricetinae
  • Drosophila melanogaster / genetics
  • Fishes / genetics
  • Gene Expression Regulation / genetics
  • Genes, Reporter
  • Glutathione Peroxidase
  • Guinea Pigs
  • Humans
  • Mammals / genetics
  • Mice
  • Multigene Family / genetics*
  • Nucleic Acid Conformation
  • PC12 Cells / metabolism
  • Peptide Termination Factors
  • Prion Proteins
  • Prions / genetics*
  • Protein Folding
  • Protein Precursors / genetics*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Rats
  • Regulatory Sequences, Nucleic Acid*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*
  • Sequence Alignment
  • Sequence Homology
  • Species Specificity
  • Structure-Activity Relationship
  • Transfection

Substances

  • 5' Untranslated Regions
  • Amyloid
  • Amyloid beta-Protein Precursor
  • PRNP protein, human
  • Peptide Termination Factors
  • Prion Proteins
  • Prions
  • Prnp protein, mouse
  • Protein Precursors
  • RNA, Messenger
  • SUP35 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Glutathione Peroxidase
  • URE2 protein, S cerevisiae