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.
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.
Maloney
Bryan
B
Departments of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Ge
Yuan-Wen
YW
Greig
Nigel
N
Lahiri
Debomoy K
DK
D020121:5' Untranslated Regions / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics; D002417:Cattle; D006224:Cricetinae; D004331:Drosophila melanogaster / Q000235:genetics; D005399:Fishes / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter; D005979:Glutathione Peroxidase; D006168:Guinea Pigs; D006801:Humans; D008322:Mammals / Q000235:genetics; D051379:Mice; D005810:Multigene Family / Q000235:genetics*; D009690:Nucleic Acid Conformation; D016716:PC12 Cells / Q000378:metabolism; D010454:Peptide Termination Factors; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D017510:Protein Folding; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D016415:Sequence Alignment; D017385:Sequence Homology; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014162:Transfection
D020121:5' Untranslated Regions; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; C512656:PRNP protein, human; D010454:Peptide Termination Factors; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011498:Protein Precursors; D012333:RNA, Messenger; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae