BACE1 gene expression and protein degradation.
Deposition of amyloid beta protein in the brain is the major pathological feature of Alzheimer's disease. Amyloid beta protein is generated from beta-amyloid precursor protein by beta-secretase and gamma-secretase. Proteolytic processing of amyloid precursor protein at the beta site by BACE1 is essential to generate amyloid beta protein. BACE1, the major beta-secretase involved in cleaving amyloid precursor protein, has been identified as a type 1 membrane-associated aspartyl protease. In this study, we found that BACE1 gene expression is controlled by a TATA-less promoter. BACE1 gene expression is tightly regulated at the transcriptional level and the transcription factor Sp1 plays an important role in regulation of BACE1 to process amyloid precursor protein generating amyloid beta protein. Furthermore, we found that BACE1 protein is ubiquitinated, and the degradation of BACE1 proteins and amyloid precursor protein processing are regulated by the ubiquitin-proteasome pathway.
Zhou
Weihui
W
Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, Canada. weihong@interchange.ubc.ca
Qing
Hong
H
Tong
Yigang
Y
Song
Weihong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D016282:Aspartic Acid Endopeptidases; D045744:Cell Line, Tumor; D003001:Cloning, Molecular / Q000379:methods; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D016296:Mutagenesis / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D013997:Time Factors; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D007546:Isoquinolines; D010446:Peptide Fragments; D016329:Sp1 Transcription Factor; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C067713:lactacystin; C017475:lucifer yellow; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D010751:Phosphopyruvate Hydratase; D000111:Acetylcysteine