Taking down the unindicted co-conspirators of amyloid beta-peptide-mediated neuronal death: shared gene regulation of BACE1 and APP genes interacting with CREB, Fe65 and YY1 transcription factors.
Major hallmarks of Alzheimer's disease (AD) include brain deposition of the amyloid-beta peptide (Abeta), which is proteolytically cleaved from a large Abeta precursor protein (APP) by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme (BACE1), has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated region (UTR) contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD.
Lahiri
Debomoy K
DK
Indiana University School of Medicine, Department of Psychiatry, Institute of Psychiatric Research, Indianapolis, IN 46202, USA. dlahiri@iupui.edu
Ge
Yuan-Wen
YW
Rogers
Jack T
JT
Sambamurti
Kumar
K
Greig
Nigel H
NH
Maloney
Bryan
B
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000378:metabolism
C091042:APBB1 protein, human; D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human