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Strong nuclear factor‐κB‐DNA binding parallels cyclooxygenase‐2 gene transcription in aging and in sporadic alzheimer's disease superior temporal lobe neocortex
Author(s) -
Lukiw Walter J.,
Bazan Nicolas G.
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19980901)53:5<583::aid-jnr8>3.0.co;2-5
Subject(s) - biology , microbiology and biotechnology , transcription factor , gene expression , transcription (linguistics) , gene , genetics , philosophy , linguistics
Cyclooxygenase‐2 (COX‐2; EC 1.14.99.1) RNA message abundance in 25 control and Consortium to Establish a Registry for Alzheimer's Disease (CERAD)‐confirmed sporadic Alzheimer's disease (AD) brains is remarkably heterogeneous when compared with 55 other AD brain RNA message levels that were previously characterized (Lukiw and Bazan: J Neurosci Res 50:937–945, 1997). Examination of nuclear protein extracts (NPXTs) that were derived from control and AD‐affected brain neocortical nuclei (n = 20; age range, 60–82 years; postmortem interval, 0.5–6.5 hours) by using gel shift, gel supershift, and cold oligonucleotide competition assay revealed a highly significant relationship between the extent of inflammatory transcription factor, nuclear factor (NF)‐κB: DNA binding and the abundance of the COX‐2 RNA signal ( P < 0.0001; analysis of variance). No strong correlation with AP‐1‐DNA binding was noted ( P > 0.045). These data are the first linking inflammation‐related transcription factor NF‐κB‐DNA binding to up‐regulation of transcription from a key inflammatory gene, COX‐2, in both normally aging brain and in AD‐affected neocortex. Systematic deletion of NF‐κB‐DNA binding sites in human COX‐2 promoter constructs attenuates COX‐2 transcriptional induction by mediators of inflammation. Strong NF‐κB‐DNA binding has been reported previously to temporally precede COX‐2 gene transcription in human epithelial (A549), hamster B‐cell (HIT‐T15), human endothelial (HUVEC), human lymphoblast (IM9), human fibroblast (IMR90), rat glioma/mouse neuroblastoma (NG108–15), human keratinocyte (NHEK), mouse fibroblast (NIH 3T3), rat neuroblastoma (SH‐SY5Y) cell lines and in mouse and rat brain hippocampus, indicating a highly conserved inflammatory signaling pathway that is common to diverse species and cell types. The mouse, rat, and human COX‐2 immediate promoters, despite 7.5 × 10 7 years of DNA sequence divergence, each retain multiple recognition sites specific for NF‐κB‐DNA binding. These data suggest that basic gene induction mechanisms, which have been conserved over long periods of evolution, that increase NF‐κB‐DNA binding may be fundamental in driving transcription from inflammation‐related genes, such as COX‐2, that operate in stressed tissues, in normally aging cell lines, and in neurodegenerative disorders that include AD brain. J. Neurosci. Res. 53:583–592, 1998. © 1998 Wiley‐Liss, Inc.