title: NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression.
abstract: Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that plays a regulatory role in targeting proteins for proteasomal degradation. UCH-L1 is highly expressed in neurons and has been demonstrated to promote cell viability and maintain neuronal integrity. Reduced UCH-L1 levels have been observed in various neurodegenerative diseases, and expression of UCH-L1 can rescue synaptic dysfunction and memory deficits in Alzheimer's Disease model mice. However, the mechanisms regulating UCH-L1 expression have not been determined. In this study, we cloned a 1782 bp of the 5' flanking region of the human UCH-L1 gene and identified a 43 bp fragment containing the transcription start site as the minimal region necessary for promoter activity. Sequence analysis revealed several putative regulatory elements including NF-κB, NFAT, CREB, NRSF, YY1, AP1, and STAT in the UCH-L1 promoter. A functional NF-κB response element was identified in the UCH-L1 promoter region. Expression of NF-κB suppressed UCH-L1 gene transcription. In the RelA knockout system where NF-κB activity is ablated, UCH-L1 expression was significantly increased. Furthermore, activation of NF-κB signaling by the inflammatory stimulator lipopolysaccharide and TNFα resulted in a decrease of UCH-L1 gene expression by inhibiting its transcription. As NF-κB is an important signaling module in inflammatory response, our study suggests a possibility that inflammation might compromise neuronal functions via the interaction of NF-κB and UCH-L1. A better understanding of the NF-κB-regulated UCH-L1 transcription will provide insights to the role of inflammatory responses in Alzheimer's disease and Parkinson's disease.
authors.affiliation: Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Wang
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Philip T T
authors.initials: PT
authors.lastname: Ly
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017421:Sequence Analysis / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051996:Transcription Factor RelA / Q000172:deficiency; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; D043222:Ubiquitin Thiolesterase