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- Title
NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression.
- Authors
Ruitao Wang; Mingming Zhang; Weihui Zhou; Ly, Philip T. T.; Fang Cai; Weihong Song
- 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 UCHL1 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-κ response element was identified in the UCHL1 promoter region. Expression of NF-κ suppressed UCHL1 gene transcription. In the RelA knockout system where NFκ activity is ablated, UCH-L1 expression was significantly increased. Furthermore, activation of NF-κ signaling by the inflammatory stimulator lipopolysaccharide and TNFa resulted in a decrease of UCH-L1 gene expression by inhibiting its transcription. As NF-κ is an important signaling module in inflammatory response, our study suggests a possibility that inflammation might compromise neuronal functions via the interaction of NF-κ and UCH-L1. A better understanding of the NF-κ-regulated UCH-L1 transcription will provide insights to the role of inflammatory responses in Alzheimer's disease and Parkinson's disease.
- Subjects
NEURODEGENERATION; UBIQUITIN; GENE expression; HYDROLASES; NEURONS; PROTEINS; ALZHEIMER'S disease
- Publication
Journal of Neurochemistry, 2011, Vol 116, Issue 6, p1160
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2011.07172.x