These authors contributed equally to this study.
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NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression
Article first published online: 28 JAN 2011
DOI: 10.1111/j.1471-4159.2011.07172.x
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Additional Information
How to Cite
Wang, R., Zhang, M., Zhou, W., Ly, P. T. T., Cai, F. and Song, W. (2011), NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression. Journal of Neurochemistry, 116: 1160–1170. doi: 10.1111/j.1471-4159.2011.07172.x
Publication History
- Issue published online: 1 MAR 2011
- Article first published online: 28 JAN 2011
- Accepted manuscript online: 6 JAN 2011 06:14PM EST
- Received December 10, 2010; revised manuscript received/accepted January 3, 2011.
- Abstract
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- Cited By
Keywords:
- neurodegenerative disorders;
- NF-κB;
- transcription;
- ubiquitin;
- UCH-L1
J. Neurochem. (2011) 116, 1160–1170.
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.