期刊
JOURNAL OF NEUROCHEMISTRY
卷 116, 期 6, 页码 1160-1170出版社
WILEY
DOI: 10.1111/j.1471-4159.2011.07172.x
关键词
neurodegenerative disorders; NF-kappa B; transcription; ubiquitin; UCH-L1
资金
- Canadian Institutes of Health Research (CIHR)
- Jack Brown and Family Alzheimer's Research Foundation
- Michael Smith Foundation for Health Research (MSFHR)
- Chinese Scholarship Council
P>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-kappa B, NFAT, CREB, NRSF, YY1, AP1, and STAT in the UCH-L1 promoter. A functional NF-kappa B response element was identified in the UCH-L1 promoter region. Expression of NF-kappa B suppressed UCH-L1 gene transcription. In the RelA knockout system where NF-kappa B activity is ablated, UCH-L1 expression was significantly increased. Furthermore, activation of NF-kappa B signaling by the inflammatory stimulator lipopolysaccharide and TNF alpha resulted in a decrease of UCH-L1 gene expression by inhibiting its transcription. As NF-kappa B is an important signaling module in inflammatory response, our study suggests a possibility that inflammation might compromise neuronal functions via the interaction of NF-kappa B and UCH-L1. A better understanding of the NF-kappa B-regulated UCH-L1 transcription will provide insights to the role of inflammatory responses in Alzheimer's disease and Parkinson's disease.
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