Transcriptional regulation of human USP 24 gene expression by NF‐kappa B

• Published in: Journal of neurochemistry Vol. 128; no. 6; pp. 818 - 828
• Main Authors: Wang, Ke, Liu, Shengchun, Wang, Juelu, Wu, Yili, Cai, Fang, Song, Weihong
• Format: Journal Article
• Language: English
• Published: 01.03.2014
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12626

Abstract Impairment of the ubiquitin proteasome pathway is believed to play an important role in the pathogenesis of Parkinson's disease. This process is carried out under tight regulation by deubiquitinating enzymes. Genetic linkage studies indicated that the region of the human ubiquitin‐specific protease 24 ( USP24 ) gene is significantly correlated with Parkinson's disease. In this study, we cloned a 1648 bp 5′ flanking region of the human USP24 gene coding sequence and a series of nested deletions into the pGL 3‐Basic vector. We analyzed promoter activities of these regions with a luciferase‐based reporter assay system. A 64‐bp region was identified to contain the transcription initiation site and a minimum promoter sequence for transcriptional activation of the USP24 gene expression. Expression of USP24 is controlled by a TATA‐box‐less promoter with several putative cis ‐acting elements. Transcriptional activation and gel‐shift assay demonstrated that the USP24 gene promoter contains a functional NFκB‐binding site. Over‐expression of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) and tumor‐necrosis factor alpha (TNFα) treatment significantly increased the USP24 promoter activity, mRNA expression and protein level in human HEK293 cells, mouse N2a cells and human neuroblastoma SH‐SY5Y cells. Deletion and mutation of the binding site abolished the regulatory effect of NFκB on human USP24 gene transcription. These results suggested that USP24 expression is tightly regulated at its transcription level and NFκB plays an important role in this process. image Impairment of the ubiquitin proteasome system (UPS) has been implicated in neurodegenerative disorders. This report showed that the expression of human ubiquitin‐specific protease 24 ( USP24 ), a deubiquitinating enzyme of UPS, is tightly regulated by NFκB. The results suggest that dysregulation of NFκB‐mediated USP24 expression may play a role in PD pathogenesis and modulating this process could have therapeutic potential.