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Transcriptional regulation of USP24 by NF-kappa B Wang, Ke

Abstract

Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. Impairment of the ubiquitin pathway is believed to play an important role in the pathogenesis of PD. The ubiquitination process regulates the available amount, correct localization, and proper activity of target proteins. This process is carried out under tight regulation not only by enzymes linking ubiquitin molecules onto their targets, but also by deubiquitinating enzymes which remove ubiquitin molecules from the ubiquitinated proteins. Little is known about the recently discovered deubiquitinating enzyme Ubiquitin Specific Protease 24 (USP24), a product of USP24 gene which spans a large area (>140,000 bp) on the chromosome 1p32 region. Recent genetic linkage studies indicated that the location of the USP24 gene is significantly correlated with the disease. These studies imply that USP24 is likely a novel "PARK" protein. As a part of the study to elucidate the participation of USP24 in PD pathogenesis and mechanisms that modulate USP24 activity, we investigated the molecular mechanism of USP24 gene transcription. Promoter of the USP24 gene was cloned into pGL3-Basic vector and analyzed by a luciferase based reporter assay system. We identified the transcription starting site(TSS) of USP24 gene and the transcription starting site located at 251 bp upstream of the translation starting site. Expression of the USP24 gene is controlled by a TATA-box-less promoter. NF-κB signaling plays an important role in multiple cellular events such as inflammation and programmed cell death. It has been reported that increased NF-κB nuclear translocation occurs in substantia nigra (SN) dopaminergic neurons of PD patients, suggesting that NF-κB signaling is involved in PD pathogenesis. An NF- κB binding site was identified on USP24 promoter. Overexpression of NF-κB or activation of NF-κB by TNF-α significantly increased USP24 promoter activity. Mutation of the binding site abolished the regulatory effect of NF-κB on the USP24 promoter. In summary, we have identified USP24 gene promoter and our study demonstrates that NF-κB signaling pathway regulates USP24 gene transcription. The results will further our understanding of the regulation of ubiquitin pathway and its involvement in PD pathogenesis.

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