Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10956787 | Molecular and Cellular Neuroscience | 2005 | 10 Pages |
Abstract
The mechanisms implicated in the aggregation of ubiquitinated proteins detected in neurodegenerative disorders remain elusive. We report that prostaglandin J2 (PGJ2), an endogenous product of inflammation, up-regulates sequestosome 1/p62 in a time- and dose-dependent manner in human neuroblastoma SK-N-SH cells. We previously demonstrated that prostaglandins of the J2 series inhibit ubiquitin hydrolases, such as UCH-L1. Herein, we show that sequestosome 1/p62 is co-localized with ubiquitinated proteins and the ubiquitin hydrolase UCH-L1 in cytoplasmic aggregates induced by PGJ2. Preventing sequestosome 1/p62 up-regulation by RNA interference abolishes the aggregation but not the accumulation of ubiquitinated proteins or PGJ2 cytotoxicity. Sequestosome 1/p62 is known to bind poly-ubiquitinated proteins through its ubiquitin-associated domain. Our data support the notion that sequestosome 1/p62 up-regulation under stress conditions contributes to the “sequestration” of poly-ubiquitinated proteins into aggregates. However, the overwhelming accumulation of ubiquitinated proteins, rather than their aggregation, is likely to be an important contributor to PGJ2 cytotoxicity.
Keywords
DRiPsGFPProstaglandin J2DTTUBAUCH-L1PGJ2COX-1CFTR3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromideDMSOMTTRNA interferenceRNAisiRNAUbiquitin-associated domaindithiothreitolDimethyl sulfoxidecystic fibrosis transmembrane conductance regulatorcyclooxygenase 1defective ribosomal productsgreen fluorescent protein
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Authors
Zhiyou Wang, Maria E. Figueiredo-Pereira,