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J. Biol. Chem., Vol. 281, Issue 30, 21377-21386, July 28, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/30/21377    most recent M601201200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Z. Articles by Figueiredo-Pereira, M. E. Search for Related Content PubMed PubMed Citation Articles by Wang, Z. Articles by Figueiredo-Pereira, M. E. Social Bookmarking                      What's this?

Prostaglandin J2 Alters Pro-survival and Pro-death Gene Expression Patterns and 26 S Proteasome Assembly in Human Neuroblastoma Cells^*

Zhiyou Wang, Virginie M. Aris, Kenyon D. Ogburn, Patricia Soteropoulos, and Maria E. Figueiredo-Pereira¹

From the Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021 and the Center for Applied Genomics, Public Health Research Institute, Newark, New Jersey 07103

Many neurodegenerative disorders are characterized by two pathological hallmarks: progressive loss of neurons and occurrence of inclusion bodies containing ubiquitinated proteins. Inflammation may be critical to neurodegeneration associated with ubiquitin-protein aggregates. We previously showed that prostaglandin J2 (PGJ2), one of the endogenous products of inflammation, induces neuronal death and the accumulation of ubiquitinated proteins into distinct aggregates. We now report that temporal microarray analysis of human neuroblastoma SK-N-SH revealed that PGJ2 triggered a "repair" response including increased expression of heat shock, protein folding, stress response, detoxification and cysteine metabolism genes. PGJ2 also decreased expression of cell growth/maintenance genes and increased expression of apoptotic genes. Over time pro-death responses prevailed over pro-survival responses, leading to cellular demise. Furthermore, PGJ2 increased the expression of proteasome and other ubiquitin-proteasome pathway genes. This increase failed to overcome PGJ2 inhibition of 26 S proteasome activity. Ubiquitinated proteins are degraded by the 26 S proteasome, shown here to be the most active proteasomal form in SK-N-SH cells. We demonstrate that PGJ2 impairs 26 S proteasome assembly, which is an ATP-dependent process. PGJ2 perturbs mitochondrial function, which could be critical to the observed 26 S proteasome disassembly, suggesting a cross-talk between mitochondrial and proteasomal impairment. In conclusion neurotoxic products of inflammation, such as PGJ2, may play a role in neurodegenerative disorders associated with the aggregation of ubiquitinated proteins by impairing 26 S proteasome activity and inducing a chain of events that culminates in neuronal cell death. Temporal characterization of these events is relevant to understanding the underlying mechanisms and to identifying potential early biomarkers.

Received for publication, February 7, 2006 , and in revised form, May 8, 2006.

Data were deposited in the Gene Expression Omnibus (GEO) repository under the accession number GSE4329 [NCBI GEO] .

^* This work was supported by National Institutes of Health Grants RR03037 (to Hunter College and M. E. F.-P., head of subproject) from NIGMS/RCMI and GM060665 (to Hunter College) from NIGMS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S3.

¹ To whom correspondence should be addressed: Dept. of Biological Sciences, Hunter College of City University of NewYork, 695 Park Ave., NY, NY 10021. Tel.: 212-650-3565; Fax: 212-772-5227; E-mail: pereira{at}genectr.hunter.cuny.edu.

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