title: Prostaglandin J2 alters pro-survival and pro-death gene expression patterns and 26 S proteasome assembly in human neuroblastoma cells.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021.
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, Public Health Research Institute, Newark, New Jersey 07103.
authors.forename: Virginie M
authors.initials: VM
authors.lastname: Aris
authors.affiliation: Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021.
authors.forename: Kenyon D
authors.initials: KD
authors.lastname: Ogburn
authors.affiliation: Center for Applied Genomics, Public Health Research Institute, Newark, New Jersey 07103.
authors.forename: Patricia
authors.initials: P
authors.lastname: Soteropoulos
authors.affiliation: Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021. Electronic address: pereira@genectr.hunter.cuny.edu.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueiredo-Pereira
mesh_terms: D015415:Biomarkers / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D009447:Neuroblastoma / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; C037112:9-deoxy-delta-9-prostaglandin D2; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D015230:Prostaglandin D2