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 prodeath 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.

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

“…Activating cAMP signaling is known to be neuroprotective [78] and to have a positive effect on the UPP [34], which in contrast is inhibited by PGJ2 [41,47,76,90]. Therefore, we explored if increasing intracellular cAMP with PACAP27 would prevent neuronal loss induced by PGJ2.…”

“…Importantly, stroke and TBI increase the long-term risk for PD [8,35,73,86]. Moreover, PGJ2 impairs the ubiquitin/proteasome pathway (UPP) [41,47,76,90] and mitochondrial function [42,43,54], and potentiates dopamine toxicity [64]. Based on all of these findings we propose that PGJ2 plays an important role in PD pathogenesis.…”

15-Deoxy-Δ12,14-prostaglandin J2 as an electrophilic mediator

“…Moreover, it has been showed that the cyclopentenone-type PG inhibits the ubiquitin-proteasome pathway via a decrease in the ubiquitin isopeptidase activity. 42) Wang et al 43) examined the proteasome activity by an in-gel assay and showed a PGJ 2 -dependent decline in the proteasome activity. This decline paralleled a shift in the 26 S proteasome to the 20 S core particle, indicating that PGJ 2 disrupted the assembly state of the 26 S proteasomes.…”

Impact of siRNA targeting pirh2 on proliferation and cell cycle control of the lung adenocarcinoma cell line A549

“…Except this, (a) Immunofluorescence; (b) Hoechst 33258 Fig. 1 Expression of pirh2 protein in A549 enzymatic reactions catalyzed by a cascade of enzymes, including ubiquitin-activating enzyme E1, ubiquitinconjugated enzyme E2, and ubiquitin-ligase enzyme E3 [6,7]. Among these three enzymes, only E3 has the ability to uniquely recognize the substrate protein [8], so attention has been paid to it.…”