Proteasome Inhibition in Neuronal Cells Induces a Proinflammatory Response Manifested by Upregulation of Cyclooxygenase-2, Its Accumulation as Ubiquitin Conjugates, and Production of the Prostaglandin PGE2
| Autor: | Hongmei Yuan, Maria E. Figueiredo-Pereira, Patricia Rockwell, Ronald P. Magnusson |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Proteasome Endopeptidase Complex
Biophysics Prostaglandin Cysteine Proteinase Inhibitors Biology Biochemistry Dinoprostone Gene Expression Regulation Enzymologic Proinflammatory cytokine Mice Neuroblastoma chemistry.chemical_compound Ubiquitin Downregulation and upregulation Mesencephalon Multienzyme Complexes Tumor Cells Cultured medicine Animals RNA Messenger Viability assay Ubiquitins Molecular Biology Cells Cultured Inflammation Neurons Neurodegeneration Membrane Proteins Cell Differentiation Embryo Mammalian medicine.disease Rats Ubiquitin ligase Cell biology Isoenzymes Cysteine Endopeptidases Kinetics chemistry Proteasome Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Enzyme Induction Cyclooxygenase 1 biology.protein |
| Zdroj: | Archives of Biochemistry and Biophysics. 374:325-333 |
| ISSN: | 0003-9861 |
| DOI: | 10.1006/abbi.1999.1646 |
| Popis: | Inclusions containing ubiquitin-protein aggregates appear in neurons of patients with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The relationship between inclusion production and cell viability is not understood. To address this issue, we investigated the response of an established mouse neuronal cell line and of embryonic rat mesencephalic cultures to inhibition of the ubiquitin/proteasome pathway. Two proteasome inhibitors, a peptidyl aldehyde and an epoxy ketone, which cause accumulation of ubiquitinated proteins, were found to enhance expression of stress-inducible genes, including HSP70i and the polyubiquitin genes UbB and UbC. Under these conditions, mRNA and protein levels of the inducible form of cyclooxygenase (COX-2) were upregulated together with its product, PGE(2), a proinflammatory prostaglandin. Proteasomal inhibition also led to stabilization of COX-2 as ubiquitin conjugates, suggesting that the ubiquitin/proteasome pathway contributes to the regulation of COX-2 protein levels. Treatment with antioxidants known to inhibit NFkappaB and AP-1 transcriptional activation failed to abrogate COX-2 upregulation. Instead, these inhibitors exacerbated the stress response by potentiating HSP70i levels while eliciting a decrease in PGE(2) production. These findings suggest that the accumulation of ubiquitinated proteins resulting from proteasome inhibition in neuronal cells is associated with a proinflammatory response that may be an important contributor to neurodegeneration. |
| Databáze: | OpenAIRE |
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