Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery
| Autor: | Ma Teresa Miras-Portugal, Jaime Huerta-Cepas, Raquel Pérez-Sen, Felipe Ortega, Verónica Morente, Esmerilda G. Delicado |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Agonist medicine.drug_class MAP Kinase Signaling System Ultraviolet Rays p38 mitogen-activated protein kinases DUSP p38 Genotoxic Stress CREB Neuroprotection MAPK protein phosphatase Models Biological p38 Mitogen-Activated Protein Kinases Nucleotide receptor P2Y13 receptor Ca2+/calmodulin-dependent protein kinase Cerebellum medicine Animals Phosphorylation Rats Wistar Receptor Molecular Biology Cell Nucleus Neurons biology Cell Death Caspase 3 Receptors Purinergic P2 Dual Specificity Phosphatase 2 Cell Biology Thionucleotides Cell biology Rats Adenosine Diphosphate Enzyme Activation Neuroprotective Agents Cytoprotection biology.protein Cisplatin DNA Damage |
| Zdroj: | Biochimica et biophysica acta. 1843(9) |
| ISSN: | 0006-3002 |
| Popis: | Nucleotides activating P2Y13 receptors display neuroprotective actions against different apoptotic stimuli in cerebellar granule neurons. In the present study, P2Y13 neuroprotection was analyzed in conditions of genotoxic stress. Exposure to cisplatin and UV radiation induced caspase-3-dependent apoptotic cell death, and p38 MAPK signaling de-regulation. Pre-treatment with P2Y13 nucleotide agonist, 2methyl-thio-ADP (2MeSADP), restored granule neuron survival and prevented p38 long-lasting activation induced by cytotoxic treatments. Microarray gene expression analysis in 2MeSADP-stimulated cells revealed over-representation of genes related to protein phosphatase activity. Among them, dual-specificity phosphatase-2, DUSP2, was validated as a transcriptional target for P2Y13 receptors by QPCR. This effect could explain 2MeSADP ability to dephosphorylate a DUSP2 substrate, p38, reestablishing the inactive form. In addition, cisplatin-induced p38 sustained activation correlated perfectly with progressive reduction in DUSP2 expression. In conclusion, P2Y13 receptors regulate DUSP2 expression and contribute to p38 signaling homeostasis and survival in granule neurons. |
| Databáze: | OpenAIRE |
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