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22(R)-hydroxycholesterol induces HuR-dependent MAP kinase phosphatase-1 expression via mGluR5-mediated Ca(2+)/PKCalpha signaling

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dc.contributor.authorKim, H-
dc.contributor.authorWoo, JH-
dc.contributor.authorLee, JH-
dc.contributor.authorJoe, EH-
dc.contributor.authorJou, I-
dc.date.accessioned2018-05-04T00:23:31Z-
dc.date.available2018-05-04T00:23:31Z-
dc.date.issued2016-
dc.identifier.issn0006-3002-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/14728-
dc.description.abstractMAP kinase phosphatase (MKP)-1 plays a pivotal role in controlling MAP kinase (MAPK)-dependent (patho) physiological processes. Although MKP-1 gene expression is tightly regulated at multiple levels, the underlying mechanistic details remain largely unknown. In this study, we demonstrate that MKP-1 expression is regulated at the post-transcriptional level by 22(R)-hydroxycholesterol [22(R)-HC] through a novel mechanism. 22(R)-HC induces Hu antigen R (HuR) phosphorylation, cytoplasmic translocation and binding to MKP-1 mRNA, resulting in stabilization of MKP-1 mRNA. The resulting increase in MKP-1 leads to suppression of JNK-mediated inflammatory responses in brain astrocytes. We further demonstrate that 22(R)-HC-induced phosphorylation of nuclear HuR is mediated by PKCalpha, which is activated in the cytosol by increases in intracellular Ca(2+) levels mediated by the phospholipase C/inositol 1,4,5-triphosphate receptor (PLC/IP3R) pathway and translocates from cytoplasm to nucleus. In addition, pharmacological interventions reveal that metabotropic glutamate receptor5 (mGluR5) is responsible for the increases in intracellular Ca(2+) that underlie these actions of 22(R)-HC. Collectively, our findings identify a novel anti-inflammatory mechanism of 22(R)-HC, which acts through PKCalpha-mediated cytoplasmic shuttling of HuR to post-transcriptionally regulate MKP-1 expression. These findings provide an experimental basis for the development of a RNA-targeted therapeutic agent to control MAPK-dependent inflammatory responses.-
dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHAstrocytes-
dc.subject.MESHCalcium-
dc.subject.MESHCerebral Cortex-
dc.subject.MESHDual Specificity Phosphatase 1-
dc.subject.MESHELAV-Like Protein 1-
dc.subject.MESHGene Expression Regulation-
dc.subject.MESHHydroxycholesterols-
dc.subject.MESHInositol 1,4,5-Trisphosphate Receptors-
dc.subject.MESHMAP Kinase Kinase 4-
dc.subject.MESHPhosphorylation-
dc.subject.MESHPrimary Cell Culture-
dc.subject.MESHProtein Binding-
dc.subject.MESHProtein Kinase C-alpha-
dc.subject.MESHRNA Stability-
dc.subject.MESHRNA, Messenger-
dc.subject.MESHRats-
dc.subject.MESHReceptor, Metabotropic Glutamate 5-
dc.subject.MESHSignal Transduction-
dc.subject.MESHType C Phospholipases-
dc.title22(R)-hydroxycholesterol induces HuR-dependent MAP kinase phosphatase-1 expression via mGluR5-mediated Ca(2+)/PKCalpha signaling-
dc.typeArticle-
dc.identifier.pmid27206966-
dc.contributor.affiliatedAuthor우, 주홍-
dc.contributor.affiliatedAuthor이, 지훈-
dc.contributor.affiliatedAuthor조, 은혜-
dc.contributor.affiliatedAuthor주, 일로-
dc.type.localJournal Papers-
dc.identifier.doi10.1016/j.bbagrm.2016.05.008-
dc.citation.titleBiochimica et biophysica acta-
dc.citation.volume1859-
dc.citation.number8-
dc.citation.date2016-
dc.citation.startPage1056-
dc.citation.endPage1070-
dc.identifier.bibliographicCitationBiochimica et biophysica acta, 1859(8). : 1056-1070, 2016-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.identifier.eissn1878-2434-
dc.relation.journalidJ000063002-
Appears in Collections:
Journal Papers > Research Organization > Inflamm-aging Translational Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
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