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

Kim, H; Woo, JH; Lee, JH; Joe, EH; Jou, I
Biochimica et biophysica acta, 1859(8):1056-1070, 2016
Journal Title
Biochimica et biophysica acta
MAP 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.
MeSH terms
AnimalsAstrocytes/cytologyAstrocytes/drug effectsAstrocytes/metabolism*Calcium/metabolismCerebral Cortex/cytologyCerebral Cortex/drug effectsCerebral Cortex/metabolismDual Specificity Phosphatase 1/genetics*Dual Specificity Phosphatase 1/metabolismELAV-Like Protein 1/agonistsELAV-Like Protein 1/genetics*ELAV-Like Protein 1/metabolismGene Expression RegulationHydroxycholesterols/pharmacology*Inositol 1,4,5-Trisphosphate Receptors/geneticsInositol 1,4,5-Trisphosphate Receptors/metabolismMAP Kinase Kinase 4/geneticsMAP Kinase Kinase 4/metabolismPhosphorylation/drug effectsPrimary Cell CultureProtein BindingProtein Kinase C-alpha/genetics*Protein Kinase C-alpha/metabolismRNA StabilityRNA, Messenger/genetics*RNA, Messenger/metabolismRatsReceptor, Metabotropic Glutamate 5/genetics*Receptor, Metabotropic Glutamate 5/metabolismSignal TransductionType C Phospholipases/geneticsType C Phospholipases/metabolism
Appears in Collections:
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
우, 주홍이, 지훈조, 은혜주, 일로
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