27 109

Cited 3 times in

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

Authors
Kim, H; Woo, JH; Lee, JH; Joe, EH; Jou, I
Citation
Biochimica et biophysica acta, 1859(8):1056-1070, 2016
Journal Title
Biochimica et biophysica acta
ISSN
0006-30021878-2434
Abstract
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
DOI
10.1016/j.bbagrm.2016.05.008
PMID
27206966
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
Files in This Item:
27206966.pdfDownload
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse