title: MAP kinase phosphatase-1 expression is regulated by 15-deoxy-Δ12,14-prostaglandin J2 via a HuR-dependent post-transcriptional mechanism.
abstract: In the present study, we demonstrate a mechanism through which 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) induces MKP-1 expression in rat primary astrocytes, leading to the regulation of inflammatory responses. We show that 15d-PGJ2 enhances the efficiency of MKP-1 pre-mRNA processing (constitutive splicing and 3'-end processing) and increases the stability of the mature mRNA. We further report that this occurs via the RNA-binding protein, Hu antigen R (HuR). Our experiments show that HuR knockdown abrogates the 15d-PGJ2-induced increases in the pre-mRNA processing and mature mRNA stability of MKP-1, whereas HuR overexpression further enhances the 15d-PGJ2-induced increases in these parameters. Using cysteine (Cys)-mutated HuR proteins, we show that the Cys-245 residue of HuR (but not Cys-13 or Cys-284) is critical for the direct binding of HuR with 15d-PGJ2 and the effects downstream of this interaction. Collectively, our data show that HuR is a novel target of 15d-PGJ2 and reveal HuR-mediated pre-mRNA processing and mature mRNA stabilization as important regulatory steps in the 15d-PGJ2-induced expression of MKP-1. The potential to use a small molecule such as 15d-PGJ2 to regulate the induction of MKP-1 at multiple levels of gene expression could be exploited as a novel therapeutic strategy aimed at combating a diverse range of MKP-1-associated pathologies.
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Joo Hong
authors: JH
authors: Woo
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Jee Hoon
authors: JH
authors: Lee
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Hyunmi
authors: H
authors: Kim
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Yuree
authors: Y
authors: Choi
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Sang Myun
authors: SM
authors: Park
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors: Eun-hye
authors: EH
authors: Joe
authors: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Republic of Korea. Electronic address: jouilo@ajou.ac.kr.
authors: Ilo
authors: I
authors: Jou
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics*; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D051959:ELAV Proteins; D012322:RNA Precursors; D012333:RNA, Messenger; D054638:Dual Specificity Phosphatase 1; D015230:Prostaglandin D2
keywords: 15d-PGJ(2); Astrocytes; HuR; Inflammation; MKP-1; Post-transcriptional regulation