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, 1849 (6), 612-25

MAP Kinase phosphatase-1 Expression Is Regulated by 15-deoxy-Δ12,14-prostaglandin J2 via a HuR-dependent Post-Transcriptional Mechanism

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MAP Kinase phosphatase-1 Expression Is Regulated by 15-deoxy-Δ12,14-prostaglandin J2 via a HuR-dependent Post-Transcriptional Mechanism

Joo Hong Woo et al. Biochim Biophys Acta.

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.

Keywords: 15d-PGJ(2); Astrocytes; HuR; Inflammation; MKP-1; Post-transcriptional regulation.

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