MAP kinase phosphatase-1 expression is regulated by 15-deoxy-Delta(12,14) prostaglandin J(2) via a HuR-dependent post-transcriptional mechanism

作者：Woo Joo Hong; Lee Jee Hoon; Kim Hyunmi; Choi Yuree; Park Sang Myun; Joe Eun hye; Jou Ilo^*

来源：Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, 2015, 1849(6): 612-625.

DOI：10.1016/j.bbagrm.2015.03.004

• 15d-PGJ(2)
• HuR
• MKP-1
• Post-transcriptional regulation
• Inflammation
• Astrocytes

In the present study, we demonstrate a mechanism through which 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) induces MKP-1 expression in rat primary astrocytes, leading to the regulation of inflammatory responses. We show that 15d-PGJ(2) 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-PGJ(2)-induced increases in the pre-mRNA processing and mature mRNA stability of MKP-1, whereas HuR overexpression further enhances the 15d-PGJ(2)-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-PGJ(2) and the effects downstream of this interaction. Collectively, our data show that HuR is a novel target of 15d-PGJ(2) and reveal HuR-mediated pre-mRNA processing and mature mRNA stabilization as important regulatory steps in the 15d-PGJ(2)-induced expression of MKP-1. The potential to use a small molecule such as 15d-PGJ(2) 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.

• 出版日期2015-6