The RNA-binding protein HuR stabilizes cytosolic phospholipase A2α mRNA under interleukin-1β treatment in non-small cell lung cancer A549 Cells.

Abstract

The activation of cytosolic phospholipase A(2)α (cPLA(2)α) plays an important role in initiating the inflammatory response. The regulation of cPLA(2)α mRNA turnover has been proposed to control cPLA(2)α gene expression under cytokine and growth factor stimulation. However, the detailed mechanism is still unknown. In this report, we have demonstrated that the cPLA(2)α mRNA stability was increased under IL-1β treatment in A549 cells. By using EMSAs, HuR was identified as binding with the cPLA(2)α mRNA 3'-UTR, and the binding region was located at nucleotides 2716-2807, a fragment containing AUUUA flanked by U-rich sequences. IL-1β treatment enhanced the association of cPLA(2)α mRNA with cytosolic HuR. The reduction of HuR expression by RNA interference technology inhibited IL-1β-induced cPLA(2)α mRNA and protein expression. Furthermore, blocking the p38 MAPK signaling pathway with SB203580 abolished the effect of IL-1β-induced cPLA(2)α gene expression. Phosphorylation at residue Thr-118 of HuR is crucial in regulating the interaction between HuR and its target mRNAs. Mutation of HuR Thr-118 reduced the association between HuR and cPLA(2)α mRNA under IL-1β treatment. This inhibitory effect was also observed in binding with COX-2 mRNA. This result indicated that p38 MAPK-mediated Thr-118 phosphorylation may play a key role in regulating the interaction of HuR with its target mRNAs in inflammation.

• Authors: Wan-Lin Liao, Wei-Chiao Wang, Wen-Chang Chang, Joseph T Tseng
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 41 Pg. 35499-35508 (Oct 14 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21862584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• ELAV Proteins
• Enzyme Inhibitors
• Imidazoles
• Interleukin-1beta
• Neoplasm Proteins
• Pyridines
• RNA, Neoplasm
• Cyclooxygenase 2
• PTGS2 protein, human
• p38 Mitogen-Activated Protein Kinases
• Group IV Phospholipases A2
• SB 203580

Topics

• 3' Untranslated Regions
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Cyclooxygenase 2 (genetics, metabolism)
• ELAV Proteins (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Group IV Phospholipases A2 (biosynthesis, genetics)
• Humans
• Imidazoles (pharmacology)
• Inflammation (genetics, mortality)
• Interleukin-1beta (pharmacology)
• Lung Neoplasms (genetics, metabolism)
• MAP Kinase Signaling System (drug effects, genetics)
• Mutation
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (drug effects, genetics)
• Pyridines (pharmacology)
• RNA Stability (drug effects)
• RNA, Neoplasm (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)