Prostanoid EP 1 receptors mediate up-regulation of the orphan nuclear receptor Nurr1 by cAMP-independent activation of protein kinase A, CREB and NF-κB

R. Ji, C. M. Sanchez, C. L. Chou, X. B. Chen, D. F. Woodward, John W Regan

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

BACKGROUND AND PURPOSE Prostaglandin E 2 (PGE 2) stimulation of the G protein-coupled prostanoid EP 1 receptor was found to up-regulate the expression of Nur-related factor 1 (Nurr1) (NR4A2), a transcription factor in the NR4A subfamily of nuclear receptors. The present studies characterize the molecular mechanism of this up-regulation. EXPERIMENTAL APPROACH The expression of Nurr1 was examined by immunoblot analysis, the polymerase chain reaction and reporter gene assays in human embryonic kidney (HEK) cells stably expressing the recombinant EP 1 receptor and in SH-SY5Y neuroblastoma cells expressing endogenous EP 1 receptors. Signalling pathway inhibitors were used to examine the roles of Rho, PKA, the cAMP response element binding protein (CREB) and NF-κB on the PGE 2 stimulated up-regulation of Nurr1. CREB and NF-κB signalling were also examined by immunoblot analysis and reporter gene assays. KEY RESULTS The EP 1 receptor mediated up-regulation of Nurr1 was blocked with inhibitors of Rho, PKA, NF-κB and CREB; but PGE 2 failed to significantly stimulate intracellular cAMP formation. PGE 2 stimulation of the EP1 receptor induced the phosphorylation and activation of CREB and NF-κB, which could be blocked by inhibition of PKA. CONCLUSIONS AND IMPLICATIONS PGE 2 stimulation of the human EP 1 receptor up-regulates the expression of Nurr1 by a mechanism involving the sequential activation of the Rho, PKA, CREB and NF-κB signalling pathways. EP 1 receptors are implicated in tumorigenesis and the up-regulation of Nurr1 may underlie the anti-apoptotic effects of PGE 2.

Original languageEnglish (US)
Pages (from-to)1033-1046
Number of pages14
JournalBritish Journal of Pharmacology
Volume166
Issue number3
DOIs
Publication statusPublished - Jun 2012

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Keywords

  • CREB
  • EP prostanoid receptor
  • G-protein coupled receptors
  • NF-κB
  • NR4A2
  • Nurr1
  • orphan nuclear receptors
  • PGE
  • PKA
  • prostaglandin E

ASJC Scopus subject areas

  • Pharmacology

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