Premium
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
Author(s) -
Ji R,
Sanchez CM,
Chou CL,
Chen XB,
Woodward DF,
Regan JW
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01817.x
Subject(s) - creb , receptor , nuclear receptor , microbiology and biotechnology , signal transduction , biology , nerve growth factor ib , transcription factor , prostaglandin e2 receptor , chemistry , biochemistry , gene , agonist
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 .