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CREB‐dependent cyclooxygenase‐2 and microsomal prostaglandin E synthase‐1 expression is mediated by protein kinase C and calcium
Author(s) -
Pham Hung,
Shafer Lindsay M.,
Slice Lee W.
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20899
Subject(s) - creb , protein kinase c , thapsigargin , agonist , signal transduction , cyclic amp response element binding protein , arachidonic acid , cyclooxygenase , chemistry , protein kinase a , prostaglandin h2 , prostaglandin , endocrinology , phosphorylation , medicine , biology , receptor , biochemistry , transcription factor , endoplasmic reticulum , enzyme , gene
Cellular production of prostaglandins (PGs) is controlled by the concerted actions of cyclooxygenases (COX) and terminal PG synthases on arachidonic acid in response to agonist stimulation. Recently, we showed in an ileal epithelial cell line (IEC‐18), angiotensin II‐induced COX‐2‐dependent PGI 2 production through p38MAPK, and calcium mobilization (J. Biol. Chem. 280: 1582–1593, 2005). Agonist binding to the AT 1 receptor results in activation of PKC activity and Ca 2+ signaling but it is unclear how each pathway contributes to PG production. IEC‐18 cells were stimulated with either phorbol‐12,13‐dibutyrate (PDB), thapsigargin (TG), or in combination. The PG production and COX‐2 and PG synthase expression were measured. Surprisingly, PDB and TG produced PGE 2 but not PGI 2 . This corresponded to induction of COX‐2 and mPGES‐1 mRNA and protein. PGIS mRNA and protein levels did not change. Activation of PKC by PDB resulted in the activation of ERK1/2, JNK, and CREB whereas activation of Ca 2+ signaling by TG resulted in the delayed activation of ERK1/2. The combined effect of PKC and Ca 2+ signaling were prolonged COX‐2 and mPGES‐1 mRNA and protein expression. Inhibition of PKC activity, MEK activity, or Ca 2+ signaling blocked agonist induction of COX‐2 and mPGES‐1. Expression of a dominant negative CREB (S133A) blocked PDB/TG‐dependent induction of both COX‐2 and mPGES‐1 promoters. Decreased CREB expression by siRNA blocked PDB/TG‐dependent expression of COX‐2 and mPGES‐1 mRNA. These findings demonstrate a coordinated induction of COX‐2 and mPGES‐1 by PDB/TG that proceeds through PKC/ERK and Ca 2+ signaling cascades, resulting in increased PGE 2 production. J. Cell. Biochem. © 2006 Wiley‐Liss, Inc.