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ET‐1 induces COX‐2/PGE2 expression via an ETA/B/PKCδ/c‐Src/PI3K/Akt‐dependent pathway in murine osteoblast‐like MC3T3‐E1 cells
Author(s) -
Li Ying-yi,
Yang Chuen-Mao
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1120.10
Subject(s) - rottlerin , protein kinase b , ly294002 , pi3k/akt/mtor pathway , mapk/erk pathway , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , phosphorylation , p38 mitogen activated protein kinases , protein kinase c , chemistry , biology , signal transduction
Induction of COX‐2 expression and PGE 2 synthesis by endothelin‐1 (ET‐1) may play an important role in inflammation and directly stimulate osteoblastic activity. However, the molecular mechanisms underlying ET‐1‐induced COX‐2 expression in murine osteoblast‐like cell line (MC3T3‐E1) were largely unknown. Here, we found that ET‐1 time‐dependently induced COX‐2 protein and mRNA expression, and PGE 2 generation in MC3T3‐E1 cells. Pretreatment with an inhibitor of ET A receptor (BQ123), ET B receptor (BQ788), Gi or Gs (GPAnt2), Gq (GPAnt2A), PKCδ (rottlerin), c‐Src (PP1), PI3K (LY294002), Akt (SH‐5), p38 MAPK (SB202190), or MEK1/2 (U0126) and transfection with siRNA of c‐Src, Akt, p42, or p38 significantly attenuated ET‐1‐induced COX‐2 protein expression and PGE 2 generation. We also found that ET‐1‐induced the phosphorylation of PKCδ, c‐Src, Akt, p42/p44 MAPK, and p38 MAPK was attenuated by the inhibitors of PKCδ, c‐Src, PI3K, Akt, MEK1/2, and p38 MAPK, respectively. Moreover, ET‐1 stimulated ATF2 phosphorylation and translocation from the cytosol to the nucleus in MC3T3‐E1 cells, which were attenuated by preincubation with rottlerin, PP1, LY294002, SH‐5, U0126, or SB202190. These results suggest that ET‐1‐induced COX‐2 expression was mediated through an ET A/B /PKCδ/c‐Src/PI3K/Akt/p42/p44 MAPK and p38 MAPK pathway and ATF2 in MC3T3‐E1 cells.