Premium
Novel suppression mechanism operating in early phase of adipogenesis by positive feedback loop for enhancement of cyclooxygenase‐2 expression through prostaglandin F 2α receptor mediated activation of MEK/ERK‐CREB cascade
Author(s) -
Ueno Toshiyuki,
Fujimori Ko
Publication year - 2011
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2011.08213.x
Subject(s) - mapk/erk pathway , creb , cyclic amp response element binding protein , protein kinase a , chemistry , adipogenesis , kinase , mek inhibitor , agonist , receptor , medicine , endocrinology , microbiology and biotechnology , biology , transcription factor , biochemistry , adipose tissue , gene
Prostaglandin (PG) F 2α suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator‐activated receptor γ. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti‐adipogenic PGF 2α and PGE 2 by enhancing cyclooxygenase (COX) 2 expression through the PGF 2α ‐activated FP receptor/extracellular‐signal‐regulated kinase (ERK)/cyclic AMP response element binding protein (CREB) cascade. COX‐2 expression was enhanced with a peak at 1 h for the mRNA level and at 3 h for the protein level after the addition of Fluprostenol, an FP receptor agonist. The Fluprostenol‐derived elevation of COX‐2 expression was suppressed by the co‐treatment with an FP receptor antagonist, AL8810, with a mitogen‐activated protein kinase (MEK; ERK kinase) inhibitor, PD98059. ERK was phosphorylated within 10 min after the addition of Fluprostenol, and its phosphorylation was inhibited by the co‐treatment with AL8810 or PD98059. Moreover, FP receptor mediated activation of the MEK/ERK cascade and COX‐2 expression increased the production of PGF 2α and PGE 2 . An FP receptor antagonist and each inhibitor for MEK and COX‐2 suppressed the PGF 2α ‐derived induction of synthesis of these PGs. Furthermore, promoter‐luciferase and chromatin immunoprecipitation assays demonstrated that PGF 2α ‐derived COX‐2 expression was activated through binding of CREB to the promoter region of the COX‐2 gene in 3T3‐L1 cells. These results indicate that PGF 2α suppresses the progression of the early phase of adipogenesis by enhancing the binding of CREB to the COX‐2 promoter via FP receptor activated MEK/ERK cascade. Thus, PGF 2α forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti‐adipogenic PGF 2α and PGE 2 .