期刊
FEBS JOURNAL
卷 278, 期 16, 页码 2901-2912出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1742-4658.2011.08213.x
关键词
3T3-L1, PGF(2 alpha); adipocytes; COX-2; CREB; MEK/ERK
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Suzuken Memorial Foundation
- Sumitomo Foundation
- Gushinkai Foundation
- Japan Foundation for Applied Enzymology
- Takeda Science Foundation
- Research Foundation for Pharmaceutical Sciences
- Grants-in-Aid for Scientific Research [21570151] Funding Source: KAKEN
Prostaglandin (PG) F-2 alpha suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor gamma. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti-adipogenic PGF(2 alpha) and PGE(2) by enhancing cyclooxygenase (COX) 2 expression through the PGF(2 alpha)-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(2 alpha) and PGE(2). An FP receptor antagonist and each inhibitor for MEK and COX-2 suppressed the PGF(2 alpha)-derived induction of synthesis of these PGs. Furthermore, promoter-luciferase and chromatin immunoprecipitation assays demonstrated that PGF(2 alpha)-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(2 alpha) 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(2 alpha) forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti-adipogenic PGF(2 alpha) and PGE(2).
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