Termination mechanism of CREB-dependent activation of COX-2 expression in early phase of adipogenesis

Mol Cell Endocrinol. 2014 Mar 25;384(1-2):12-22. doi: 10.1016/j.mce.2013.12.014. Epub 2013 Dec 27.

Abstract

We elucidated the molecular mechanism of prostaglandin (PG) E2- and PGF2α-mediated suppression of the early phase of adipogenesis through enhanced COX-2 expression in 3T3-L1 cells. 3-Isobutyl-1-methylxanthine, an inhibitor of phosphodiesterase which catalyzes the conversion of cAMP to AMP, enhanced the activity of protein kinase A (PKA). Dibutyryl cAMP activated PKA and enhanced the phosphorylation of cAMP response element (CRE)-binding protein (CREB). The ability of CREB binding to the CRE of the COX-2 promoter was elevated for enhancement of the expression of the COX-2 gene. CREB siRNA suppressed the expression of the COX-2 gene. Furthermore, okadaic acid, a protein phosphatase (PP) 1/2A inhibitor, suppressed the progression of adipogenesis by preventing PP1/2A-mediated suppression of CREB-dependent COX-2 expression, thus resulting in increased production of anti-adipogenic PGE2 and PGF2α. These results indicate that CREB-dependent expression of COX-2 for the production of anti-adipogenic PGs is critical for the regulation of the early phase of adipogenesis.

Keywords: Adipocytes; COX-2; CREB; PKA; PP1/2A; Prostaglandin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipogenesis / genetics*
  • Animals
  • Bucladesine / pharmacology
  • CREB-Binding Protein / antagonists & inhibitors
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism*
  • Cell Differentiation
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Dinoprostone / biosynthesis
  • Gene Expression Regulation
  • Mice
  • Okadaic Acid / pharmacology
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Phosphatase 1 / antagonists & inhibitors
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction

Substances

  • RNA, Small Interfering
  • Okadaic Acid
  • Bucladesine
  • Cyclic AMP
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Phosphatase 1
  • Protein Phosphatase 2
  • Phosphoric Diester Hydrolases
  • Dinoprostone
  • 1-Methyl-3-isobutylxanthine