RT Journal Article
SR Electronic
T1 Enhanced CCAAT/Enhancer-Binding Protein β-Liver-Enriched Inhibitory Protein Production by Oltipraz, Which Accompanies CUG Repeat-Binding Protein-1 (CUGBP1) RNA-Binding Protein Activation, Leads to Inhibition of Preadipocyte Differentiation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 660
OP 669
DO 10.1124/mol.105.012997
VO 68
IS 3
A1 Bae, Eun Ju
A1 Kim, Sang Geon
YR 2005
UL http://molpharm.aspetjournals.org/content/68/3/660.abstract
AB The CCAAT/enhancer-binding protein (C/EBP) β-isoforms liver-enriched activator protein (LAP) and truncated dominant-negative liver-enriched inhibitory protein (LIP) differentially regulate adipogenesis. We previously demonstrated that oltipraz (5-[2-pyrazinyl]-4-methyl-1,2-dithiol-3-thione), a cancer-chemopreventive agent, promotes C/EBPβ-LAP activation in hepatocytes. This study investigated whether oltipraz affects adipocyte differentiation and, if so, the molecular basis for the alterations in adipogenesis. The expression of LIP notably increased 6 to 48 h after oltipraz treatment of 3T3-L1 preadipocytes, whereas that of LAP was minimally changed. Oltipraz treatment ∼3-fold elevated the ratio of LIP to LAP. Immunoblot, gel-shift, and Southwestern analyses revealed that oltipraz enhanced the levels of nuclear LIP and LAP and their binding to the C/EBP-binding site. Cotransfection of predipocytes with the plasmid encoding LIP interfered with LAP-mediated luciferase expression, confirming the inhibitory role of LIP in gene expression. Likewise, LAP-mediated luciferase gene transactivation was inhibited by oltipraz, as was observed by cotransfection of a dominant-negative mutant form of C/EBP. Oltipraz enhanced cytoplasmic translocation and RNA binding of CUG repeat-binding protein-1 (CUGBP1) but not calreticulin, another RNA-binding protein that interacts with C/EBPβ mRNA. When 3T3-L1 preadipocytes were induced to differentiate by exposure to 3-isobutyl-1-methylxanthine, dexamethasone, and insulin, oltipraz markedly inhibited hormone-induced adipocyte differentiation. In primary cultured rat preadipocytes, oltipraz enhanced LIP production and inhibited adipocyte differentiation. In conclusion, oltipraz inhibits adipogenesis by promoting LIP production and activation, and the enhanced LIP production accompanies cytoplasmic translocation of CUGBP1 and its binding to the GC-rich region of C/EBPβ mRNA. Our finding holds significance in that adipogenesis can be pharmacologically controlled by LIP production.