PT  - JOURNAL ARTICLE
AU  - Yoshitake Cho
AU  - Mitsuhide Noshiro
AU  - Mihwa Choi
AU  - Kentaro Morita
AU  - Takeshi Kawamoto
AU  - Katsumi Fujimoto
AU  - Yukio Kato
AU  - Makoto Makishima
TI  - The Basic Helix-loop-helix Proteins DEC1 and DEC2 Function as Corepressors of Retinoid X Receptors
AID  - 10.1124/mol.109.057000
DP  - 2009 Sep 28
TA  - Molecular Pharmacology
PG  - mol.109.057000
4099  - http://molpharm.aspetjournals.org/content/early/2009/09/28/mol.109.057000.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/09/28/mol.109.057000.full
AB  - The basic helix-loop-helix proteins differentiated embryo chondrocyte 1 (DEC1) and DEC2 are involved in circadian rhythm control. Since the metabolism of dietary nutrients has been linked to circadian regulation, we examined the effect of DEC1 and DEC2 on the function of metabolite-sensing nuclear receptors, ligand-dependent transcription factors including retinoid X receptor (RXR) and liver X receptor (LXR). Transfection assays showed that DEC1 and DEC2 repressed ligand-dependent transactivation by RXR. Knockdown of endogenous DEC1 and DEC2 expression with small interfering RNAs augmented ligand-dependent RXRα transactivation. DEC1 and DEC2 interacted directly with RXRα and ligand addition enhanced their association. DEC1 and DEC2 modified interaction of RXRα with cofactor proteins. Transfection assays using DEC1 and DEC2 mutants revealed that the C-terminal region of DEC2 is required for repression and that a LXXLL motif in DEC1 and DEC2 is necessary for RXRα repression. DEC1 and DEC2 repressed the induction of LXR target genes, associated with the promoter of an LXR target gene, and dissociated from the promoter with ligand treatment. Knockdown of endogenous DEC1 and DEC2 enhanced the LXR target gene expression in hepatocytes. Expression of Dec1, Dec2 and Srebp-1c showed a circadian rhythm in the liver of mice, while that of Lxrα, Lxrα and Rxrα was not rhythmic. DEC1 and DEC2 also repressed transactivation of other RXR heterodimers, such as farnesoid X receptor, vitamin D receptor and retinoic acid receptor. Thus, the repressor function of DEC1 and DEC2 may be extended to other RXR heterodimer nuclear receptors.The American Society for Pharmacology and Experimental Therapeutics