The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors.
The basic helix-loop-helix proteins differentiated embryo chondrocyte 1 (DEC1) and DEC2 are involved in circadian rhythm control. Because the metabolism of dietary nutrients has been linked to circadian regulation, we examined the effect of DEC1 and DEC2 on the function of the 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 RXRalpha transactivation. DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association. DEC1 and DEC2 modified interaction of RXRalpha with cofactor proteins. Transfection assays using DEC1 and DEC2 mutants revealed that the C-terminal region of DEC2 is required for repression and that an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha 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, whereas that of Lxralpha, Lxrbeta, and Rxralpha was not rhythmic. DEC1 and DEC2 also repressed the 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.
Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
Yoshitake
Y
Cho
Mitsuhide
M
Noshiro
Mihwa
M
Choi
Kentaro
K
Morita
Takeshi
T
Kawamoto
Katsumi
K
Fujimoto
Yukio
Y
Kato
Makoto
M
Makishima
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002460:Cell Line; D019902:Chondrocytes / Q000502:physiology*; D015536:Down-Regulation; D005982:Glutathione Transferase / Q000096:biosynthesis; D006655:Histone Deacetylases / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis / Q000502:physiology; D047488:Retinoid X Receptors / Q000096:biosynthesis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D005982:Glutathione Transferase; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D047490:Retinoid X Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C422085:BHLHE41 protein, human; C470968:Bhlhb3 protein, mouse; C491539:Bhlhe40 protein, mouse; C403671:DELEC1 protein, human