The Basic Helix-Loop-Helix Proteins Differentiated Embryo Chondrocyte (DEC) 1 and DEC2 Function as Corepressors of Retinoid X Receptors

Cho, Yoshitake; Noshiro, Mitsuhide; Choi, Mihwa; Morita, Kentaro; Kawamoto, Takeshi; Fujimoto, Katsumi; Kato, Yukio; Makishima, Makoto

doi:10.1124/mol.109.057000

Cited by 57 publications

(63 citation statements)

References 40 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10,25) We examined the effects of HR on the interaction of VDR with cofactors in a mammalian two-hybrid assay as reported previously. 26) 1,25(OH) 2 D 3 and, to a lesser extent, LCA increased the association of VDR with SRC-1 (Fig. 3A), consistent with our previous reports.…”

Section: 7)supporting

confidence: 81%

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes.2,3) While corepressors bind to the VDR-RXR heterodimer in the absence of ligand, the ligand binding reduces the affinity of corepressors and increases the affinity for coactivators, a structural transition that induces transcription of specific genes. The VDR-RXR heterodimer binds preferentially to a DNA response element that consists of a two hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides (DR3).4) The DR3 VDRbinding element has been identified in the regulatory regions of many target genes, including cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), cathelicidin antimicrobial peptide (CAMP), and osteopontin.2,4) An everted repeat of the hexanucleotide motif separated by six nucleotides (ER6) is another VDR-binding element that regulates expression of the human CYP3A4 gene.2) Dynamic and coordinated interactions of VDR with RXR and cofactor complexes are required for the efficient regulation of transcription.3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 . 9) Indeed, LCA induces the interaction of VDR with RXR, steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in a manner distinct from 1,25(OH) 2 D 3 in cells.3)Although the role of VDR in mediating the biological effects of 1,25(OH) 2 D 3 has been investigated for decades, an understanding of the biology of VDR regulation by LCA is only now emerging.Hairless (HR) is a nuclear protein that functions as a corepressor of nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors and VDR.10-12) HR interacts with VDR via multiple protein-protein interfaces in the absence of ligand and represses VDR transactivation by 1,25(OH) 2 D 3 and LCA.12,13) Interestingly, LCA but not 1,25(OH) 2 D 3 enhances the interaction, 12) suggesting that LCA induces a conformation of the VDR-RXR heterodimer with enhanced affinity for HR binding. In both mice and humans, mutation of HR results in hair-loss phenotypes similar to VDR mutation, suggesting a functional interaction of HR and VDR in vivo. 14) In contrast to the in vitro interaction, 1,25(OH) 2 D 3 treatment decreases HR binding to VDR in keratinocytes. 15) Although the in vivo role of HR in VDR function remains ...

show abstract

Section: 7)supporting

confidence: 81%

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, the À1.5 and À2 kb region of the p-MITF region contains three E-boxes that could bind Bhlhb2; one of these E-box is conserved in the mouse promoter. Bhlhb2 has a known transcriptional repression activity towards numerous target genes (Choi et al, 2008;Cho et al, 2009;Bhawal et al, 2011). Bhlhb2 is involved in the control of circadian rhythms (Honma et al, 2002;Nakashima et al, 2008), and has an anti-apoptotic activity (Ehata et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells

et al. 2011

View full text Add to dashboard Cite

Melanomas are very aggressive neoplasms with notorious resistance to therapeutics. It was recently proposed that the remarkable phenotypic plasticity of melanoma cells allows for the rapid development of both resistance to chemotherapeutic drugs and invasive properties. Indeed, the capacity of melanoma cells to form distant metastases is the main cause of mortality in melanoma patients. Therefore, the identification of the mechanism controlling melanoma phenotype is of paramount importance. In the present report, we show that deletion of microphthalmiaassociated transcription factor (MITF), the master gene in melanocyte differentiation, is sufficient to increase the metastatic potential of mouse and human melanoma cells. MITF silencing also increases fibronectin and Snail, two mesenchymal markers that might explain the increased invasiveness in vitro and in vivo. Furthermore, ablation of this population by Forskolin-induced differentiation or MITF-forced expression significantly decreases tumour and metastasis formation, suggesting that eradication of low-MITF cells might improve melanoma treatment. Moreover, we demonstrate that a hypoxic microenvironment decreases MITF expression through an indirect, hypoxia-inducible factor 1 (HIF1)a-dependant transcriptional mechanism, and increases the tumourigenic and metastatic properties of melanoma cells. We identified Bhlhb2, a new factor in melanoma biology, as the mediator of hypoxia/HIF1a inhibitory effect on MITF expression. Our results reveal a hypoxia-HIF1a-BHLHB2-MITF cascade controlling the phenotypic plasticity in melanoma cells and favouring metastasis development. Targeting this pathway might be helpful in the design of new anti-melanoma therapies.

show abstract

“…DEC1 also enhances the recruitment of HDAC1 to the ATPbinding cassette transporter A1 (ABCA1) gene, a target gene of retinoid X receptor (RXR)/liver X receptor heterodimer by interacting with RXR (Cho et al, 2009). Although DEC1 prevents neither C/EBPβ nor RXR from binding to its target gene, DEC1 prevents bHLH domain containing transactivators such as BMAL1, MyoD and SREBP-1c, from binding to their target DNA by either protein-protein interaction or by directly binding to their responsive elements containing an E-box (Azmi et al, 2004;Choi et al, 2008;Li et al, 2004).…”

Section: Dec1 Is Recruited On the Promoter Of Pparγ2mentioning

confidence: 99%

Differentiated Embryo Chondrocyte 1 (DEC1) Represses PPARγ2 Gene through Interacting with CCAAT/Enhancer Binding Protein β (C/EBPβ)

Park

2012

Molecules and Cells

View full text Add to dashboard Cite

DEC1 is a transcription repressor that is induced by Hypoxia-Inducible Factor-α/β (HIF-α/β). In this study, we found that either hypoxic treatment or ectopic expression of DEC1 blocks induction of a master adipogenic transactivator, peroxisome proliferative activated receptor-γ2 (PPARγ2) in 3T3-L1 cells. DEC1 did not prevent C/EBPβ, which is an upstream transactivator for PPARγ2, from occupying the PPARγ2 promoter. DEC1 occupied the PPARγ2 promoter by interacting with DNA-bound C/EBPβ. DEC1 occupancy was accompanied by a reduction of acetylated histones and an increase in histone deacetylase 1 (HDAC1) occupancy on the PPARγ2 promoter. Based on the fact that DEC1 interacts with HDAC1, this study suggests that DEC1 blocks adipogenesis by reinforcing HDAC1 recruitment to the PPARγ2 promoter. This study implies that DEC1 is one of the mediators that reset the pattern of PPARγ2 expression in response to hypoxia.

show abstract

The Basic Helix-Loop-Helix Proteins Differentiated Embryo Chondrocyte (DEC) 1 and DEC2 Function as Corepressors of Retinoid X Receptors

Cited by 57 publications

References 40 publications

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells

Differentiated Embryo Chondrocyte 1 (DEC1) Represses PPARγ2 Gene through Interacting with CCAAT/Enhancer Binding Protein β (C/EBPβ)

Contact Info

Product

Resources

About