scholarly journals A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs.

1994 ◽  
Vol 14 (7) ◽  
pp. 4360-4372 ◽  
Author(s):  
M E Carter ◽  
T Gulick ◽  
D D Moore ◽  
D P Kelly
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Gene Promoter ◽  
Response Element ◽  
Binding Motifs ◽  
Receptor Response ◽  
Dehydrogenase Gene ◽  
Chain Acyl ◽  
Acyl Coenzyme A

We previously identified a complex regulatory element in the medium-chain acyl coenzyme A dehydrogenase gene promoter that confers transcriptional regulation by the retinoid receptors RAR and RXR and the orphan nuclear receptor HNF-4. In this study we demonstrate a trans-repressing regulatory function for the orphan receptor COUP-TF at this same nuclear receptor response element (NRRE-1). The transcriptional regulatory properties and receptor binding sequences of each nuclear receptor response element within NRRE-1 are also characterized. NRRE-1 consists of four potential nuclear hormone receptor hexamer binding sites, arranged as [<--1-(n)s-2-->-3-->(n)4<--4], three of which are used in alternative pairwise binding by COUP-TF and HNF-4 homodimers and by RAR-RXR heterodimers, as demonstrated by mobility shift assays and methylation interference analysis. Binding and transactivation studies with mutant NRRE-1 elements confirmed the existence of distinct retinoid, COUP-TF, and HNF-4 response elements that define novel receptor binding motifs: COUP-TF homodimers bound sites 1 and 3 (two hexamer repeat sequences arranged as an everted imperfect repeat separated by 14 bp or ER14), RAR-RXR heterodimers bound sites 1 and 2 (ER8), and HNF-4 homodimers bound sites 2 and 3 (imperfect DR0). Mixing cotransfection experiments demonstrated that the nuclear receptor dimers compete at NRRE-1 to modulate constitutive and ligand-mediated transcriptional activity. These data suggest a mechanism for the transcriptional modulation of genes encoding enzymes involved in cellular metabolism.

A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs

1994 ◽  
Vol 14 (7) ◽  
pp. 4360-4372
Author(s):  
M E Carter ◽  
T Gulick ◽  
D D Moore ◽  
D P Kelly
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Gene Promoter ◽  
Response Element ◽  
Binding Motifs ◽  
Receptor Response ◽  
Dehydrogenase Gene ◽  
Chain Acyl ◽  
Acyl Coenzyme A

We previously identified a complex regulatory element in the medium-chain acyl coenzyme A dehydrogenase gene promoter that confers transcriptional regulation by the retinoid receptors RAR and RXR and the orphan nuclear receptor HNF-4. In this study we demonstrate a trans-repressing regulatory function for the orphan receptor COUP-TF at this same nuclear receptor response element (NRRE-1). The transcriptional regulatory properties and receptor binding sequences of each nuclear receptor response element within NRRE-1 are also characterized. NRRE-1 consists of four potential nuclear hormone receptor hexamer binding sites, arranged as [<--1-(n)s-2-->-3-->(n)4<--4], three of which are used in alternative pairwise binding by COUP-TF and HNF-4 homodimers and by RAR-RXR heterodimers, as demonstrated by mobility shift assays and methylation interference analysis. Binding and transactivation studies with mutant NRRE-1 elements confirmed the existence of distinct retinoid, COUP-TF, and HNF-4 response elements that define novel receptor binding motifs: COUP-TF homodimers bound sites 1 and 3 (two hexamer repeat sequences arranged as an everted imperfect repeat separated by 14 bp or ER14), RAR-RXR heterodimers bound sites 1 and 2 (ER8), and HNF-4 homodimers bound sites 2 and 3 (imperfect DR0). Mixing cotransfection experiments demonstrated that the nuclear receptor dimers compete at NRRE-1 to modulate constitutive and ligand-mediated transcriptional activity. These data suggest a mechanism for the transcriptional modulation of genes encoding enzymes involved in cellular metabolism.

scholarly journals The Human Medium Chain Acyl-CoA Dehydrogenase Gene Promoter Consists of a Complex Arrangement of Nuclear Receptor Response Elements and Sp1 Binding Sites

1995 ◽  
Vol 270 (27) ◽  
pp. 16308-16314 ◽  
Author(s):  
Teresa C. Leone ◽  
Sharon Cresci ◽  
M. Eric Carter ◽  
Zhifang Zhang ◽  
Deepak S. Lala ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Binding Sites ◽  
Gene Promoter ◽  
Response Elements ◽  
Medium Chain ◽  
Receptor Response ◽  
Dehydrogenase Gene ◽  
Chain Acyl ◽  
Complex Arrangement

scholarly journals The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.

1997 ◽  
Vol 17 (9) ◽  
pp. 5400-5409 ◽  
Author(s):  
R Sladek ◽  
J A Bader ◽  
V Giguère
Keyword(s):  
Nuclear Receptor ◽  
Coenzyme A ◽  
Tumor Cell Line ◽  
Response Element ◽  
Receptor Alpha ◽  
Medium Chain ◽  
Brown Adipose ◽  
Chain Acyl ◽  
Acyl Coenzyme A ◽  
Estrogen Related Receptor

Estrogen-related receptor alpha (ERR alpha) is an orphan member of the superfamily of nuclear hormone receptors. ERR alpha was initially isolated based on its sequence homology to the estrogen receptor but is not activated by classic estrogens. To identify possible physiologic functions for this orphan receptor, we cloned the mouse ERR alpha cDNA and used it to characterize the expression of ERR alpha transcripts and to identify potential ERR alpha target genes. RNA in situ hybridization studies detect ERR alpha transcripts in an organ-specific manner through mid- to late embryonic development, with persistent high-level expression in brown adipose tissue and intestinal mucosa. In the adult mouse, ERR alpha is most highly expressed in kidney, heart, and brown adipocytes, tissues which preferentially metabolize fatty acids. Binding site selection experiments show that ERR alpha preferentially binds to an ERR alpha response element (ERRE) containing a single consensus half-site, TNAAGGTCA. An ERRE is present in the 5'-flanking region of the gene encoding medium-chain acyl coenzyme A dehydrogenase (MCAD), a key enzyme involved in the mitochondrial beta-oxidation of fat. The MCAD nuclear receptor response element 1 (NRRE-1) interacts in vitro with ERR alpha expressed in COS-7 cells. Supershift experiments show that endogenous ERR alpha present in nuclear extracts obtained from a brown fat tumor cell line (HIB) interacts with NRRE-1. In the absence of its putative ligand, ERR alpha does not activate the MCAD promoter in transient transfection studies; however, a VP16-ERR alpha chimera activates natural and synthetic promoters containing NRRE-1. In addition, ERR alpha efficiently represses retinoic acid induction mediated by NRRE-1. These results demonstrate that ERR alpha can control the expression of MCAD through the NRRE-1 and thus may play an important role in regulating cellular energy balance in vivo.

scholarly journals Functional interference between estrogen-related receptor alpha and peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene

2003 ◽  
Vol 31 (1) ◽  
pp. 47-60 ◽  
Author(s):  
K Maehara ◽  
T Hida ◽  
Y Abe ◽  
A Koga ◽  
K Ota ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Retinoic Acid Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Receptor Response ◽  
Chain Acyl ◽  
Acyl Coenzyme A ◽  
Estrogen Related Receptor

We undertook a study of molecular interference of nuclear orphan receptors. Nuclear receptor response element-1 (NRRE-1) from the human medium-chain acyl coenzyme A dehydrogenase (MCAD) gene promoter was shown to contain three hexamer elements (site 1 through 3) that are known to interact with a number of nuclear receptors including chicken ovalbumin upstream promoter transcription factor (COUP-TF) and estrogen-related receptor alpha (ERRalpha). We demonstrated that the peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha (PPARalpha/RXRalpha) heterodimer complex can also bind to the two hexamer repeat sequences (between site 1 and site 3) arranged as an everted imperfect repeat separated by 14 bp (ER14). Mutations of the putative core elements have shown that these three sites are differentially involved in ERRalpha and PPARalpha/RXRalpha binding. Homodimer of ERRalpha was shown to interact between site 1 and site 3 (ER14). To date, no nuclear receptor is known to bind to response elements over such long intervals. Interestingly, site 1 was shown to be essential for ERRalpha binding while site 3 supports its binding only in the presence of site 1. Furthermore, it was shown that the binding profile of ERRalpha and PPARalpha/RXRalpha are competitive rather than making a high order complex within NRRE-1. At the cellular level, transcriptional activation driven by the PPARalpha/RXRalpha complex was counteracted by the expression of ERRalpha in HeLa cells. These results suggest that ERRalpha and PPARalpha/RXRalpha could interfere with each other's function through binding to similar DNA elements, thereby finetuning the transcriptional outcome of the target gene. Our findings suggest a mechanism whereby multiple nuclear receptors can activate or repress DNA binding or transcription via a single pleiotropic regulatory element.

scholarly journals Coregulatory protein–orphan nuclear receptor interactions in the human adrenal cortex

2005 ◽  
Vol 186 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Sinead N Kelly ◽  
T Joseph McKenna ◽  
Leonie S Young
Keyword(s):  
Transcriptional Regulation ◽  
Adrenal Cortex ◽  
Nuclear Receptor ◽  
Tumour Cell Line ◽  
Zona Fasciculata ◽  
Orphan Nuclear Receptor ◽  
Response Element ◽  
Coregulatory Proteins ◽  
Coregulatory Protein ◽  
In Cells

The capacity of the adrenal to produce steroids is controlled in part through the transcriptional regulation of steroid enzymes. The orphan nuclear receptor steroidogenic factor 1 (SF-1) is central to the transcriptional regulation of all steroid hydroxylase enzymes, whereas nur77 can preferentially regulate steroid enzyme genes relevant to cortisol production. We hypothesised that, in the presence of secretagogues, SF-1 and nur77 may differentially interact with coregulatory proteins in the human adrenal cortex. Both coregulatory proteins, steroid receptor coactivator (SRC-1) and silencing mediator for retinoid and thyroid hormones (SMRT), were found to be expressed in the zona fasciculata and reticularis in the human adrenal cortex, but were largely absent from the zona glomerulosa. Both coregulatory proteins were colocalised with SF-1 and nur77. In the H295R adrenal tumour cell line, SF-1 and nur77 transcripts were increased in cells in the presence of forskolin, whereas nur77 mRNA was also induced with angiotensin II (AII). The coactivator SRC-1 mRNA was increased in the presence of both forskolin and AII. Forskolin induced recruitment of SRC-1 to the SF-1 response element and induced SRC-1–SF-1 interactions, whereas AII increased recruitment of SRC-1 to the nur77 response element and induced SRC-1–nur77 interactions. The corepressor SMRT interacted with SF-1 in the presence of AII and with nur77 in cells treated with forskolin. Orphan nuclear receptor–coregulatory protein interactions may have consequences for the regulation of key steroidogenic enzymes in the human adrenal cortex.

scholarly journals Germ Cell Nuclear Factor Relieves cAMP-response Element Modulator τ-mediated Activation of the Testis-specific Promoter of Human Mitochondrial Glycerol-3-phosphate Dehydrogenase

2004 ◽  
Vol 279 (50) ◽  
pp. 52493-52499 ◽  
Author(s):  
Mirjana Rajković ◽  
Ralf Middendorff ◽  
Marianne G. Wetzel ◽  
Danijel Frković ◽  
Sebastian Damerow ◽  
...  
Keyword(s):  
Germ Cell ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Regulation Mechanism ◽  
Nuclear Factor ◽  
Camp Response Element ◽  
Down Regulation ◽  
Response Element ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Germ Cell Nuclear Factor

Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is an essential component of the glycerol phosphate shuttle that transfers reduction equivalents from the cytosol into the mitochondrion. Within the testis, immunohistological analysis localized human mGPDH to late spermatids and to the midpiece of spermatozoa. The expression of human mGPDH is regulated by two somatic promoters, and here, we describe a third testis-specific promoter of human mGPDH. The usage of this testis-specific promoter correlates with the expression of a shortened mGPDH transcript of ∼2.4 kb in length, which is solely detectable from testicular RNA. Within the testis-specific promoter, we detected a cAMP-response element (CRE) site at -51, which binds the testis-specific transcriptional activator CRE modulator τ (CREMτ) in electrophoretic mobility shift assays. This recognition site overlaps with a nuclear receptor binding half-site at -49, which binds the testis-specific transcriptional repressor germ cell nuclear factor (GCNF). Both factors compete for binding to the same DNA response element. Ectopic expression of CREMτ in HepG2 cells activated a promoter-driven luciferase construct in transient transfection experiments. Additional cotransfection of GCNF relieved this activity, suggesting a down-regulation of CREMτ-mediated activation by GCNF. This effect was preserved by introducing the CRE/nuclear receptor-binding element into a heterologous promoter context. Our data suggest a down-regulation of CREMτ-mediated gene expression by GCNF, which might be a general regulation mechanism for several postmeiotically expressed genes with a temporal expression peak during early spermatid development.

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