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Query: UNIPROT:P06889 (Mol)
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The ligand-binding domains of thyroid hormone (L-triiodothyronine [T3]) receptors (T3Rs), all-trans retinoic acid (RA) receptors (RARs), and 9-cis RA receptors (RARs and RXRs) contain a series of heptad motifs thought to be important for dimeric interactions. Using a chimera containing amino acids 120 to 392 of chicken T3R alpha (cT3R alpha) positioned between the DNA-binding domain of the yeast GAL4 protein and the potent 90-amino-acid transactivating domain of the herpes simplex virus VP16 protein (GAL4-T3R-VP16), we provide functional evidence that binding of ligand releases T3Rs and RARs from an inhibitory cellular factor. GAL4-T3R-VP16 does not bind T3 and does not activate transcription from a GAL4 reporter when expressed alone but is able to activate transcription when coexpressed with unliganded T3R or RAR. This activation is reversed by T3 or RA, suggesting that these receptors compete with GAL4-T3R-VP16 for a cellular inhibitor and that ligand reverses this effect by dissociating T3R or RAR from the inhibitor. A chimera containing the entire ligand-binding domain of cT3R alpha (amino acids 120 to 408) linked to VP16 [GAL4-T3R(408)-VP16] is activated by unliganded receptor as well as by T3. In contrast, GAL4-T3R containing the amino acid 120 to 408 ligand-binding region without the VP16 domain is activated only by T3. The highly conserved ninth heptad, which is involved in heterodimerization, appears to participate in the receptor-inhibitor interaction, suggesting that the inhibitor is a related member of the receptor gene family. In striking contrast to T3R and RAR, RXR activates GAL4-T3R-VP16 only with its ligand, 9-cis RA, but unliganded RXR does not appear to be the inhibitor suggested by these studies. Further evidence that an orphan receptor may be the inhibitor comes from our finding that COUP-TF inhibits activation of GAL4-T3R-VP16 by unliganded T3R and the activation of GAL4-T3R by T3. These and other results suggest that an inhibitory factor suppresses transactivation by the T3Rs and RARs while these receptors are bound to DNA and that ligands act, in part, by inactivating or promoting dissociation of a receptor-inhibitor complex.
Mol Cell Biol 1994 Sep
PMID:Functional evidence for ligand-dependent dissociation of thyroid hormone and retinoic acid receptors from an inhibitory cellular factor. 806 10

Orphan receptors of the FTZ-F1-related group of nuclear receptors (xFF1r) were identified in Xenopus laevis by isolation of cDNAs from a neurula stage library. Two cDNAs were found, which encode full length, highly related receptor proteins, xFF1rA and B, whose closet relative known so far is the murine LRH-1 orphan receptor. xFF1rA protein expressed by a recombinant vaccinia virus system specifically binds to FTZ-F1 response elements (FRE; PyCAAGGPyCPu). In cotransfection studies, xFF1rA constitutively activates transcription, in a manner dependent on the number of FREs. The amounts of at least four mRNAs encoding full-length receptors greatly increase between gastrula and early tailbud stages and decrease at later stages. At early tailbud stages, xFTZ-F1-related antigens are found in all nuclei of the embryo.
Mol Cell Biol 1994 Apr
PMID:FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis. 813 76

The Oct-3/4 gene product, which belongs to the POU family of transcription factors, is a good candidate for regulating initial differentiation decisions. It is expressed in the earliest stages of embryogenesis and repressed in subsequent stages. Retinoic acid (RA)-induced differentiation of embryonal carcinoma (EC) cells is accompanied by decreased expression of the Oct-3/4 gene. Previous findings show that sequences in the Oct-3/4 enhancer region (designated RARE1) are targets for RA-mediated repression (H. Okazawa, K. Okamoto, F. Ishino, T. Ishino-Kaneko, S. Takeda, Y. Toyoda, M. Muramatsu, and H. Hamada, EMBO J. 10:2997-3005, 1991). Our present results demonstrate conclusively that the TATA-less Oct-3/4 promoter is also a target for RA-induced repression. We identified a novel cis element in the Oct-3/4 promoter harbors a putative Sp1 binding site and a RA-responsive element (designated RAREoct), which are juxtaposed to one another. Protein binding to the Sp1 site is independent of protein binding to the RAREoct sequence. Unlike the RARE1 situated in the Oct-3/4 enhancer which does not contain a typical RAR recognition site, the RAREoct identified in this study consists of three directly repeated motifs that exhibit extensive homology to RARE sequences located in RA-responsive genes. Moreover, the RAREoct shows different DNA-binding characteristics and DNase I footprint patterns with nuclear proteins isolated from undifferentiated versus RA-differentiated EC cells. This suggests that the RAREoct element binds different nuclear proteins in RA-treated and untreated EC cells which most probably belong to the RA receptor, retinoid X receptor, or orphan receptor families of transcription factors. Using site-directed mutagenesis, we show that the RAREoct contributes to the transcriptional activation of Oct-3/4 promoter in P19 cells and, most interestingly, mediates the RA-induced repression in RA-differentiated EC cells. Thus, the RAREoct element could be one of the points of integration of several signalling pathways influencing Oct-3/4 expression. In accordance with the suggestion that suppression of Oct-3/4 expression is a crucial step during embryogenesis, the Oct-3/4 upstream region contains multiple targets for RA-induced repression, probably to ensure accurate and prompt repression of Oct-3/4 expression. It is possible that these repressors are differentially used at specific stages of development in response to various signals.
Mol Cell Biol 1994 Feb
PMID:Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. 828 83

The cytochrome P450 aromatase gene is transcriptionally regulated by FSH and steroids in granulosa cells of developing ovarian follicles. To characterize the molecular mechanisms by which this regulation occurs, the promoter of the rat aromatase gene has been analyzed by 1) mapping the transcriptional start site, 2) constructing deletion mutant reporter genes for transfection assays, and 3) determining DNA-protein interactions by gel shift assays. Transient transfection assays indicated that promoter sequences between -176 and -31 basepairs (bp) were required for cAMP inducibility of reporter constructs in primary cultures of granulosa cells and for expression in rat R2C Leydig cells, which constitutively express high amounts of aromatase mRNA. Nuclear extract proteins from granulosa cells and R2C Leydig cells specifically bound a labeled -176/13-bp fragment and were competed by cold competitor fragment as well as by a shorter region (-90/-66 bp) containing an AGGTCA hexameric motif. Competition was inhibited by mutation of the central GGs and was affected by adjacent 5' contextual sequences. A possible candidate for the binding activity observed in granulosa cells and R2C cell nuclear extracts binds an oligonucleotide containing the aromatase AGGTCA motif and is an orphan member of the steroid/thyroid hormone superfamily. These results are the first to characterize cis-acting DNA elements in the aromatase promoter, identify a region that confers cAMP inducibility in granulosa cells and constitutive expression in R2C cells, and localize a hexameric sequence within this region that binds at least one member of the orphan receptor class of transcription factors.
Mol Endocrinol 1993 Mar
PMID:cis-acting elements of the rat aromatase promoter required for cyclic adenosine 3',5'-monophosphate induction in ovarian granulosa cells and constitutive expression in R2C Leydig cells. 838 57

The 26S proteasome complex plays a general role in turnover of both short and long lived proteins by specifically degrading ubiquitinated proteins. Recent evidence suggests that this large protease has more specific functions in a number of important cellular processes, ranging from activation of the transcription factor NFkB and antigen processing to transit through mitosis. We have identified a component of the 26S proteasome that interacts specifically with MB67, an orphan member of the nuclear hormone receptor superfamily. MIP224 (MB67 interacting protein) was isolated using the yeast two hybrid system and is apparently identical to the human 26S proteasome component TBP7. MIP224/TBP7 is one of several proteasomal proteins that share a strongly conserved ATPase domain (CAD) which is also present in a rapidly expanding superfamily of proteins with diverse functions. In yeast, MIP224 interacts specifically with MB67 and another closely related orphan receptor, but does not interact with several other receptor superfamily members tested. In mammalian cells, coexpression of MIP224 inhibits transactivation by MB67. MIP224 also interacts in yeast with other CAD proteins, including MSS1, which is proteasomal, and TRIP1, which is associated with transcriptional activation. This interaction of a proteasomal protein with a transcriptional protein suggests a previously unexpected link between the processes of protein degradation and transcriptional regulation.
J Steroid Biochem Mol Biol 1996 Jan
PMID:A component of the 26S proteasome binds on orphan member of the nuclear hormone receptor superfamily. 860 43

Rev-erbA alpha is an orphan steroid receptor that is expressed in skeletal muscle. Rev-erbA alpha binds to single/tandem copies of an AGGTCA motif, is transcribed on the noncoding strand of the c-erbA- alpha gene locus, and is postulated to modulate the thyroid hormone (T3) response. T3 induces terminal muscle differentiation and regulates fiber type composition via direct activation of the muscle-specific myoD gene family (e.g. myoD, myogenin). The myoD gene family can direct the fate of mesodermal cell lineages and activate muscle differentiation. Hence we investigated the expression and physiological role of Rev-erbA alpha during myogenesis. We observed abundant levels of Rev-erbA alpha mRNA in dividing C2C12 myoblasts, which were suppressed when the cells differentiated into postmitotic multinucleated myotubes. This decrease in Rev-erbA alpha mRNA correlated with the appearance of muscle-specific mRNAs (e.g. myogenin and alpha-actin). Constitutive overexpression of full length Rev-erbA alpha cDNA in the myogenic cells completely abolished differentiation, suppressed myoD mRNA levels, and abrogated the induction of myogenin mRNA. We then demonstrated that 1) GAL4-REV-erbA alpha chimeras that contain the 'AB' region and lack the 'E' region activated transcription of GAL4 response elements in the presence of 8-Br-cAMP and 2) the ligand-binding domain (LBD) contains an active transcriptional silencer. Overexpression of Rev-erbA alpha (delta AB) in myogenic cells had no impact on the ability of these cells to morphologically or biochemically differentiate. Furthermore, this orphan receptor 1) down-regulated thyroid hormone receptor (TR)/T3 mediated transcriptional activity from the myogenin promoter and thyroid hormone response element (TRE) an 2) disrupted TR homodimer and TR/retinoid X receptor (RXR) heterodimer formation on a number of TREs found in the myoD gene family. In conclusion, Rev-erbA alpha functions as a negative regulator of myogenesis by targeting the expression of the myoD gene family. The mechanism of action may involve inhibition of functional TR/RXR heterodimer formation on critical TREs and dominant trans-repression of gene expression.
Mol Endocrinol 1995 Dec
PMID:Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family. 861 3

Vitamin A and other fat-soluble hormones and vitamins have important roles as modulators of essential biological processes such as homeostasis, development, differentiation, and oncogenesis and also as regulators of the immune system. The active form of vitamin A, retinoic acid, as well as vitamin D3 and thyroid hormones exert their actions by binding to specific nuclear receptors that represent one subfamily of the steroid/thyroid hormone receptor superfamily. To identify new members of the retinoid/thyroid hormone receptor subfamily that could play a role in the immune system, a screening of a T cell cDNA library was performed using a retinoid X receptor probe. A clone was isolated encoding a novel nuclear receptor expressed mainly in the thymus and T cell lines. This new receptor, TOR (thymus orphan receptor), is most closely related in both its DNA-binding domain and ligand-binding domain, 90% and 53%, respectively, to ROR alpha/RZR alpha and clusters with these two receptors and RZR beta in a phylogenetic tree, when both the DNA-binding domain and the ligand-binding domain sequences of nuclear receptors are compared. Thus, TOR is part of a subgroup of receptors, one of which has recently been reported to be activated by melatonin. TOR binds specifically to a direct repeat of the half-site sequence 5'-AGGTCA-3' with a four- or five-nucleotide spacer, DNA sequences that also serve as binding sites for thyroid hormone (TR), and retinoic acid receptors (RAR). In transient transfection experiments TOR does not activate a reporter gene carrying these sequences in the absence or the presence of any known nuclear receptor ligands. TOR, however, is able to repress TR and RAR activity on DR-4-TREs or DR-5-RAREs, respectively. Therefore, our data suggest that TOR, similar to COUP-TF, can negatively regulate retinoic acid and thyroid hormone signals. However, the response elements recognized by TOR and COUP-TF differ as do the expression patterns of these receptors. Thus, one important role of TOR could be to modulate retinoid and thyroid hormone signals in the thymus.
Mol Endocrinol 1995 Dec
PMID:TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. 861 4

The nuclear (steroid/thyroid/retinoid) receptor superfamily is a set of evolutionarily related ligand-inducible regulators of transcription. One subgroup within this family has been termed the orphan receptors because the potential ligands required for their activity have not been identified. We have cloned a novel orphan receptor, MINOR, which is mitogen inducible in a variety of cell types. Unlike NGFI-B/Nur77, another mitogen-inducible orphan receptor, MINOR gene expression is inhibited in Jurkat cells by the immunosuppressant cyclosporin A, suggesting that it is regulated by distinct second messenger pathways. The conservation of the DNA-binding domain between MINOR and other orphan receptors is reflected in the fact that they are able to bind to the same sequence, AAAG-GTCA [termed the NBRE (NGFI-B response element)]. The marked divergence in other domains, particularly the N-terminal putative transactivation domain, may result in qualitative or quantitative differences in other functions among these proteins. One of these differences may be the apparent squelching of peak levels of MINOR-mediated transcription by supraoptimal levels of MINOR expression, an effect not obtained with NGFI-B/Nur77. When MINOR i coexpressed with submaximal levels of NGFI-B/Nur77, synergistic or additive levels of reporter gene expression are obtained. However, at maximal levels of NGFI-B/Nur77 expression, MINOR antagonizes the level of reporter gene expression in a dose-dependent fashion. These cooperative/competitive interactions, together with the nonidentical expression patterns of MINOR and NGFI-B/Nur77, suggest complexity in the regulation of genes responsive to orphan receptors which bind to the NBRE.
Mol Endocrinol 1995 Dec
PMID:The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor. 861 5

We have cloned cDNA encoding a mouse nuclear receptor mROR alpha which is a homolog of human retinoic acid receptor-related orphan receptor (hROR alpha). Cotransfection experiments revealed that mROR alpha activates transcription through a retinoic acid responsive element of the laminin B1 gene (lamRARE), but not through a RARE of RAR beta gene (beta RARE) or a synthetic palindromic thyroid hormone responsive element (TREpal). The most distal AGGTCA half-site among the three half-sites of lamRARE was sufficient for binding of mROR alpha and consequently for activation of transcription. Transactivation by mROR alpha was dependent on serum in culture medium after transfection, suggesting the presence of a possible ligand. Northern hybridization and in situ hybridization analyses revealed that mROR alpha is expressed in specific areas of the brain including thalamus and olfactory bulb as well as cerebellum where it is present at highest levels in Purkinje cells. In addition to regionally heterogeneous expression in brain, its expression was temporally regulated during differentiation of P19 cells into neural cells, but not into muscle cells. These observations suggest that mROR alpha plays important roles as a transcription factor not only in differentiation of neural cell lineages but also in the mature brain.
Brain Res Mol Brain Res 1995 Nov
PMID:An orphan nuclear receptor, mROR alpha, and its spatial expression in adult mouse brain. 875 Aug 80

Degenerate oligonucleotides and cDNA converted from Choristoneura fumiferana embryonic RNA were used in a polymerase chain reaction (PCR) procedure to isolate a 683 bp cDNA fragment. Comparison of the deduced amino acid sequence of this cDNA fragment showed that it was a region of an MHR3-like gene from C. fumeferana; we therefore named it Choristoneura hormone receptor 3 (CHR3). This CHR3 cDNA fragment was used as a probe to screen a C. fumiferana embryonic cDNA library. Twenty clones were isolated and two overlapping clones were sequenced. The longest open reading frame of CHR3 cDNA codes for 546 amino acids. The deduced amino acid sequence of this open reading frame contained all five regions typical of a steroid hormone nuclear receptor. The C domain showed the highest identity to Manduca hormone receptor 3 (MHR3), Drosophila hormone receptor 3 (DHR3) and Galleria hormone receptor 3 (GHR3). The A/B, D and E domains also showed significant amino acid similarity with MHR3, DHR3 and GHR3. The 683 bp CHR3 cDNA probe detected two mRNAs of 3.8 and 4.5 kb present during the ecdysteroid peaks for embryonic, larval, pupal and adult molts but were not detected during the intermolt periods. In sixth instar larvae, the 3.8 and 4.5 kb mRNA were detected in the epidermis, fat body and midgut tissues and the maximum expression was observed during the prepupal peak of ecdysteroids in the hemolymph. CHR3 mRNA was induced in 20-hydroxyecdysone treated CF-203 cells as well as in the midgut, fat body and epidermis of larvae that were fed the non-steroidal molting hormone agonist, RH-5992. In vitro transcription and translation of the CHR3 cDNA yielded a 61 kDa protein that bound to the retinoid related orphan receptor response element.
Insect Biochem Mol Biol 1996 May
PMID:Cloning and developmental expression of Choristoneura hormone receptor 3, an ecdysone-inducible gene and a member of the steroid hormone receptor superfamily. 876 67


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