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At least 235 records · Page 13Linked to original sources
PubMed2003

TR3 orphan receptor is expressed in vascular endothelial cells and mediates cell cycle arrest.

OBJECTIVE: Endothelial cells play a pivotal role in vascular homeostasis. In this study, we investigated the function of the nerve growth factor-induced protein-B (NGFI-B) subfamily of nuclear receptors comprising the TR3 orphan receptor (TR3), mitogen-induced nuclear orphan receptor (MINOR), and nuclear orphan receptor of T cells (NOT) in endothelial cells. METHODS AND RESULTS: The mRNA expression of TR3, MINOR, and NOT in atherosclerotic lesions was assessed in human vascular specimens. Each of these factors is expressed in smooth muscle cells, as described before, and in subsets of endothelial cells, implicating that they might affect endothelial cell function. Adenoviral overexpression of TR3 in cultured endothelial cells resulted in decreased [3H]thymidine incorporation, whereas a dominant-negative TR3 variant that inhibits the activity of endogenous TR3-like factors enhanced DNA synthesis. TR3 interfered with progression of the cell cycle by upregulating p27Kip1 and downregulating cyclin A, whereas expression levels of a number of other cell cycle-associated proteins remained unchanged. CONCLUSIONS: These findings demonstrate that TR3 is a modulator of endothelial cell proliferation and arrests endothelial cells in the G1 phase of the cell cycle by influencing cell cycle protein levels. We hypothesize involvement of TR3 in the maintenance of integrity of the vascular endothelium.

Adenoviridae↗
PubMed2002

Multiple phosphorylation events control chicken ovalbumin upstream promoter transcription factor I orphan nuclear receptor activity.

Chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) is an orphan member of the nuclear hormone receptor superfamily that comprises key regulators of many biological functions, such as embryonic development, metabolism, homeostasis, and reproduction. Although COUP-TFI can both actively silence gene transcription and antagonize the functions of various other nuclear receptors, the COUP-TFI orphan receptor also acts as a transcriptional activator in certain contexts. Moreover, COUP-TFI has recently been shown to serve as an accessory factor for some ligand-bound nuclear receptors, suggesting that it may modulate, both negatively and positively, a wide range of hormonal responses. In the absence of any identified cognate ligand, the mechanisms involved in the regulation of COUP-TFI activity remain unclear. The elucidation of several putative phosphorylation sites for MAPKs, PKC, and casein kinase II within the sequence of this orphan receptor led us to investigate phosphorylation events regulating the various COUP-TFI functions. After showing that COUP-TFI is phosphorylated in vivo, we provide evidence that in vivo inhibition of either MAPK or PKC signaling pathway leads to a specific and pronounced decrease in COUP-TFI-dependent transcriptional activation of the vitronectin gene promoter. Focusing on the molecular mechanisms underlying the MAPK- and PKC-mediated regulation of COUP-TFI activity, we show that COUP-TFI can be directly targeted by PKC and MAPK. These phosphorylation events differentially modulate COUP-TFI functions: PKC-mediated phosphorylation enhances COUP-TFI affinity for DNA and MAPK-mediated phosphorylation positively regulates the transactivation function of COUP-TFI, possibly through enhancing specific coactivator recruitment. These data provide evidence that COUP-TFI is likely to integrate distinct signaling pathways and raise the possibility that multiple extracellular signals influence biological processes controlled by COUP-TFI.

Animals↗
PubMed1994

Cloning of a novel orphan receptor (GCNF) expressed during germ cell development.

We have cloned a novel member of the nuclear receptor superfamily that has been identified from complementary DNA libraries derived from mouse tissues using a low stringency cross hybridization strategy. The deduced protein sequence contains 495 amino acids and consists of the characteristic DNA-binding and ligand-binding domains of the nuclear receptor superfamily. The primary sequence of this new orphan is distinct from those of previously cloned members and subgroups. Analysis of the DNA-binding properties of the in vitro synthesized protein revealed that this new orphan receptor binds to the sequence TCAAGGTCA that includes the steroidogenic factor-1 half-site and direct repeat with 0 bp spacing elements. Northern blot and ribonuclease protection assays showed that the receptor was predominantly expressed in the testis. Results from in situ hybridization experiments confirmed this observation and showed it to be located in the spermatogenic cells. High level expression was also detected in developing oocytes in the ovary. Thus, high level expression of this gene is restricted to developing germ cells, the oocytes and spermatogenic cells. We speculate that this orphan receptor may be a molecule involved in regulating some aspect of meiosis, and that the major function of this factor is likely to be involved in the regulation of gene expression in germ cell development during gametogenesis. It has been designated germ cell nuclear factor.

Amino Acid Sequence↗
PubMed1994

A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb.

We have isolated complementary DNA clones encoding a novel orphan member of the nuclear receptor superfamily, termed BD73. This protein shows strong amino acid sequence similarity to the previously described Rev-ErbA alpha. Unlike Rev-Erb, in which the opposite strand of the C-terminal coding region encodes the C-terminal portion of a variant thyroid hormone receptor isoform, the opposite strand of the C-terminal coding region of BD73 does not have any extensive open reading frames. BD73 messenger RNA is expressed in a wide variety of tissues and cell lines. In quiescent HepG2 cells, BD73 messenger RNA levels are strongly induced by planar aromatic antioxidants. Like Rev-Erb, BD73 binds as a monomer to a DNA sequence which consists of a specific A/T-rich sequence upstream of the consensus hexameric half-site specified by the P box of the DNA-binding domain. Amino acid sequence comparisons suggest that the A box sequence, which has been suggested to mediate monomer binding by other superfamily members, lies closer to the DNA-binding domain in BD73 and Rev-Erb than in other receptors. Under the conditions examined, neither BD73 nor Rev-Erb activated reporters containing multiple copies of their common binding site. Thus, these two orphans may require an as yet unidentified ligand or other signal for such activation. Together, BD73 and Rev-Erb define a subgroup of orphan receptors that bind as monomers to a half-site flanked by a specific and extended A/T-rich sequence.

Amino Acid Sequence↗
PubMed1997

Coordination of larval and prepupal gene expression by the DHR3 orphan receptor during Drosophila metamorphosis.

The DHR3 orphan receptor gene is induced directly by the steroid hormone ecdysone at the onset of Drosophila metamorphosis. DHR3 expression peaks in early prepupae, as the early puff genes are repressed and betaFTZ-F1 is induced. Here we provide evidence that DHR3 directly contributes to both of these regulatory responses. DHR3 protein is bound to many ecdysone-induced puffs in the polytene chromosomes, including the early puffs that encode the BR-C and E74 regulatory genes, as well as the E75, E78 and betaFTZ-F1 orphan receptor loci. Three DHR3 binding sites were identified downstream from the start site of betaFTZ-F1 transcription, further indicating that this gene is a direct target of DHR3 regulation. Ectopic expression of DHR3 revealed that the polytene chromosome binding pattern is of functional significance. DHR3 is sufficient to repress BR-C, E74A, E75A and E78B transcription as well as induce betaFTZ-F1. DHR3 thus appears to function as a switch that defines the larval-prepupal transition by arresting the early regulatory response to ecdysone at puparium formation and facilitating the induction of the betaFTZ-F1 competence factor in mid-prepupae. This study also provides evidence for direct cross-regulation among orphan members of the nuclear receptor superfamily and further implicates these genes as critical transducers of the hormonal signal during the onset of Drosophila metamorphosis.

Animals↗
PubMed2006

Reverse serial analysis of gene expression (SAGE) characterization of orphan SAGE tags from human embryonic stem cells identifies the presence of novel transcripts and antisense transcription of key pluripotency genes.

Serial analysis of gene expression (SAGE) is a powerful technique for the analysis of gene expression. A significant portion of SAGE tags, designated as orphan tags, however, cannot be reliably assigned to known transcripts. We used an improved reverse SAGE (rSAGE) strategy to convert human embryonic stem cell (hESC)-specific orphan SAGE tags into longer 3' cDNAs. We show that the systematic analysis of these 3' cDNAs permitted the discovery of hESC-specific novel transcripts and cis-natural antisense transcripts (cis-NATs) and improved the assignment of SAGE tags that resulted from splice variants, insertion/deletion, and single-nucleotide polymorphisms. More importantly, this is the first description of cis-NATs for several key pluripotency markers in hESCs and mouse embryonic stem cells, suggesting that the formation of short interfering RNA could be an important regulatory mechanism. A systematic large-scale analysis of the remaining orphan SAGE tags in the hESC SAGE libraries by rSAGE or other 3' cDNA extension strategies should unravel additional novel transcripts and cis-NATs that are specifically expressed in hESCs. Besides contributing to the complete catalog of human transcripts, many of them should prove to be a valuable resource for the elucidation of the molecular pathways involved in the self-renewal and lineage commitment of hESCs.

Cells, Cultured↗
PubMed1997

The nuclear orphan receptors COUP-TFII and Ear-2 act as silencers of the human oxytocin gene promoter.

We have previously shown that COUP-TFII and Ear-2, two members of the nuclear orphan receptor family, are able to repress oestrogen-stimulated transcriptional activity of the human oxytocin (OT) gene promoter by binding to a site that overlaps with the oestrogen response element (ERE) present in the 5' flanking region of the gene. Although most nuclear receptor-mediated transcriptional repression conforms with the paradigm of passive repression and involves competitive binding to an activator site, active repression, i.e. silencing of basal promoter activity, has been observed in a limited number of cases. Here we show by co-transfection experiments using COUP-TFII and Ear-2 expression vectors and reporter constructs containing OT gene promoter fragments linked to the chloramphenicol acetyltransferase gene that both COUP-TFII and Ear-2 are capable of silencing basal OT gene promoter activity by 54 and 75% respectively. 5' Deletion and footprint analyses revealed two areas of functionally important interaction sites: (1) a direct TGACC(T/C) repeat overlapping the ERE and (2) a more promoter-proximal area centred at - 90 containing three imperfect direct repeats (R1-R3) spaced by four nucleotides each. Mutagenesis of reporter constructs as well as electrophoretic mobility-shift assays demonstrated that each of the three proximal repeats R1-R3 contributed to orphan receptor binding and the silencing effect. Inasmuch as the orphan receptor-binding sites are not involved in mediating basal transcriptional activity of the OT gene promoter, the observed effects are best interpreted as active repression or promoter silencing. Moreover, since COUP-TFII and Ear-2 are both co-expressed in OT-expressing uterine epithelial cells, the novel transcriptional effects described here are likely to be of functional importance in the fine-tuning of uterine OT gene expression in vivo.

Animals↗
PubMed1997

The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness.

Estrogen receptor-related orphan receptor alpha 1 is a member of the steroid/thyroid nuclear receptor superfamily. We have previously cloned the human estrogen receptor-related orphan receptor alpha 1 (hERR alpha 1) cDNA and demonstrated that it enhances estrogen responsiveness of the lactoferrin gene promoter in transfected human endometrial carcinoma cells. In the present study, we used the hERR alpha 1 cDNA as a probe and isolated the mouse homologue of ERR alpha 1 from the cDNA libraries of the brain and kidney. Sequence comparison between human and mouse ERR alpha 1 (mERR alpha 1) revealed that the homologies are 89% in nucleotides and 97% in amino acids. By electrophoresis mobility shift assay, we showed that the glutathione S-transferase-mERR alpha 1 fusion protein produced in a bacterial system bound to the human ERR alpha 1 DNA-binding element. Mouse uterine nuclear extract also interacted with this DNA element and produced three complexes in the mobility shift assay, one of which was supershifted by the hERR alpha 1 antiserum. A 2.2 kbp transcript was detected by Northern analysis in all adult mouse tissues tested; however, large variations in the amount of ERR alpha 1 mRNA were found among them. Multiple immunoreactive forms of mouse ERR alpha 1 were detected by Western analysis in non-reproductive tissues, whereas a major 53 kDa protein was found in reproductive tissues such as uterus, cervix and vagina. Diethylstilbestrol (DES) stimulated the expression of ERR alpha 1 mRNA in the uterus of 19-day-old mouse. We showed that DES and estradiol, but not progesterone or dexamethasone, enhanced the level of immunoreactive ERR alpha 1 in the mouse uterus. These results demonstrated that the ERR alpha 1 is an estrogen-responsive gene in the mouse uterus and provides a model system with which to study the biological roles of this nuclear orphan receptor.

Amino Acid Sequence↗
PubMed2003

A specific and unusual nuclear localization signal in the DNA binding domain of the Rev-erb orphan receptors.

The orphan receptors Rev-erbalpha and Rev-erbbeta are members of the nuclear receptors superfamily and act as transcriptional repressors. Rev-erbalpha is expressed with a robust circadian rhythm and is involved in liver metabolism through repression of the ApoA1 gene, but no role has been yet defined for Rev-erbbeta. To gain better understanding of their function and mode of action, we characterized the proteins encoded by these two genes. Both Rev-erbalpha and Rev-erbbeta proteins were nuclear when transiently transfected in COS-1 cells. The major nuclear location signal (NLS) of Rev-erbalpha is in the amino-terminal region of the protein. Fusion of green fluorescent protein (GFP) to the amino terminus of Rev-erbalpha deletion mutants showed that the NLS is located within a 53 amino acid segment of the DNA binding domain (DBD). The homologous region of Rev-erbbeta fused to GFP also targeted the fusion protein to the nucleus, suggesting that the location of this NLS is conserved among all the Rev-erb group members. Interestingly, members of the phylogenetically closest nuclear orphan receptor group (ROR), which exhibit 58% amino acid identity with Rev-erb in the DBD, do not have their NLS located within the DBD. GFP/DBD. RORalpha or GFP/DBD.RORbeta remained cytoplasmic, in contrast to GFP/DBD. Rev-erb fusion proteins. Alignment of human Rev-erb and ROR DBD amino acid sequences predicted that the two basic residues, K167 and R168, located just upstream from the second zinc finger, could play a critical part in the nuclear localization of Rev-erb proteins. Substitution of these two residues with those found in ROR, in the GFP/DBD. Rev-erb context, resulted in cytoplasmic proteins. In contrast, the reverse mutation of the GFP/DBD. RORalpha towards the Rev-erbalpha residues targeted the fusion protein to the nucleus. Our data demonstrate that Rev-erb proteins contain a functional NLS in the DBD. Its location is unusual within the nuclear receptor superfamily and suggests that Rev-erb orphan receptors control their intracellular localization via a mechanism different from that of other nuclear receptors.

Amino Acid Sequence↗
PubMed2006

Orphan nuclear receptors, excellent targets of drug discovery.

To date, the pharmaceutical industry has placed a considerable amount of interest in the discovery of drug targets and diagnostics. One of the most challenging areas of drug discovery today is the search for novel receptor-ligand pairs. Nuclear receptors comprise a large superfamily of ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, differentiation, and homeostasis. Orphan nuclear receptors, for which the ligands are not yet identified, represent the most ancient component of the nuclear receptor superfamily. Orphan nuclear receptors not only offer a unique system to uncover novel signaling pathways that impact human health, but also provide excellent targets of drug discoveries for a variety of human diseases. This review highlights advances made on ligand identification for orphan nuclear receptors using transgenic mouse models, cell-based screening, direct binding, structure-based assays, and computer-aided virtual screening. With rapid advances in combinatorial chemistry and high throughput screening, along with other modern technologies, this field promises a bountiful harvest.

Animals↗
PubMed1982

Learning ability of orphan foals, of normal foals and of their mothers.

The maze learning ability of six pony foals that had been weaned at birth was compared to that of six foals reared normally. The foals' learning ability was also compared to their mothers' learning ability at the same task; the correct turn in a single choice point maze. The maze learning test was conducted when the foals were 6 to 8 mo old and after the mothered foals had been weaned. There was no significant difference between the ability of orphaned (weaned at birth) and mothered foals in their ability to learn to turn left (6 +/- .7 and 5.1 +/- .1 trials, respectively) or to learn the reversal, to turn right (6.7 +/- .6 and 6.2 +/- .6 trials, respectively). The orphan foals spent significantly more time in the maze in their first exposure to it than the mothered foals (184 +/- 42 vs 55 +/- 15 s. Mann Whitney U = 7, P less than .05). The mothers of the foals (n = 11) learned to turn left as rapidly as the foals (5.9 +/- .7 trials), but they were slower to learn to turn right (9.8 +/- 1.4 vs 6.4 +/- .4 trials, Mann Whitney U = 33, P less than .05), indicating that the younger horses learned more rapidly. There was no correlation between the trials to criteria of the mare and those of her foal, but there was a significant negative correlation between rank in trials to criteria and age (r = -65, P less than .05) when data from the mare and foal trials were combined. The dominance hierarchy of the mares was determined using a paired feeding test in which two horses competed for one bucket of feed. Although there was no correlation between rank in the hierarchy and maze learning ability, there was a correlation between body weight and rank in the hierarchy (r = .7, P less than .05). This may indicate either that heavier horses are likely to be dominant or that horses high in dominance gain more weight. Maternal deprivation did not appear to seriously retard learning of a simple maze by foals, although the orphans moved more slowly initially. The lack of maternal influence on learning is also reflected in the lack of correlation between the mare's learning ability and that of her foal. Young horses appear to learn more rapidly than older horses.

Age Factors↗
PubMed1998

Cloning of a cDNA for xDOR2, a novel TR2-related nuclear orphan receptor, expressed during neurulation in Xenopus laevis embryos.

We isolated from neurulating Xenopus laevis (X. laevis) embryos a cDNA encoding a novel nuclear orphan receptor, Developmental Orphan Receptor 2 (xDOR2), closely related to Ambystoma mexicanum DORI (aDOR1) and to Testicular Receptor-2 (TR2) orphan receptor family members. The xDOR2 cDNA sequence which is truncated both at its 5' and 3' ends predicts a protein sequence of 542 amino acids. While the DNA-binding domain of xDOR2 shares 91%, and 92%, identity with those of aDOR1 and the TR2s, respectively, considerable divergence is observed at both extremities of the peptides. At the N-terminus, xDOR2 is 66% identical to aDOR1 and 64% to the TR2s. At the C-terminus, xDOR2 which is longer by 126 amino acids compared to aDOR1, shares 62%, identity with aDOR1 and appears to contain a complete ligand-binding domain. The DOR receptors appear to form a subtype distinct from the TR2s, and may play a role in the development and differentiation of neural tissues.

Amino Acid Sequence↗
PubMedDate not supplied

Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells.

Orphan nuclear receptors constitute a subgroup of the superfamily of steroid/thyroid/retinoid receptors for which no endogenous ligand has been identified. The orphan nuclear receptor ROR alpha has been shown to be involved in the control of cell growth and differentiation. We have previously shown that, in DU 145 androgen-independent prostate cancer cells, ROR alpha activation brings about a significant decrease of cell proliferation and affects cell cycle progression through the modulation of cell cycle-related genes. The experiments here described have been performed to clarify whether ROR alpha might also be involved in the control of the metastatic behavior of DU 145 cells. We have shown that the thiazolidinedione derivative CGP 52608, the specific ROR alpha ligand and activator, reduces the ability of DU 145 cells to invade a reconstituted basement membrane (Matrigel). CGP 52608 also significantly decreased the capacity of prostate cancer cells to migrate towards a chemotactic stimulus (fibronectin), when plated in the upper compartment of a Boyden's chamber. Moreover, ROR alpha activation resulted in a decreased expression of alpha v beta 3 integrin and an increased level of expression of beta 4 integrin subunit. These findings indicate that the activation of the orphan nuclear receptor ROR alpha reduces the invasive and migratory capacities of androgen-independent prostate cancer cells, at least partially, by affecting integrin expression.

Basement Membrane↗
PubMed2002

Orphan nuclear receptors in T lymphocyte development.

Lymphocyte development is initiated from hematopoietic stem cells and can be divided into multiple phenotypically distinct stages. Transcription factors play important roles in programming the developmental process of lymphocytes. Recent studies have identified key roles of several orphan nuclear receptors in T lymphocyte development. The orphan nuclear receptor RORgamma has been shown to promote thymocyte survival by activating the expression of antiapoptotic protein Bcl-x(L). RORgamma is also required for the development of lymph nodes and Peyer's patches. The orphan receptors Nur77 and Nor1 are involved in TCR-mediated cell death and thymocyte-negative selection. These studies provide novel insights into the molecular mechanisms of T lymphocyte development.

Animals↗
PubMed1960

Animal "orphan" enteroviruses.

Since the discovery, some ten years ago, of the pathogenic effect of polioviruses on non-nervous-tissue cells, tissue-culture methods have come to be widely used in virological research. Through these improved techniques for studying viruses, a large number of new cytopathogenic agents have been isolated from the intestinal tract of man. Many of these agents have been obtained from persons suffering from polio-like disease, but others have been isolated from apparently normal persons. The term "orphans" is used to designate those viruses which cannot definitely be associated with any recognized disease syndrome.The existence of these enteric pathogenic human orphan (ECHO) viruses, and their association with clinical disease in certain cases, stimulated interest in their animal counter-parts, which might constitute a serious threat to both human and animal health. In this paper, the author reviews the information at present available on the occurrence of the so-called "orphan" enteroviruses in monkeys, cattle, swine, and other animals in various parts of the world, and discusses the possible interrelationships of these animal viruses with each other and with the human enteroviruses.

Animals↗
PubMedDate not supplied

[Present-day sociomedical problems of orphans].

The specific features of physical and mental development, health status, and lifestyle were found in orphans of sensitive age under the present socioeconomic conditions. The specific features of the adaptive capacities were first studied in these children. Abnormalities in the physical development and health status of orphans were shown to form under their institutional conditions of life, nutrition, and education, and upbringing. Guidelines for medical workers of orphan's institutions and for workers of sanitary-and-epidemiological service are substantiated.

Adolescent↗
PubMedDate not supplied

Estimates of the number of motherless youth orphaned by AIDS in the United States.

OBJECTIVE: To estimate the number of youth in the United States who have been or will be left motherless by the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, in order to project the need for family supports, age-appropriate foster and congregate care, and mental health and social services. DESIGN: Orphans are defined as youth whose mothers (the usual caregiving parent) die of HIV/AIDS-related causes. A mathematical model was constructed to estimate the number of such motherless youth. Cumulative fertility rates were applied to the number of reported AIDS deaths (1981 through 1990) and projected deaths (1991 through 1995) of adult women less than 50 years old. The results were adjusted for underreporting of HIV/AIDS-related mortality, pediatric AIDS deaths, infant mortality, ethnic and racial variation in fertility, and decreased fertility associated with late-stage HIV disease. Estimates were made for the number who were children (less than 13 years of age), adolescents (13 to 17 years of age), or young adults (18 years of age or older) at the time of their mothers' death. RESULTS: By the end of 1995, maternal deaths caused by the HIV/AIDS epidemic will have orphaned an estimated 24,600 children and 21,000 adolescents in the United States; unless the course of the epidemic changes dramatically, by the year 2000, the overall number of motherless children and adolescents will exceed 80,000. In 1991, an estimated 13% of US children and 9% of adolescents whose mothers died of all causes were children of women who died of HIV/AIDS-related diseases. These proportions will surpass 17% and 12%, respectively, by 1995. The vast majority of these motherless youth will come from poor communities of color. CONCLUSIONS: A large and rapidly growing number of American youth are being orphaned by the HIV/AIDS epidemic. Unless increased attention and resources are devoted to this vulnerable population, a social catastrophe is unavoidable.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The orphans of Eritrea: a comparison study.

The social-emotional state and cognitive development was compared between a group of 74 4-7-year-old Eritrean orphans and refugee children living in families. Both groups had been exposed to the chronic stresses of war and drought, and the orphans had, in addition, lost both parents to the violence of war, and were living in an overcrowded orphanage. Contrary to expectations, there were relatively few clinically significant differences between comparison groups. The orphans showed more behavioral symptoms of emotional distress, but performed at a more advanced level on cognitive and language performance measures. The findings suggest that when group care is child-centered, it can under some circumstances be a viable solution for unaccompanied children in countries where adoption and foster care are not realistic alternatives.

Child↗