Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators are a diverse group of compounds that cause hepatic hypertrophy and hyperplasia, increase peroxisome number, and on chronic high-dose administration, lead to rodent liver tumorigenesis. Various lines of evidence have led to the conclusion that these agents induce their pleiotropic effects exclusively via agonism of peroxisome proliferator-activated receptor (PPAR)alpha, a member of the steroid receptor superfamily involved in the regulation of fatty acid metabolism. Recently, agonists of two other members of this receptor family have been identified. PPARgamma is predominantly expressed in adipocytes where it mediates differentiation; PPARdelta is a widely expressed orphan receptor with yet unresolved physiologic functions. In the course of characterizing newer PPAR ligands, we noted that highly selective PPARgamma agonists or dual PPARgamma/PPARdelta agonists, lacking apparent murine PPARalpha agonist activity, cause peroxisome proliferation in CD-1 mice. We therefore made use of PPARalpha knockout mice to investigate whether these effects resulted from agonism of PPARalpha by these agents at very high dose levels or whether PPARgamma (or PPARdelta) agonism alone can result in peroxisome proliferation. We report here that several parameters linked to the hepatic peroxisome proliferation response in mice that were seen with these agents resulted from PPARalpha-independent effects.
Mol Pharmacol 2000 Sep
PMID:Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specific agonists in PPARalpha-null mice. 1095 38

Hepatocyte nuclear factor 4alpha (HNF4alpha) is an orphan receptor of the nuclear receptor superfamily and expressed in vertebrates as a tissue-specific transcription factor in liver, kidney, intestine, stomach, and pancreas. It also plays a crucial role in early embryonic development and has been identified as a maternal component in the Xenopus egg. We now report on an activity present in Xenopus embryos that inhibits the DNA binding of HNF4. This HNF4 inhibitor copurifies with a 25-kDa protein under nondenaturing conditions but can be separated from this protein by sodium dodecyl sulfate treatment. Protease treatment of the inhibitor results in a core fragment of about 5 kDa that retains full inhibitory activity. The activity of the HNF4 inhibitor can also be monitored in the absence of DNA, as it alters the mobility of the HNF4 protein in native polyacrylamide gels and the accessibility of antibodies. Comparing the activity of the HNF4 inhibitor with acyl coenzyme A's, recently proposed to be ligands of HNF4, we observe a more stringent specificity for the HNF4 inhibitor activity. Using deletion constructs of the HNF4 protein, we could show that the potential ligand-binding domain of HNF4 is not required, and thus the HNF4 inhibitor does not represent a classical ligand as defined for the nuclear receptor superfamily. Based on our previous finding that maternal HNF4 is abundantly present in Xenopus embryos but the target gene HNF1alpha is only marginally expressed, we propose that the HNF4 inhibitor functions in the embryo to restrict the activity of the maternal HNF4 proteins.
Mol Cell Biol 2000 Dec
PMID:Inhibitor of the tissue-specific transcription factor HNF4, a potential regulator in early Xenopus development. 1107 69

Leukocyte chemoattractants are involved in the inflammatory response act via G protein-coupled receptors. We report the cloning of a novel human gene encoding the putative orphan receptor, C5L2, belonging to a subfamily of C3a, C5a and formyl Met-Leu-Ph receptors that are related to the chemokine receptor family. C5L2 transcript levels were abundant in granulocytes and immature dendritic cells but not in mature dendritic cells. We speculate that this receptor may regulate the activation of immature dendritic cells and play a role in the chemoattraction of leukocytes to inflammatory regions.
Mol Immunol 2000 Jun
PMID:A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. 1109 Aug 75

Coregulators for nuclear receptors (NR) are factors that either enhance or repress their transcriptional activity. Both coactivators and corepressors have been shown to use similar but functionally distinct NR interacting determinants containing the core motifs LxxLL and PhixxPhiPhi, respectively. These interactions occur through a hydrophobic cleft located on the surface of the ligand-binding domain (LBD) of the NR and are regulated by ligand-dependent activation function 2 (AF-2). In an effort to identify novel coregulators that function independently of AF-2, we used the LBD of the orphan receptor RVR (which lacks AF-2) as bait in a yeast two-hybrid screen. This strategy led to the cloning of a nuclear protein referred to as CIA (coactivator independent of AF-2 function) that possesses both repressor and activator functions. Strikingly, we observed that CIA not only interacts with RVR and Rev-ErbAalpha in a ligand-independent manner but can also form complexes with estrogen receptor alpha (ERalpha) and ERbeta in vitro and enhances ERalpha transcriptional activity in the presence of estradiol (E(2)). CIA-ERalpha interactions were found to be independent of AF-2 and enhanced by the antiestrogens EM-652 and ICI 182,780 but not by 4-hydroxytamoxifen and raloxifene. We further demonstrate that CIA-ERalpha interactions require the presence within CIA of a novel bifunctional NR recognition determinant containing overlapping LxxLL and PhixxPhiPhi motifs. The identification and functional characterization of CIA suggest that hormone binding can create a functional coactivator interaction interface in the absence of AF-2.
Mol Cell Biol 2001 Jan
PMID:CIA, a novel estrogen receptor coactivator with a bifunctional nuclear receptor interacting determinant. 1111 8

Calcitonin gene-related peptide (CGRP) is a potent vasodilator. Our group has reported that exogenous CGRP may prevent or reverse hypoxic pulmonary hypertension in rats. The vasodilatory action of CGRP is mediated primarily by CGRP1 receptors. The calcitonin receptor-like receptor (CRLR) and the orphan receptor RDC-1 have been proposed as CGRP1 receptors, and recent evidence suggests that CRLR can function as either a CGRP1 receptor or an adrenomedullin (ADM) receptor. Receptor activity-modifying proteins (RAMPs) determine the ligand specificity of CRLR: coexpression of CRLR and RAMP1 results in a CGRP1 receptor, whereas coexpression of CRLR and RAMP2 or -3 results in an ADM receptor. We used qualitative, semiquantitative, and real-time quantitative RT-PCR to detect and quantitate the relative expression of these agents in the lungs of rats exposed to normoxia (n = 3) and 1 and 2 wk of chronic hypobaric hypoxia (barometric pressure 380 mmHg, equivalent to an inspired O(2) level of 10%; n = 3/time period). Our results show upregulation of RDC-1, RAMP1, and RAMP3 mRNAs in hypoxic rat lung and no change in CRLR and RAMP2 mRNAs. These findings support a functional role for CGRP and ADM receptors in regulating the adult pulmonary circulation.
Am J Physiol Lung Cell Mol Physiol 2001 Mar
PMID:mRNA expression of novel CGRP1 receptors and their activity-modifying proteins in hypoxic rat lung. 1115 39

We report the discovery and tissue distributions of four novel human genes, GPR61, GPR62, GPR63 and GPR77, all of which encode G protein-coupled receptors (GPCRs). GPR61 was discovered in a search of the patent literature which retrieved a rabbit DNA sequence partially encoding a novel GPCR. This sequence was used to obtain a full-length human cDNA encoding GPR61, a receptor of 417 amino acid length. A search of the GenBank genomic sequence databases revealed three previously unrecognized intronless genes encoding the orphan GPCrs (oGPCRs) GPR62, GPR63 and GPR77, with respective amino acid lengths of 368, 419 and 337. Sequence analysis revealed that GPR61 and GPR62, and a published orphan receptor p47MNR, shared the highest level of identities to each other, ranging from 36 to 45% in the transmembrane (TM) domains. Together, these three oGPCRs appear to comprise a novel subfamily of GPCRs, most closely related to the serotonin 5-HT(6) receptor. Sequence analysis of GPR63 and GPR77 revealed highest sequence identities in the TM regions with the oGPCR PSP24 (58%) and the anaphylatoxin C5a receptor (49%) respectively. Tissue distribution analyses detected the expression of all four novel genes in the human brain. GPR61 mRNA expression was detected in the caudate, putamen and thalamus of human brain, with a more widespread expression pattern in rat brain, with mRNA signals in areas of the cortex, hippocampus, thalamus, hypothalamus and midbrain. GPR62 mRNA expression was detected in the basal forebrain, frontal cortex, caudate, putamen, thalamus and hippocampus. GPR63 mRNA expression was detected in the frontal cortex, with lower levels in the thalamus, caudate, hypothalamus and midbrain. Analysis of GPR77 mRNA expression revealed signals in the frontal cortex, hippocampus and hypothalamus with high transcript levels in the liver.
Brain Res Mol Brain Res 2001 Jan 31
PMID:Identification of four novel human G protein-coupled receptors expressed in the brain. 1116 67

Vascular polarity is a fundamental feature of angiogenesis and left-right asymmetry of the vascular network. Contrary to this importance, the molecular basis of vascular polarity is completely unknown. In this report, we show that the combinatorial function of angiopoietin-1 and the orphan receptor TIE1 is critical specifically for the development of the right-hand side venous system but is dispensable for the left-hand side venous system. Furthermore, our current finding reveals the existence of a distinct genetic program for the establishment of the right-hand side and left-hand side vascular networks well before the network asymmetry becomes morphologically discernible.
Mol Cell 2001 Jan
PMID:A combinatorial role of angiopoietin-1 and orphan receptor TIE1 pathways in establishing vascular polarity during angiogenesis. 1117 28

The cytochrome P450 gene CYP2H1 is highly induced by phenobarbital in chick embryo hepatocytes. Recent studies have established that the orphan nuclear receptor CAR plays a critical role in the induction mechanism. Here, we show that a high concentration of the potent glucocorticoid and progesterone receptor antagonist RU486 almost completely blocks phenobarbital-induced accumulation of CYP2H1 mRNA in hepatocytes yet has no effect on basal expression. In marked contrast, CYP2H1 mRNA induced by the phenobarbital-type inducers glutethimide and 2-allylisopropylacetamide is not affected by RU486. RU486 inhibition is not mediated through the glucocorticoid or progesterone receptors. Transient transfection studies showed that RU486 does not repress through activation of the orphan receptor PXR and subsequent competition with CAR for binding to the upstream drug-responsive 556-base-pair enhancer. Additionally, none of the known functional transcription factor binding sites found in the enhancer region was a target of RU486 inhibition. Using an artificial construct containing multiple CAR binding sites, we also established that RU486 has no direct effect on the activity of exogenously expressed CAR. There is no evidence that phenobarbital binds to CAR; we propose that RU486 inhibits phenobarbital induction, either by interfering with a phenobarbital-dependent mechanism responsible for nuclear import of CAR or with the metabolism of phenobarbital to the true inducer. Whether a novel nuclear receptor that binds RU486 at high concentrations plays a role in the inhibitory action of RU486 is an interesting possibility.
Mol Pharmacol 2001 Aug
PMID:The antiglucocorticoid RU486 inhibits phenobarbital induction of the chicken CYP2H1 gene in primary hepatocytes. 1145 14

Receptors of the insulin/insulinlike growth factor (IGF) family have been implicated in the regulation of pancreatic beta-cell growth and insulin secretion. The insulin receptor-related receptor (IRR) is an orphan receptor of the insulin receptor gene (Ir) subfamily. It is expressed at considerably higher levels in beta cells than either insulin or IGF-1 receptors, and it has been shown to engage in heterodimer formation with insulin or IGF-1 receptors. To address whether IRR plays a physiologic role in beta-cell development and regulation of insulin secretion, we have characterized mice lacking IRR and generated a combined knockout of Ir and Irr. We report that islet morphology, beta-cell mass, and secretory function are not affected in IRR-deficient mice. Moreover, lack of IRR does not impair compensatory beta-cell hyperplasia in insulin-resistant Ir(+/-) mice, nor does it affect beta-cell development and function in Ir(-/-) mice. We conclude that glucose-stimulated insulin secretion and embryonic beta-cell development occur normally in mice lacking Irr.
Mol Cell Biol 2001 Aug
PMID:Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. 1146 43

The identification of potential endogenous or synthetic ligands for orphan receptors in the steroid receptor superfamily is important both for discerning endogenous regulatory pathways and for designing receptor inhibitors. The insect nuclear receptor Ultraspiracle (USP), an ortholog of vertebrate RXR, has long been treated as an orphan receptor. We have tested here the fit of terpenoid ligands to the JH III-binding site of monomeric and homo-oligomeric USP from Drosophila melanogaster (dUSP). dUSP specifically bound juvenile hormone III (JH III), but not control farnesol or JH III acid, and also specifically changed in conformation upon binding of JH III in a fluorescence binding assay. Juvenile hormone III binding caused intramolecular changes in receptor conformation, and stabilized the receptor's dimeric/oligomeric quaternary structure. In both a radiometric competition assay and the fluorescence binding assay the synthetic JH III agonist methoprene specifically competed with JH III for binding to dUSP, the first demonstration of specific binding of a biologically active JH III analog to an insect nuclear receptor. The recombinant dUSP bound with specificity to a DR12 hormone response element in a gel shift assay. The same DR12 element conferred enhanced transcriptional responsiveness of a transfected juvenile hormone esterase core promoter to treatment of transfected cells with JH III, but not to treatment with retinoic acid or T3. The activity of JH III or JH III-like structures, but not structures without JH III biological activity, to bind specifically to dUSP and activate its conformational change, provide evidence of a terpenoid endogenous ligand for Ultraspiracle, and offer the prospect that synthetic, terpenoid structures may be discovered that can agonize or antagonize USP function in vivo.
Insect Biochem Mol Biol 2001 Dec
PMID:Juvenile hormone III-dependent conformational changes of the nuclear receptor ultraspiracle. 1171 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>