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)

The ventromedial hypothalamic nucleus (VMN) is known to mediate autonomic responses in feeding and reproductive behaviors. To date, the most definitive molecular marker for the VMN is the orphan nuclear receptor steroidogenic factor-1 (SF-1). However, it is unclear whether SF-1 functions in the VMN as it does in peripheral endocrine organ development where loss of SF-1 results in organ agenesis due to apoptosis. Here, we provide evidence that SF-1 has a distinct role in later stages of VMN development by demonstrating the persistence of VMN precursors, the misexpression of an early marker (NKX2-1) concomitant with the absence of a late marker (BDNF neurotrophin), and the complete loss of projections to the bed nucleus of stria terminalis and the amygdala in sf-1 null mice. Our findings demonstrate that SF-1 is required for terminal differentiation of the VMN and suggest that transcriptional targets of SF-1 mediate normal circuitry between the hypothalamus and limbic structures in the telencephalon.
Mol Cell Neurosci 2003 Apr
PMID:Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons. 1272 42

FSH is a heterodimeric glycoprotein hormone secreted from the gonadotrope cell population of the anterior pituitary. Despite its crucial role in mammalian reproduction, very little is known about regulation of the FSH beta-subunit gene at the molecular level. In this report, we examine the basis for cell-specific expression of FSH beta using the mouse L beta T2 and alpha T3-1 gonadotrope-derived cell lines. Characterization of the hormonal content of L beta T2 and alpha T3-1 cells at the protein level classifies these cells as relatively mature and immature gonadotropes, respectively. We studied L beta T2 cell-specific expression of FSH beta using 398 bp of the mouse FSH beta regulatory region linked to a luciferase reporter gene in transient transfection assays. This mouse FSH beta promoter can direct reporter gene expression specifically to L beta T2 cells when compared with other pituitary- and non-pituitary-derived cell lines, including alpha T3-1 cells. Furthermore, it is induced by activin, and interruption of the autocrine activin loop in L beta T2 cells by the addition of follistatin reduces its expression. Truncation analysis indicates that several regions of the promoter are involved in this specificity and that these can be dissociated from activin regulation. We identify binding sites for the orphan nuclear receptor steroidogenic factor-1 and the heterotrimeric transcription factor nuclear factor Y and show that these elements functionally interact to regulate FSH beta gene expression in an L beta T2 cell-specific manner. Moreover, steroidogenic factor-1 and nuclear factor Y are shown to physically interact with each other. This study is the first to demonstrate the presence of basal FSH beta protein in L beta T2 cells and to identify specific elements within the FSH beta promoter that contribute to basal and cell-specific expression of the gene.
Mol Endocrinol 2003 Aug
PMID:Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specific expression of the mouse Follicle-stimulating hormone-beta gene. 1273 Mar 28

NGFI-B is an immediate-early gene that encodes an orphan nuclear receptor. In the rat ovary, the preovulatory surge of LH induces NGFI-B expression in granulosa cells of preovulatory follicles, reaching a peak within 1 h and declining to control levels at 6 h. The LH-stimulated NGFI-B expression is abolished by alpha-amanitin, but superinduced by cycloheximide. Similarly, treatment of human luteinized granulosa cells with LH causes a rapid and transient stimulation of NGFI-B expression. Interestingly, the induction of NGFI-B expression in response to LH stimulation in preovulatory granulosa cells requires signaling through protein kinase Czeta. Furthermore, two other NGFI-B family members, Nurr1 and Nor1, are also rapidly stimulated by LH in granulosa cells of preovulatory follicles through the activation of protein kinase Czeta. The cell-type specific expression and LH induction of NGFI-B suggests a potential role of NGFI-B in the ovulatory process.
Mol Cell Endocrinol 2003 Apr 28
PMID:Regulation of NGFI-B expression during the ovulatory process. 1277 Jul 26

We have cloned T-cell factor 4N (TCF-4N), an alternative isoform of TCF-4, from developing pituitary and 3T3-L1 preadipocytes. This protein contains the N-terminal interaction domain for beta-catenin but lacks the DNA binding domain. While TCF-4N inhibited coactivation by beta-catenin of a TCF/lymphoid-enhancing factor (LEF)-dependent promoter, TCF-4N potentiated coactivation by beta-catenin of several non-TCF/LEF-dependent promoters. For example, TCF-4N synergized with beta-catenin to activate the alpha-inhibin promoter through functional and physical interactions with the orphan nuclear receptor steroidogenic factor 1 (SF-1). In addition, TCF-4N and beta-catenin synergized with the adipogenic transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) to induce leptin promoter activity. The mechanism by which beta-catenin and TCF-4N coactivated C/EBPalpha appeared to involve p300, based upon synergy between these important transcriptional regulators. Consistent with TCF-4N's redirecting the actions of beta-catenin in cells, ectopic expression of TCF-4N in 3T3-L1 preadipocytes partially relieved the block of adipogenesis caused by beta-catenin. Thus, we propose that TCF-4N inhibits coactivation by beta-catenin of TCF/LEF transcription factors and potentiates the coactivation by beta-catenin of other transcription factors, such as SF-1 and C/EBPalpha.
Mol Cell Biol 2003 Aug
PMID:T-cell factor 4N (TCF-4N), a novel isoform of mouse TCF-4, synergizes with beta-catenin to coactivate C/EBPalpha and steroidogenic factor 1 transcription factors. 1286 Oct 22

In the anterior pituitary, expression of the common glycoprotein hormone alpha-subunit (alphaGSU) is mediated in part by multiple response elements residing in the distal promoter (-435 bp). One such site is the gonadotrope-specific element (GSE), which is bound by the orphan nuclear receptor steroidogenic factor-1 (SF-1) and confers pituitary adenylate cyclase-activating polypeptide (PACAP)-stimulated alphaGSU expression. Here we investigated the functional importance of the GSE and SF-1 phosphorylation in both basal and stimulated alphaGSU transcription. Mutation of the GSE reduced basal and PACAP-stimulated alphaGSU promoter activity in the alphaT3-1 gonadotrope cell line. Overexpression of wild-type SF-1, but not an S203A mutant form of SF-1, enhanced basal and PACAP-stimulated alphaGSU promoter activity. The effect of PACAP on alphaGSU promoter activity was inhibited after overexpression of MAPK phosphatase. Helix assembly of the SF-1 ligand-binding domain was stimulated by PACAP in vitro via a MAPK-dependent pathway, as determined using a mammalian two-hybrid assay. PACAP quickly activated MAPK (within 5 min) and also resulted in elevated levels of phospho-cAMP response element-binding protein and phospho-SF-1, as judged by a specific antiphospho-S203 antibody; this effect was blocked by the MAPK kinase inhibitor, UO126. Collectively, these data demonstrate that SF-1 binds to the GSE and activates both basal and PACAP-stimulated alphaGSU transcription, which is further increased by phosphorylation at Ser203 via MAPK. These data suggest strongly that the induction of alphaGSU gene expression by peptide hormone signaling is coupled directly to the posttranslational status of SF-1.
Mol Endocrinol 2003 Nov
PMID:Steroidogenic factor-1 and the gonadotrope-specific element enhance basal and pituitary adenylate cyclase-activating polypeptide-stimulated transcription of the human glycoprotein hormone alpha-subunit gene in gonadotropes. 1292 Feb 32

The orphan nuclear receptor steroidogenic factor-1 (SF-1) plays pivotal roles in the development and function of steroidogenic organs. It transcriptionally regulates an array of factors required for biosynthesis of steroid hormones and is also necessary for the expression of genes in the pituitary and the male reproductive tract. Here we describe the identification of a novel zinc finger protein that modifies the transcriptional potential of SF-1. This factor, which we call Zip67 (zinc finger protein 67 kDa), was cloned through a two-hybrid screen of a human testis cDNA library using the C-terminal part of SF-1 as the bait. Transient transfection experiments demonstrated that Zip67 represses SF-1-dependent transcription in the context of both multimerized SF-1-binding sites and natural SF-1-inducible promoters. The interaction between Zip67 and SF-1 was dependent on an intact activation function-2 domain of SF-1, and we propose a mechanism whereby Zip67 represses transcription through competition with p160 coactivators for binding to SF-1. Zip67 was detected in SF-1 expressing tissues such as testis, adrenal, ovary and spleen in addition to other tissues. In line with the broader expression pattern, we found that Zip67 also affected transcription mediated by several other nuclear receptors. In conclusion, we have isolated a novel zinc-finger protein that influences gene activation through interaction with the functionally important activation function-2 domain of nuclear receptors.
Mol Endocrinol 2003 Nov
PMID:Cloning and characterization of a novel zinc finger protein that modulates the transcriptional activity of nuclear receptors. 1292 Feb 34

Steroid biosynthesis in ovary is enhanced by the orphan nuclear receptor, steroidogenic factor-1 (SF-1); however, we reported that liver receptor homolog-1 (LRH-1), a closely related receptor to SF-1, is also expressed in mouse ovary. To further investigate the role of LRH-1 in mouse ovary, we used in situ hybridization to identify the cell types that express LRH-1 versus SF-1, and carried out functional studies to determine the role of LRH-1 in the regulation of the human (h) ovary-specific CYP19 promoter. LRH-1 expression was found to be abundant and highly restricted to cells involved in estrogen biosynthesis-granulosa cells during the estrous cycle, and in corpora lutea (CL) of pregnancy. In contrast, SF-1 was expressed most highly in C(19)-steroid-producing theca cells and interstitium, and at low levels in granulosa and luteal cells. Transfection studies using granulosa cells demonstrated that LRH-1 is a potent regulator of both basal and forskolin-induced transcription of the ovary-specific hCYP19 promoter. This activity was dependent upon two nuclear receptor half-sites within the proximal hCYP19 promoter. Based on these findings, we propose that LRH-1 plays an important role as a competence factor in regulating aromatase, and thus estrogen biosynthesis, in ovary.
Mol Cell Endocrinol 2003 Sep 30
PMID:Expression of LRH-1 and SF-1 in the mouse ovary: localization in different cell types correlates with differing function. 1297 82

The Drosophila Dhr78 orphan nuclear receptor has been proposed to play a role in molting of the tracheal cuticle and regulate gene expression during the third larval instar, possibly in response to a novel systemic hormonal signal. Here, we show that there are no essential maternal functions for Dhr78 during development, and that mutants missing both maternal and zygotic Dhr78 function die primarily during second and third instar larval development. We show that defects in the tracheal system can be observed as early as the first instar, manifested as regions of fluid in the dorsal tracheal trunks. In addition, Dhr78 mutant tracheae show a highly penetrant defect in gas filling at the first-to-second instar larval molt. Dhr78 expression in only the tracheal system is sufficient to rescue the lethality of Dhr78 mutants, and selective inactivation of Dhr78 function in the tracheae by targeted RNAi is sufficient to result in tracheal defects. Finally, we see no evidence for widespread activation of the Dhr78 ligand binding domain in third instar larvae using the GAL4-LBD system, arguing against a systemic hormone for the receptor at this stage in development. Taken together, our results indicate that Dhr78 exerts its essential functions during molting of the tracheal cuticle in Drosophila.
Insect Biochem Mol Biol 2003 Dec
PMID:Essential roles for the Dhr78 orphan nuclear receptor during molting of the Drosophila tracheal system. 1459 92

The proto-oncogene c-mos is specifically expressed in male and female germ cells. Previous studies have shown that the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF) contributes to the repression of c-mos in somatic cells by binding to an inverted hexamer repeat within the c-mos regulatory region. In the present study, we demonstrate that another nuclear receptor superfamily member, germ cell nuclear factor (GCNF), binds to a sequence overlapping the c-mos COUP-TF binding site. Electrophoretic mobility shift assays with recombinant GCNF and both wild-type and mutant c-mos oligonucleotides demonstrated the binding of GCNF to an extended half site, CCAAGTTCA, which overlaps the first hexamer of the COUP-TF binding site. Transient transfection assays in NIH 3T3 cells further demonstrated that GCNF fused to a VP16 activation domain stimulated transcription from reporter constructs containing the c-mos GCNF binding site. Since GCNF is expressed in male and female germ cells at the same stages of development at which c-mos is transcribed, these results suggest that GCNF may serve as a regulator of c-mos transcription. Mol. Reprod. Dev. 67: 55-64, 2004.
Mol Reprod Dev 2004 Jan
PMID:A binding site for germ cell nuclear factor within c-mos regulatory sequences. 1464 74

Glucocorticoids exert their metabolic effect via their intracellular receptor, the glucocorticoid receptor (GR). In a yeast two-hybrid screening, we found the chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), an orphan nuclear receptor that plays important roles in glucose, cholesterol, and xenobiotic metabolism, as a partner of GR. In an in vitro glutathione-S-transferase pull-down assay, COUP-TFII interacted via its DNA-binding domain with the hinge regions of both GRalpha and its splicing variant GRbeta, whereas COUP-TFII formed a complex with GRalpha, but not with GRbeta, in an in vivo chromatin immunoprecipitation and a regular immunoprecipitation assay. Accordingly, GRalpha, but not GRbeta, enhanced COUP-TFII-induced transactivation of the simple COUP-TFII-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas COUP-TFII repressed GRalpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. Importantly, mutual protein-protein interaction of GRalpha and COUP-TFII was necessary for glucocorticoid-induced enhancement of the promoter activity and the endogenous mRNA expression of the COUP-TFII-responsive phosphoenolpyruvate carboxykinase, the rate-limiting enzyme of hepatic gluconeogenesis. We suggest that COUP-TFII may participate in some of the metabolic effects of glucocorticoids through direct interactions with GRalpha. These interactions influence the transcription of both COUP-TFII- and GRalpha-responsive target genes, seem to be promoter specific, and can be in either a positive or negative direction.
Mol Endocrinol 2004 Apr
PMID:The glucocorticoid receptor and the orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II interact with and mutually affect each other's transcriptional activities: implications for intermediary metabolism. 1473 55


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