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

Steroidogenic factor-1 (SF-1), an orphan receptor of the nuclear hormone receptor family, binds to the AAGGTCA motif in the promoter elements of several diverse target genes, including some that mediate steroidogenesis and sexual differentiation. In addition, SF-1 is expressed in embryonic forebrain, suggesting that it plays a role in neural development. This study was undertaken to study the distribution and regulation of SF-1 mRNA expression in the rat brain. SF-1 mRNA levels were measured in tissue dissections by ribonuclease protection assay. A 452 nt 32P-labeled cRNA probe, complementary to the putative ligand-binding domain of the rat SF-1 mRNA, was synthesized from the rat SF-1 cDNA inserted into pBluescript II KS, using a Sty 1 fragment and T3 polymerase. The probe protected a single 390 nt transcript in the medial basal hypothalamus (MBH) and peripheral steroidogenic tissues of the male rat. The size of this protected band corresponded to that of the protected sense RNA standard (HindIII fragment of the SF-1 cDNA transcribed with T7 polymerase). No SF-1 mRNA was detected in the preoptic area, amygdala or cingulate cortex. The levels of SF-1 mRNA in MBH were not affected by gonadectomy or androgen treatment, nor was there a sex difference in its expression in adults. In situ hybridization histochemistry revealed that SF-1 was localized to the ventromedial nucleus of the adult hypothalamus. The levels of SF-1 mRNA were high on gestational day 18 after which they fell by approximately 30% and remained constant throughout gestation, the first week of neonatal life, and into adulthood. These results demonstrate that the gene encoding SF-1 is expressed in a discrete region of the rat hypothalamus and appears to be developmentally regulated, but not affected by gonadal hormones in adults.
Brain Res Mol Brain Res 1997 Feb
PMID:Expression of the orphan receptor steroidogenic factor-1 mRNA in the rat medial basal hypothalamus. 903 Jun 99

The numerous members of the steroid/nuclear hormone receptor superfamily act as direct transducers of circulating signals, such as steroids, thyroid hormone, and vitamin or lipid metabolites, and modulate the transcription of specific target genes, primarily as dimeric complexes. The receptors for 9-cis retinoic acid and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], RXR and VDR, respectively, as members of this superfamily, form a heterodimeric complex and bind cooperatively to vitamin D responsive elements (VDREs) to activate or repress the transcription of a multitude of genes which regulate a variety of physiological functions. To directly investigate RXR- and VDR-mediated transactivation, we developed a cell-free transcription system for 1,25(OH)2D3 signaling by utilizing crude nuclear extracts and a G-free cassette-based assay. Transcriptional enhancement in vitro was dependent on purified, exogenous RXR and VDR and was responsive to physiological concentrations of 1,25(OH)2D3. We found that RXR and VDR transactivated selectively from VDRE-linked templates exclusively as a heterodimeric complex, since neither receptor alone enhanced transcription in vitro. By the addition of low concentrations of the anionic detergent Sarkosyl to limit cell-free transcription to a single round and the use of agarose gel mobility shift experiments to assay factor complex assembly, we observed that 1,25(OH)2D3 enhanced RXR:VDR-mediated stabilization or assembly of preinitiation complexes to effect transcriptional enhancement from VDRE-linked promoter-containing DNA.
Mol Cell Biol 1997 Apr
PMID:Retinoid X receptor:vitamin D3 receptor heterodimers promote stable preinitiation complex formation and direct 1,25-dihydroxyvitamin D3-dependent cell-free transcription. 912 40

Nuclear hormone receptors are believed to modulate target gene expression by interacting with the general transcriptional machinery of the cell. We demonstrate here that two otherwise closely related members of the nuclear hormone receptor family, retinoid acid receptors (RARs) and retinoid X receptors (RXRs), exhibit significant differences in their interactions with the transcriptional machinery. RARs display a strong constitutive interaction with transcription factor II-B (TFIIB) that requires the TFIIB C-terminus, whereas RXR exhibits a weaker, hormone-stimulated interaction with the TFIIB that maps outside of the TFIIB C-terminus. Use of a dominant-negative mutant of TFIIB suggests that the TFIIB interaction is essential for full transcriptional activation by RXR.
Mol Cell Endocrinol 1997 Apr 25
PMID:Retinoid X and retinoic acid receptors interact with transcription factor II-B by distinct mechanisms. 917 29

Two nuclear hormone receptor superfamily members, DAX1 and SF1, are required for normal adrenal cortical development. Mutations in DAX1 are responsible for X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. Steroidogenic Factor 1 (SF1) regulates the expression of a number of steroidogenic genes and a putative SF1 response element (SF1-RE) in the DAX1 promoter which binds SF1 specifically. Therefore, we examined deletions in the DAX1 promoter driving expression of beta-galactosidase, with and without coexpression of SF1, in the human adrenocortical carcinoma cell line NCI-H295. We defined the DAX initiation start site and localized the putative SF1-RE at -135 to -143 bp. Loss of the putative SF1-RE region or specific removal of the 9-bp SF1 site resulted in decreased transcriptional activity by 2.3-to 2.5-fold. When cotransfected with 1550 bp of the DAX1 promoter, an SF1-containing expression vector increased the transcriptional activity of the DAX1 promoter by 4-fold. No significant change above baseline occurred when the cells were cotransfected with the 1541-bp fragment containing the entire 1550-bp promoter region minus the 9-bp SF1-RE. We conclude that the SF1-RE is an enhancer element within the DAX1 promoter and speculate that SF1 may be a transcription factor that acts, at least in part, through DAX1 for normal adrenal cortical development.
Biochem Mol Med 1997 Jun
PMID:DAX1 gene expression upregulated by steroidogenic factor 1 in an adrenocortical carcinoma cell line. 923 90

SHP (short heterodimer partner) is a novel orphan receptor that lacks a conventional DNA binding domain and interacts with other members of the nuclear hormone receptor superfamily. We have characterized the SHP sequences required for interaction with other superfamily members, and have defined an SHP repressor domain. In the mammalian two-hybrid system, a fusion of full-length SHP to the GAL4 DNA binding domain shows 9-cis-retinoic acid-dependent interaction with a VP16-retinoid X receptor alpha (RXR alpha) fusion. By deletion analysis, sequences required for this RXR interaction map to the central portion of SHP (amino acids 92 to 148). The same region is required for interaction with RXR in vitro and in the yeast two-hybrid system, and results from the yeast system suggest that the same SHP sequences are required for interaction with other members of the nuclear hormone receptor superfamily such as thyroid hormone receptor and retinoic acid receptor. In mammalian cells, a GAL4-SHP fusion protein shows about 10-fold-decreased transcriptional activation relative to GAL4 alone, and fusion of SHP to the C terminus of a GAL4-VP16 fusion to generate a triple chimera also results in a strong decrease in transactivation activity. Sequences required for this repressor function were mapped to the C terminus of SHP. This region is distinct from that required for corepressor interaction by other members of the nuclear hormone receptor superfamily, and SHP did not interact with N-CoR in either the yeast or mammalian two-hybrid system. Together, these results identify novel receptor interaction and repressor domains in SHP and suggest two distinct mechanisms for inhibition of receptor signaling pathways by SHP.
Mol Cell Biol 1997 Dec
PMID:Novel receptor interaction and repression domains in the orphan receptor SHP. 937 44

The DAX-1 gene encodes an unusual member of the nuclear hormone receptor superfamily. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita associated with hypogonadotropic hypogonadism. We have shown that DAX-1 binds to hairpin secondary structures and blocks steroidogenesis in adrenal cells via transcriptional repression of the steroidogenic acute regulatory protein (StAR) promoter. Here we have investigated the molecular mechanism of DAX-1-mediated repression. We show that the DAX-1 C terminus contains a potent transcriptional silencing activity, which can be transferred to a heterologous DNA-binding domain. Deletion analysis and modeling of DAX-1 structure identify two cooperating domains required for the silencing function, one located within helix H3 and the other within H12. The silencing function is cell- and promoter-specific. Strikingly, two point mutations (R267P and deltaV269) found in adrenal hypoplasia patients impair silencing. These findings suggest that transcriptional silencing by DAX-1 plays a critical role in the pathogenesis of adrenal hypoplasia congenita.
Mol Endocrinol 1997 Dec
PMID:A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. 941 99

The identification of XY females carrying a duplication of a region of the X chromosome (Xp21) led to the hypothesis that a double dose of a gene in the duplicated region causes sex reversal (DSS; dosage sensitive sex reversal). A gene isolated from this region, named DAX-1 (DSS-AHC critical region on the X), encodes a new member of the nuclear hormone receptor family. Here, we describe the isolation of porcine Dax-1 and the analysis of its pattern of expression both during foetal development and in several adult tissues. Dax-1 is expressed in the adrenals, the pituitary gland and the gonads at various stages of differentiation. In gonads, Dax-1 expression starts between 21 and 23 days post coitum in both XX and XY urogenital ridges then continues to be expressed until adult age. The expression in these tissues indicates the involvement of DAX-1 in the development and the function of the reproductive system at multiple levels.
Mol Cell Endocrinol 1997 Nov 30
PMID:Porcine Dax-1 gene: isolation and expression during gonadal development. 945 40

From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.
J Mol Endocrinol 1997 Dec
PMID:Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. 946 Jun 43

The lactogenic hormones, i.e., prolactin and glucocorticoids, act in concert to stimulate transcription factors responsible for hormone-dependent milk protein gene expression. In the mammary gland, prolactin activates Stat5a and Stat5b and glucocorticoids activate the glucocorticoid receptor (GR). Immunoprecipitation experiments revealed that in mammary cells, Stat5a, Stat5b, and the GR are physically associated in vivo. The association is not dependent on lactogenic hormone treatment and is evident at all stages of mammary gland development. Immunodepletion experiments indicated that a fraction of GR and Stat5 proteins are not associated, suggesting that there are different intracellular pools of these proteins. Lactogenic hormone treatment of HC11 mammary cells resulted in tyrosine phosphorylation of Stat5a and Stat5b, dimerization, and rapid nuclear translocation of both Stat5 proteins. Following hormone treatment, Stat5a-Stat5b heterodimers were detected by their coimmunoprecipitation. In addition, immunodepletion experiments followed by gel shift analyses revealed the presence of active Stat5a and Stat5b homodimers. In mammary cells, Stat5b homodimers are less abundant than Stat5a homodimers. Although the GR does not bind the Stat5 DNA binding site directly, it could be detected with the Stat5-DNA complex. These results suggest that glucocorticoids affect milk protein gene expression via association of the GR with Stat5. Thus, there is a functional coupling between Stat-dependent and nuclear hormone receptor-dependent gene transcription.
Mol Cell Biol 1998 Apr
PMID:Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. 952 50

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the hormonal ligand for vitamin D3, is a potent inducer of myeloid-leukemic-cell differentiation. Such cells differentiate exclusively into monocytes/macrophages in response to this ligand. Since 1,25(OH)2D3 transduces its hormone signal through the vitamin D3 receptor (VDR), a ligand-modulated transcription factor and member of the nuclear hormone receptor superfamily, we sought to identify direct VDR target genes induced during this differentiation process. To do so, we applied a modified differential screen with a nascent-RNA purification strategy using biases for immediate-early-response genes induced by 1,25(OH)2D3 in the myelomonocytic cell line U937. Using this screen, we had previously identified p21Waf1/Cip1 as a gene transcriptionally induced by 1,25(OH)2D3 and demonstrated that this induction facilitates the differentiation of U937 cells into monocytes/macrophages (24). Here, we describe in detail our differential screen strategy and the identification and isolation of 20 1,25(OH)2D3-inducible genes or unknown cDNAs by means of this screen. One gene newly identified as a target of VDR regulation in myeloid cells is the homeobox HoxA10 gene. HoxA10 protein may act as a general regulator of cell growth, since overexpression of HoxA10 facilitated the differentiation of U937 cells into monocytes/macrophages independent of 1,25(OH)2D3 and acted to strongly inhibit the growth of the breast cancer cell line MCF-7 by arresting these cells in G1.
Mol Cell Biol 1998 Apr
PMID:A differential screen for ligand-regulated genes: identification of HoxA10 as a target of vitamin D3 induction in myeloid leukemic cells. 952 62


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