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Query: UNIPROT:P06889 (Mol)
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Cholesterol conversion to bile acids in the liver is regulated by the rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1). CYP7A1 activity is regulated by feedback repression by bile acids at the transcriptional level. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, was recently demonstrated to function as the bile acid receptor and its high level of expression in the liver implicates it in the transcriptional regulation of CYP7A1. This study compares the potencies of various bile acids in their ability to mediate recruitment of the transcriptional coactivator protein, steroid receptor coactivator-1 (SRC-1), to the FXR ligand binding domain with their ability to repress CYP7A1 expression in HepG2 cells. A mammalian two-hybrid assay was utilized to assess the ability of FXR to recruit SRC-1 in a ligand-dependent manner. Chenodeoxycholic acid (CDCA) was the most potent and efficacious compound in the SRC-1 recruitment assay (EC(50) = 11.7 microM) followed by deoxycholic acid (DCA; EC(50) = 19.0 microM). Ursodeoxycholic acid (UDCA) displayed minimal activity while cholic acid (CA) was inactive. In order to directly compare the potencies of the bile acids in the coactivator recruitment assay to their ability to repress CYP7A1 expression, a branched DNA assay was developed to rapidly measure CYP7A1 mRNA levels from HepG2 cells cultured in 96-well plates. The rank order and absolute potency was conserved (CDCA IC(50) = 8.7 microM, DCA IC(50) = 27.2 microM, UDCA and CA inactive) consistent with bile acid repression of CYP7A1 being mediated by FXR.
Mol Genet Metab 2000 Dec
PMID:Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids. 1113 53

Adrenal gland development is complex and poorly understood at the molecular level. Only a subset of patients with adrenal hypoplasia congenita (AHC) carry mutations in DAX1, a member of the nuclear hormone receptor superfamily. Therefore we set out to identify other candidate genes responsible for AHC by characterizing genes involved in fetal adrenal development. To identify these genes, we studied the differential expression of genes in fetal rat adrenals comparing tissues at 14 and 15 days postcoitum (dpc) since this period encompasses major morphological change in rat adrenal development. Fetal rat adrenals were dissected, cDNAs were prepared, and suppressive subtractive hybridization was performed. We isolated 126 clones of putatively differentially expressed clones and approximately 250 bp of each of the clones was sequenced. The most interesting putative developmental genes were examined. One member of the extracellular PTN/MDK (pleiotrophin/midkine) heparin-binding protein family involved in regulation of growth and differentiation was selected for initial study. We obtained full-length transcript by 3' rapid amplification of cDNA ends and performed Northern analysis on rat adrenal RNA from fetuses at 13, 14, 15, 17, and 19 dpc and newborns. Results from those analyses demonstrated the highest Mdk expression at days 13 and 14 followed by a moderate decrease of expression during the fetal stages thereafter. In the newborn, Mdk expression is nearly undetectable. Our results indicate that Mdk has a very specific pattern of fetal expression in the adrenals. We conclude that Mdk is involved early in fetal development of the rat adrenal. Therefore, MDK is a candidate gene for AHC not due to DAX1 mutations.
Mol Genet Metab 2000 Dec
PMID:Midkine is expressed early in rat fetal adrenal development. 1113 54

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.
J Mol Endocrinol 2001 Feb
PMID:Molecular cloning and characterization of thyroid hormone receptors in teleost fish. 1117 54

Thiazolidinediones (TZDs) are a new class of compounds that improve the insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as in rodent models of NIDDM. These compounds act as high-affinity ligands for a member of the nuclear hormone receptor superfamily PPARgamma, which has been shown to play an important role in adipocyte differentiation. The strong correlation between the antidiabetic activity of TZDs and their ability to activate PPARgamma has led to suggestions that PPARgamma or downstream regulated genes mediate the effects of TZDs. To identify novel genes that potentially mediate the effects of TZDs, we have isolated genes that are differentially expressed during thiazolidinedione-stimulated differentiation of 3T3-L1 cells. Using mRNA differential display, we have compared 3T3-L1 cells treated to differentiate in the presence of BRL49653 with untreated 3T3-L1 cells and identified Fos-related antigen 1 (Fra-1), a member of the Fos protein family, as a novel molecular target for BRL49653 action in 3T3-L1 cells. Analysis of all members of the Fos-Jun family of transcription factors showed that Fra-1 was the only member that was specifically up-regulated by BRL49653. The only other member of the Fos-Jun family expressed in differentiated 3T3-L1 cells was JunD and a complex of Fra-1 and JunD was formed on a consensus AP-1 binding element in differentiated 3T3-L1 cells, suggesting that the complex of Fra-1 and JunD may play a role in the stimulation of the differentiation process of 3T3-L1 cells observed after treatment of the cells with insulin sensitizers.
Mol Pharmacol 2001 Mar
PMID:The transcription factor Fos-related antigen 1 is induced by thiazolidinediones during differentiation of 3T3-L1 cells. 1117 52

Ligand-dependent exchange of coactivators and corepressors is the fundamental regulator of nuclear hormone receptor (NHR) function. The interaction surfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR and SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferred corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR interacts almost exclusively with CoRNR2. Second, the NHR preference for N-CoR or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepressor interaction and preference suggest that repression is regulated by the permissibility of selected receptor-CoRNR-corepressor combinations. Interestingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, suggesting a model to explain corepressor binding to NHR heterodimers.
Mol Cell Biol 2001 Mar
PMID:Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors. 1123 12

Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54(nrb). Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.
Mol Cell Biol 2001 Apr
PMID:PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors. 1125 80

The receptor for the pituitary glycoprotein hormone FSH (FSHR) and the nuclear hormone receptor steroidogenic factor 1 (SF-1) play important roles in control of the hypothalamic-pituitary- gonadal axis. FSHR is essential for integrating the pituitary FSH signal to gonadal response, while SF-1 is an important transcriptional regulator of many genes that function within this axis and is essential for the development of gonads and adrenal glands. Given the critical role of SF-1 in regulation of the gonads and the coexpression of FSHR and SF-1 in Sertoli and granulosa cells, we examined the ability of SF-1 to regulate transcription of the FSHR gene. We found that SF-1 stimulated rat FSHR promoter activity in a dose-dependent and promoter-specific manner. Examination of various promoter deletion mutants indicated that SF-1 acts through the proximal promoter region and upstream promoter sequences. An E box element within the proximal promoter is essential for activation of the FSHR promoter by SF-1. This element binds the transcriptional regulators USF1 and USF2 (upstream stimulatory factors 1 and 2) but not SF-1, as shown by electrophoretic mobility shift assays. In addition, functional studies identified a requirement for the USF proteins in SF-1 activation of FSHR and mapped an important regulatory domain within exons 4 and 5 of USF2. Cotransfection studies revealed that activation of protein kinase A leads to inhibition of SF-1-stimulated transcription of FSHR, while it synergized with SF-1 to activate the equine LH beta-promoter (ebeta). Thus, stimulation of the cAMP pathway differentially regulates SF-1 activation of the FSHR and ebeta-promoters.
Mol Endocrinol 2001 May
PMID:Activation of the rat follicle-stimulating hormone receptor promoter by steroidogenic factor 1 is blocked by protein kinase a and requires upstream stimulatory factor binding to a proximal E box element. 1132 53

The Drosophila bonus (bon) gene encodes a homolog of the vertebrate TIF1 transcriptional cofactors. bon is required for male viability, molting, and numerous events in metamorphosis including leg elongation, bristle development, and pigmentation. Most of these processes are associated with genes that have been implicated in the ecdysone pathway, a nuclear hormone receptor pathway required throughout Drosophila development. Bon is associated with sites on the polytene chromosomes and can interact with numerous Drosophila nuclear receptor proteins. Bon binds via an LxxLL motif to the AF-2 activation domain present in the ligand binding domain of betaFTZ-F1 and behaves as a transcriptional inhibitor in vivo.
Mol Cell 2001 Apr
PMID:Bonus, a Drosophila homolog of TIF1 proteins, interacts with nuclear receptors and can inhibit betaFTZ-F1-dependent transcription. 1133 99

The promoter regions of the genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), contain transcriptional regulatory sequences termed peroxisome proliferator-response elements (PPRE) that are bound by the peroxisome proliferator-activated receptor alpha (PPARalpha) and 9-cis-retinoic acid receptor (RXRalpha) heterodimeric complex. In this study, the role of the short heterodimer partner (SHP) receptor in modulating PPARalpha-mediated gene transcription from the PPREs of the genes encoding AOx and HD was investigated both in vitro and in vivo. In vitro binding assays using glutathione-S-transferase-tagged chimeric receptors for PPARalpha and SHP were used to verify the interaction between PPARalpha and SHP. This interaction was unaffected by the presence of the peroxisome proliferator, Wy-14,643. SHP has been proposed to act as a negative regulator of nuclear hormone receptor activity, and SHP inhibited transcription by PPARalpha/RXRalpha heterodimers from the AOx-PPRE. Surprisingly, SHP potentiated transcription by PPARalpha/RXRalpha heterodimers from the HD-PPRE. This is the first demonstration of positive transcriptional activity attributable to SHP. Together, these results suggest that SHP can modulate PPARalpha/RXRalpha-mediated transcription in a response element-specific manner.
Mol Cell Endocrinol 2001 May 15
PMID:The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. 1136 42

The gene for estrogen receptor-alpha (ERalpha) was disrupted in embryonic stem cells by homologous recombination and these cells were used to generate mice with a targeted mutation in the ERalpha gene (alphaERKO mice). It was found that males homozygous for the mutation are infertile, indicating that estrogen signaling through this nuclear hormone receptor is required for male reproductive function. Although spermatogenesis appears normal in juvenile and young adult alphaERKO mice, the sperm produced are unable to fertilize eggs in vitro. To determine whether ERalpha is required by somatic or germ cells in the male reproductive tract, we transplanted germ cells from homozygous mutant (ERalpha(-/-)) males to the testes of wild-type (ERalpha(+/+)) males depleted of germ cells by busulfan treatment. The recipients ('surrogate fathers') sired offspring heterozygous for the mutation (ERalpha(+/-)) and carrying the coat-color marker of the infertile donor males. This indicated that ERalpha(-/-) germ cells are able to produce sperm competent to fertilize when they are supported by ERalpha(+/+) somatic cells. When ERalpha(+/-) offspring produced by germ cell transplantation were mated to produce ERalpha(-/-) males, these mice were found to have the same phenotype as originally reported for alphaERKO males. These studies showed that male germ cells do not require ERalpha for regulation of their own genes for development and function, and strongly imply that somatic cells of the male reproductive tract require ERalpha to support the production of sperm that are capable of fertilization.
Mol Cell Endocrinol 2001 Jun 10
PMID:Estrogen receptor-alpha is required by the supporting somatic cells for spermatogenesis. 1140 95


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