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Query: UNIPROT:P06889 (Mol)
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Tissue-specific expression of the glycoprotein hormone alpha-subunit gene in pituitary gonadotropes relies on a gonadotrope-specific element (GSE), which binds an approximately 54-kilodalton protein termed GSE-binding protein 1 (GSEB1). We report here that GSEB1 is the orphan nuclear receptor steroidogenic factor-1 (SF-1), which has been shown to be a primary regulator of steroidogenic enzymes in the adrenal gland and gonadal tissues. GSEB1 from alpha T3-1 pituitary gonadotrope cells and SF-1 from Y1 adrenocortical cells and R2C testicular Leydig cells display identical binding properties with both the GSE and SF-1 elements. Antiserum specific to the SF-1 DNA-binding domain abolishes the binding of both GSEB1 and SF-1 to both elements. SF-1 mRNA is found in the mouse pituitary and in the alpha T3-1 cell line but not in other pituitary cell lines, consistent with the pattern of GSEB 1-binding activity. The GSE element specifically enhances transcription in SF-1-containing cells. The discovery that an orphan nuclear receptor regulates the expression of both the gonadotropin hormones in the pituitary and the steroidogenic enzymes in the gonad provides a potential molecular mechanism for coordinate control in reproductive function, perhaps through an as yet unidentified endocrine ligand for SF-1.
Mol Endocrinol 1994 Jul
PMID:The orphan nuclear receptor, steroidogenic factor-1, regulates the glycoprotein hormone alpha-subunit gene in pituitary gonadotropes. 752 22

The immediate-early gene NGFI-B encodes an orphan nuclear receptor that binds DNA as a monomer and activates transcription through a canonical response element (NBRE). NGFI-B is expressed under basal conditions and in response to external stimuli in many mammalian tissues. In particular, NGFI-B expression is dramatically elevated in the adrenal cortex in response to stress and in Y1 adrenocortical cells in response to adrenocorticotropin. NGFI-B activates transcription through an NBRE of the gene encoding 21-hydroxylase (P450c21) in Y1 cells. Steroidogenic factor 1 (SF-1), a homolog of NGFI-B, also activates the P450c21 promoter. To examine the influence of these factors on P450c21 expression in vivo and the function of the hypothalamic-pituitary-adrenocortical axis as a whole, we generated NGFI-B (-/-) mice. These mice thrive and reproduce normally and maintain normal basal adrenocorticotropin, corticosterone, and P450c21 mRNA levels. In response to increases in adrenocorticotropin, NGFI-B (-/-) and wild-type mice demonstrated equivalent increases in serum corticosterone levels. Furthermore, and in contrast to in vitro results, no increases in P450c21 mRNA levels were observed in response to increases in adrenocorticotropin in NGFI-B (-/-) or wild-type mice. While SF-1 mRNA levels were not increased with increased steroidogenic demand, adrenal expression of Nurr1, a close homolog of NGFI-B, was induced to a greater extent by lipopolysaccharide in NGFI-B (-/-) mice than in wild-type mice. Finally, when the administration of dexamethasone for suppression was stopped, P450c21 mRNA and serum corticosterone levels recovered at the same rate in wild-type and NGFI-B (-/-) mice. Thus, while NGFI-B appears poised to affect the structure and function of the adrenal gland, the gland functions normally in its absence, suggesting that other factors, including Nurr1 and SF-1, are sufficient to drive P450c21 expression in mice and maintain normal steroidogenesis.
Mol Cell Biol 1995 Aug
PMID:Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. 762 27

Rev-Erb is an orphan nuclear receptor which binds as a monomer to the thyroid/retinoic acid receptor half-site AGGTCA flanked 5' by an A/T-rich sequence, referred to here as a Rev monomer site. Fusion of Rev-Erb to the DNA binding domain of yeast GAL4 strongly repressed basal transcription of a GAL4-luciferase reporter gene as a result of the presence of a C-terminal domain containing both the hinge and heptad repeat regions. Nevertheless, wild-type Rev-Erb did not repress basal transcription from the Rev monomer binding site. Therefore, a DNA binding site selection strategy was devised to test the hypothesis that Rev-Erb may function on a different site as a dimer. This approach identified sequences containing two Rev monomer sites arranged as direct repeats with the AGGTCA motifs separated by 2 bp (Rev-DR2). Remarkably, Rev-Erb bound as a homodimer to Rev-DR2 but not to other direct repeats or to a standard DR2 sequence. The DNA binding domain contained all of the determinants for Rev-DR2-specific homodimerization. Rev-Erb bound cooperatively as a homodimer to Rev-DR2, and this interaction was 5 to 10 times more stable than Rev-Erb monomer binding to the Rev monomer site. Functionally, Rev-Erb markedly repressed the basal activity of a variety of promoters with a strong Rev-DR2 specificity. The C terminus was required for this repression, consistent with the GAL4 results. However, the Rev-DR2 specificity did not require the C terminus in vivo, since fusion of C-terminally truncated Rev-Erb to a heterologous transactivation domain created a transcriptional activator specific for Rev-DR2. In addition to idealized Rev-DR2 sites, Rev-Erb also repressed basal as well as retinoic acid-induced transcription from a naturally occurring Rev-DR2 in the CRBPI gene. Thus, although Rev-Erb is distinguished from other thyroid/steroid receptor superfamily members by its ability to bind DNA as a monomer, it functions as a homodimer to repress transcription of genes containing a novel DR2 element.
Mol Cell Biol 1995 Sep
PMID:The monomer-binding orphan receptor Rev-Erb represses transcription as a dimer on a novel direct repeat. 765 96

A novel member of the steroid/thyroid/retinoid superfamily of nuclear receptors has been isolated as part of a screen to identify genes related to the recently characterized orphan receptor ROR alpha. This new orphan receptor, cloned from a mouse brain cDNA library, is closely related to the rat Rev-ErbA alpha gene product (97% and 68% identity in the DNA- and ligand-binding domains, respectively) and referred to as RVR. Northern blot analysis reveals that two RVR mRNA species are expressed during mouse embryogenesis and widely expressed in adult tissues. Studies with in vitro translated RVR protein show that it binds the DNA sequence ATAACTAGGTCA, a hormone response element composed of a 6-base pair AT-rich sequence preceding a single nuclear receptor recognition half-site core motif PuGGTCA. We show that RVR recognizes this hormone response element with a specificity similar to that of the orphan receptor ROR alpha 2. However, cotransfection studies indicate that RVR does not activate transcription when this hormone response element is linked to a reporter gene but rather acts as a potent competitive repressor of ROR alpha function. These results indicate the existence of an orphan nuclear receptor-based signaling pathway with the intrinsic ability to regulate the expression of specific gene networks through competition between transcriptional activators and repressors for the same recognition site.
Mol Endocrinol 1994 Sep
PMID:Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. 783 56

We have cloned Rev-erb beta, a novel isoform of the Rev-erb alpha orphan nuclear receptor. The DNA binding domains of Rev-erb alpha and beta are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas ROR alpha 1 constitutively activates transcription through this sequence, both isoforms of Rev-erb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of ROR alpha 1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks.
Mol Endocrinol 1994 Sep
PMID:Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. 783 58

nur77, an immediate-early gene that encodes an orphan nuclear receptor, is rapidly and transiently induced by nerve growth factor (NGF) stimulation or membrane depolarization in the rat pheochromocytoma-derived cell line PC12. The Nur77 protein can act as a potent transcription activator and may function to regulate the expression of downstream genes in response to extracellular stimuli. We show here that activation of nur77 by NGF treatment and membrane depolarization is signalled through distinct pathways. These distinct signals appear to converge on the same transcription factors acting on the same promoter elements. We show that nur77 activation by both processes requires two cis-acting AP1-like elements, NAP1 and NAP2, which contain the core sequence TGCGTCA centered at 67 and 38 nucleotides upstream of the transcription start site. The NAP elements can confer inducibility by NGF and membrane depolarization on an otherwise unresponsive heterologous promoter. We identified JunD as a key mediator of nur77 activation by reason of the following observations. (i) JunD, but not CREB or other members of the Fos/Jun family, is a component of NAP binding activity in PC12 cell nuclear extracts. (ii) JunD, but not other Fos/Jun family members, specifically transactivates the nur77 promoter through the NAP elements (iii) A dominant-negative mutant of JunD effectively abolishes the activation of nur77 by either NGF treatment or membrane depolarization. These data draw a contrast between the regulation of nur77 with that of c-fos, in which the sequence requirements for activation by NGF treatment and membrane depolarization appear separable, and CREB appears to play a role in activation by both NGF and membrane depolarization.
Mol Cell Biol 1994 Dec
PMID:Involvement of JunD in transcriptional activation of the orphan receptor gene nur77 by nerve growth factor and membrane depolarization in PC12 cells. 796 16

We previously identified a complex regulatory element in the medium-chain acyl coenzyme A dehydrogenase gene promoter that confers transcriptional regulation by the retinoid receptors RAR and RXR and the orphan nuclear receptor HNF-4. In this study we demonstrate a trans-repressing regulatory function for the orphan receptor COUP-TF at this same nuclear receptor response element (NRRE-1). The transcriptional regulatory properties and receptor binding sequences of each nuclear receptor response element within NRRE-1 are also characterized. NRRE-1 consists of four potential nuclear hormone receptor hexamer binding sites, arranged as [<--1-(n)s-2-->-3-->(n)4<--4], three of which are used in alternative pairwise binding by COUP-TF and HNF-4 homodimers and by RAR-RXR heterodimers, as demonstrated by mobility shift assays and methylation interference analysis. Binding and transactivation studies with mutant NRRE-1 elements confirmed the existence of distinct retinoid, COUP-TF, and HNF-4 response elements that define novel receptor binding motifs: COUP-TF homodimers bound sites 1 and 3 (two hexamer repeat sequences arranged as an everted imperfect repeat separated by 14 bp or ER14), RAR-RXR heterodimers bound sites 1 and 2 (ER8), and HNF-4 homodimers bound sites 2 and 3 (imperfect DR0). Mixing cotransfection experiments demonstrated that the nuclear receptor dimers compete at NRRE-1 to modulate constitutive and ligand-mediated transcriptional activity. These data suggest a mechanism for the transcriptional modulation of genes encoding enzymes involved in cellular metabolism.
Mol Cell Biol 1994 Jul
PMID:A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs. 800 45

As part of its trophic action to maintain the steroidogenic capacity of adrenocortical cells, corticotropin (ACTH) increases the transcription of the cytochrome P-450 steroid hydroxylase genes, including the gene encoding steroid 21-hydroxylase (21-OHase). We previously identified several promoter elements that regulate 21-OHase gene expression in mouse Y1 adrenocortical tumor cells. One of these elements, located at nucleotide -65, closely resembles the recognition sequence of the orphan nuclear receptor NGFI-B, suggesting that NGFI-B regulates this essential steroidogenic enzyme. To explore this possibility, we first used in situ hybridization to demonstrate high levels of NGFI-B transcripts in the adrenal cortex of the adult rat. In cultured mouse Y1 adrenocortical cells, treatment with ACTH, the major regulator of 21-OHase transcription, rapidly increased NGFI-B expression. Gel mobility shift and DNase I footprinting experiments showed that recombinantly expressed NGFI-B interacts specifically with the 21-OHase -65 element and identified one complex formed by Y1 extracts and the 21-OHase -65 element that contains NGFI-B. Expression of NGFI-B significantly augmented the activity of the intact 21-OHase promoter, while mutations of the -65 element that abolish NGFI-B binding markedly diminished NGFI-B-mediated transcriptional activation. Specific mutations of NGFI-B shown previously to impair either DNA binding or transcriptional activation diminished the effect of NGFI-B coexpression on 21-OHase expression. Finally, an oligonucleotide containing the NGFI-B response element conferred ACTH response to a core promoter from the prolactin gene, showing that this element is sufficient for ACTH induction. Collectively, these results identify a cellular promoter element that is regulated by NGFI-B and implicate NGFI-B in the transcriptional induction of 21-OHase by ACTH.
Mol Cell Biol 1993 Feb
PMID:The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. 838 Aug 97

The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) is required for development and maintenance of the liver phenotype. HNF-4 activates several hepatocyte-specific genes, including the gene encoding apolipoprotein AI (apoAI), the major protein component of plasma high-density lipoprotein. The apoAI gene is activated by HNF-4 through a nuclear receptor binding element (site A) located in its liver-specific enhancer. To decipher the mechanism whereby HNF-4 enhances apoAI gene transcription, we have reconstituted its activity in a cell-free system. Functional HNF-4 was purified to homogeneity from a bacterial expression system. In in vitro transcription assays employing nuclear extract from HeLa cells, which do not contain HNF-4, recombinant HNF-4 stimulated transcription from basal promoters linked to site A. Activation by HNF-4 did not exhibit a ligand requirement, but phosphorylation of HNF-4 in the in vitro transcription system was observed. The activation function of HNF-4 was localized to a domain displaying strong homology to the conserved AF-2 region of nuclear receptors. Dissection of the transcription cycle revealed that HNF-4 activated transcription by facilitating assembly of a preinitiation complex intermediate consisting of TBP, the TATA box-binding protein component of TFIID and TFIID, via direct physical interactions with TFIIB. However, recruitment of TFIIB by HNF-4 was not sufficient for activation, since HNF-4 deletion derivatives lacking AF-2 bound TFIIB. On the basis of these results, HNF-4 appears to activate transcription at two distinct levels. The first step involves AF-2-independent recruitment of TFIIB to the promoter complex; the second step is AF-2 dependent and entails entry of preinitiation complex components acting downstream of TFIIB.
Mol Cell Biol 1996 Apr
PMID:TFIIB-directed transcriptional activation by the orphan nuclear receptor hepatocyte nuclear factor 4. 865 58

The alpha1-fetoprotein (AFP) gene is located between the albumin and alpha-albumin genes and is activated by transcription factor FTF (fetoprotein transcription factor), presumed to transduce early developmental signals to the albumin gene cluster. We have identified FTF as an orphan nuclear receptor of the Drosophila FTZ-F1 family. FTF recognizes the DNA sequence 5'-TCAAGGTCA-3', the canonical recognition motif for FTZ-F1 receptors. cDNA sequence homologies indicate that rat FTF is the ortholog of mouse LRH-1 and Xenopus xFF1rA. Rodent FTF is encoded by a single-copy gene, related to the gene encoding steroidogenic factor 1 (SF-1). The 5.2-kb FTF transcript is translated from several in-frame initiator codons into FTF isoforms (54 to 64 kDa) which appear to bind DNA as monomers, with no need for a specific ligand, similar KdS (approximately equal 3 x 10(-10) M), and similar transcriptional effects. FTF activates the AFP promoter without the use of an amino-terminal activation domain; carboxy-terminus-truncated FTF exerts strong dominant negative effects. In the AFP promoter, FTF recruits an accessory trans-activator which imparts glucocorticoid reactivity upon the AFP gene. FTF binding sites are found in the promoters of other liver-expressed genes, some encoding liver transcription factors; FTF, liver alpha1-antitrypsin promoter factor LFB2, and HNF-3beta promoter factor UF2-H3beta are probably the same factor. FTF is also abundantly expressed in the pancreas and may exert differentiation functions in endodermal sublineages, similar to SF-1 in steroidogenic tissues. HepG2 hepatoma cells seem to express a mutated form of FTF.
Mol Cell Biol 1996 Jul
PMID:The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. 866 3


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