UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The orphan nuclear receptor steroidogenic factor 1 (SF-1) is expressed in the adrenal cortex and gonads and regulates the expression of several P450 steroid hydroxylases in vitro. We examined the role of SF-1 in the adrenal glands and gonads in vivo by a targeted disruption of the mouse SF-1 gene. All SF-1-deficient mice died shortly after delivery. Their adrenal glands and gonads were absent, and persistent Mullerian structures were found in all genotypic males. While serum levels of corticosterone in SF-1-deficient mice were diminished, levels of adrenocorticotropic hormone (ACTH) were elevated, consistent with intact pituitary corticotrophs. Intrauterine survival of SF-1-deficient mice appeared normal, and they had normal serum level of corticosterone and ACTH, probably reflecting transplacental passage of maternal steroids. We tested whether SF-1 is required for P450 side-chain-cleavage enzyme (P450scc) expression in the placenta, which expresses both SF-1 and P450scc, and found that in contrast to its strong activation of the P450scc gene promoter in vitro, the absence of SF-1 had no effect on P450scc mRNA levels in vivo. Although the region targeted by our disruption is shared by SF-1 and by embryonal long terminal repeat-binding protein (ELP), a hypothesized alternatively spliced product, we believe that the observed phenotype reflects absent SF-1 alone, as PCR analysis failed to detect ELP transcripts in any mouse tissue, and sequences corresponding to ELP are not conserved across species. These results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established.
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PMID:Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. 747 14

The CYP17 gene contains in its promoter region at least two cis-acting elements (cAMP-responsive sequence 1 and 2, CRS1 and CRS2) that are necessary for adrenocorticotropin (ACTH) induced transcription. The CRS2 element contains a 6 bp repeat similar to binding sites for members of the nuclear hormone receptor superfamily of transcription factors. We present data that establish the repeated part of CRS2 (repCRS2) as a target of two nuclear orphan receptors; steroidogenic factor 1 (SF-1) and chicken ovalbumin upstream promoter transcription factor (COUP-TF). The repCRS2 element was found to form COUP-TF-related complexes with nuclear extracts from all cell lines tested, whereas SF-1-related complexes were only formed with extracts from steroidogenic Y1 cells. Transfection studies of steroidogenic cells demonstrated that SF-1 acts as an activator of repCRS2-dependent transcription of reporter genes.
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PMID:Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence 2. 758 16

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.
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PMID:Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. 762 27

This review highlights contributions from my laboratory in which the sites and mechanisms of action of the adrenocorticotropic hormone (ACTH) in the adrenal cortex have been explored. Early studies showing that ACTH stimulates adrenal steroidogenesis by interacting with specific receptors at the cell surface are summarized. Next, the development of a strategy of genetic analysis to define the signalling events that follow ACTH interaction with its receptor is described. This strategy involved the isolation and characterization of mutant adrenal cell lines harboring specific defects in the ACTH-responsive steroidogenic pathway. I describe the isolation and characterization of several of these mutants and demonstrate how these mutants have helped to establish obligatory roles for adenylyl cyclase, cyclic AMP (cAMP), and cAMP-dependent protein kinase in the steroidogenic actions of ACTH. Finally, some of our studies on the regulated expression of the steroidogenic cytochrome P450 enzymes in Y1 adrenal cells are reviewed. These latter studies have led to the discovery of a novel promoter element and transcription factor (designated steroidogenic factor 1) that participates in the coordinate expression of these cytochrome P450 enzymes and that is required for their regulated expression by ACTH and cAMP.
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PMID:The 1994 Upjohn Award Lecture. Molecular and genetic approaches to the study of signal transduction in the adrenal cortex. 856 76

Steroid hormone biosynthesis in the adrenal cortex is controlled by the peptide hormone adrenocorticotropin (ACTH), which acts to increase intracellular cAMP, resulting in the activation of cAMP-dependent protein kinase (PKA) and subsequent increase in steroidogenic gene transcription. We have identified three proteins interacting with the human CYP17 cAMP responsive sequence (CRS): steroidogenic factor 1 (SF-1), p54nrb, and polypyrimidine tract-binding protein-associated splicing factor (PSF). Nuclear extracts isolated from cAMP stimulated of H295R cells showed cAMP-inducible binding to the human CYP17 (hCYP17) CRS. This cAMP-inducible binding was dependent on a dual-specificity phosphatase (DSP). DSP activity was subsequently shown to be is essential for conveying ACTH/cAMP-stimulated transcription of several steroidogenic genes in the human adrenal cortex. We report here that the transactivation potential of SF-1 is also dependent on phosphatase activity; suggesting that SF-1 is dephosphorylated in response to ACTH/cAMP stimulation. Finally, we demonstrate a role for mitogen-activated protein kinase phosphatase 1 (MKP-1), a nuclear DSP, in conveying SF-1-dependent transcription of an hCYP17 promoter-reporter construct in the H295R human adrenocortical cell line. We conclude that a DSP, possibly MKP-1, is essential for enhancing hCYP17 transcription in the adrenal cortex by desphosphorylating of SF-1, thereby increasing the binding affinity of SF-1, p54nrb, and PSF for the hCYP17 promoter.
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PMID:Transcriptional complexes at the CYP17 CRS. 1253 Jun 62

Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5' deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocyte-specific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor gamma (PPARgamma) and its heterodimeric partner retinoid X receptor alpha (RXRalpha) in adipocyte nuclear extracts. Co-transfection of PPARgamma2/RXRalpha with the pMC2-R(-112/+105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPARgamma/RXRalpha binding resulted in a complete abrogation of the pMC2-R(-112/+105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.
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PMID:A peroxisome proliferator-response element in the murine mc2-r promoter regulates its transcriptional activation during differentiation of 3T3-L1 adipocytes. 1502 12

Bone marrow stem cells develop into haematopoietic and mesenchymal lineages, but have not been known to participate in steroidogenic cell production. Steroidogenic factor 1 (SF-1), also designated adrenal 4 binding protein (Ad4BP), is an essential orphan nuclear receptor for steroidogenesis as well as for adrenal and gonadal gland development. In the present study, we revealed that the adenovirus-mediated forced expression of SF-1 can transform cultured primary long-term cultured bone marrow cells into steroidogenic cells, showing the de novo synthesis of multiple steroid hormones in response to adrenocorticotropic hormone (ACTH). This finding may provide an initial step in innovative autograft cell transfer therapy for steroid hormone deficiencies.
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PMID:SF-1/Ad4BP transforms primary long-term cultured bone marrow cells into ACTH-responsive steroidogenic cells. 1556 55

Early researchers found that lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia and obesity in a variety of species including humans, which led them to designate the VMH as the brain's "satiety center." Many researchers later dismissed a role for the VMH in feeding behavior when Gold claimed that lesions restricted to the VMH did not result in overeating and that obesity was observed only with lesions or knife cuts that extended beyond the borders of the VMH and damaged or severed the ventral noradrenergic bundle (VNAB) or paraventricular nucleus (PVN). However, anatomical studies done both before and after Gold's study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight. Several other important differences have also been found between VMH and both PVN and VNAB lesion-induced obesity. Concerns regarding (a) motivation to work for food and (b) the effects of nonirritative lesions have also been addressed and answered in many studies. Lesion studies with weanling rats and adult pair-tube-fed rats, as well as recent studies of knockout mice deficient in the orphan nuclear receptor steroidogenic factor 1, indicate that VMH lesion-induced obesity is in large part a metabolic obesity (due to autonomic nervous system disorders) independent of hyperphagia. However, there is ample evidence that the VMH also plays a primary role in feeding behavior. Neuroimaging studies in humans have shown a marked increase in activity in the area of the VMH during feeding. The VMH has a large population of glucoresponsive neurons that dynamically respond to blood glucose levels and numerous histamine, dopamine, serotonin, and GABA neurons that respond to feeding-related stimuli. Recent studies have implicated melanocortins in the VMH regulation of feeding behavior: food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor (BDNF) neurons. Moderate hyperphagia and obesity have also been observed in female rats with damage to the efferent projections from the posterodorsal amygdala to the VMH. Hypothalamic obesity can result from damage to either the POMC or BDNF neurons. The concept of hypothalamic feeding and satiety centers is outdated and unnecessary, and progress in understanding hypothalamic mechanisms of feeding behavior will be achieved only by appreciating the different types of neural and blood-borne information received by the various nuclei, and then attempting to determine how this information is integrated to obtain a balance between energy intake and energy output.
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PMID:The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. 1641 83

The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis. Here, we show that its targeted deletion in mice is associated with altered expression of several glucocorticoid-dependent components of HPA regulation (e.g., corticotropin-releasing hormone, vasopressin, ACTH, glucocorticoid receptors), suggestive of hyperactivity under basal conditions. At the same time, TIF-2(-/-) mice display significantly lower basal corticosterone levels and a sluggish and blunted initial secretory response to brief emotional and prolonged physical stress. Subsequent analysis revealed this discrepancy to result from pronounced aberrations in the structure and function of the adrenal gland, including the cytoarchitectural organization of the zona fasciculata and basal and stress-induced expression of key elements of steroid hormone synthesis, such as the steroidogenic acute regulatory (StAR) protein and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In addition, altered expression levels of two nuclear receptors, DAX-1 and steroidogenic factor 1 (SF-1), in the adrenal cortex strengthen the view that TIF-2 deletion disrupts adrenocortical development and steroid biosynthesis. Thus, hyperactivity of the hypothalamo-pituitary unit is ascribed to insidious adrenal insufficiency and impaired glucocorticoid feedback.
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PMID:Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. 1713 62

In the human adrenal cortex, adrenocorticotropin (ACTH) activates CYP17 transcription by promoting the binding of the nuclear receptor steroidogenic factor 1 (SF1) (Ad4BP, NR5A1) to the promoter. We recently found that sphingosine is an antagonist for SF1 and inhibits cyclic AMP (cAMP)-dependent CYP17 gene transcription. The aim of the current study was to identify phospholipids that bind to SF1 and to characterize the mechanism by which ACTH/cAMP regulates the biosynthesis of this molecule(s). Using tandem mass spectrometry, we show that in H295R human adrenocortical cells, SF1 is bound to phosphatidic acid (PA). Activation of the ACTH/cAMP signal transduction cascade rapidly increases nuclear diacylglycerol kinase (DGK) activity and PA production. PA stimulates SF1-dependent transcription of CYP17 reporter plasmids, promotes coactivator recruitment, and induces the mRNA expression of CYP17 and several other steroidogenic genes. Inhibition of DGK activity attenuates the binding of SF1 to the CYP17 promoter, and silencing of DGK-theta expression inhibits cAMP-dependent CYP17 transcription. LXXLL motifs in DGK-theta mediate a direct interaction of SF1 with the kinase and may facilitate binding of PA to the receptor. We conclude that ACTH/cAMP stimulates PA production in the nucleus of H295R cells and that this increase in PA concentrations facilitates CYP17 induction.
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PMID:Cyclic AMP-stimulated interaction between steroidogenic factor 1 and diacylglycerol kinase theta facilitates induction of CYP17. 1766 81

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