Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

The complete exonic and partial intronic sequence of the bovine CYP17 (P45017 alpha) gene has been determined. The gene contains eight exons with exon/intron boundaries which are identical to those determined previously for the human CYP17 gene. The site of initiation of transcription of this gene is located within a 6-base sequence 52 bp from the initiation of translation. Considerable sequence homology (58.7%) is found when approximately 500 bp of the 5'-flanking sequences of the bovine and human CYP17 genes are compared. A computer-based search of this region of bovine CYP17 for consensus sequences associated with binding of transcription factors (i.e., GR, PR, CREB/ATF, AP1, AP2, AP3, AP4, AP5, OTF, CTF/NF1, SP1) shows only the consensus CREB/ATF sequence TGACGT which is also found to be at approximately the same position in the human CYP17 gene. In bovine adrenal cortex, transcription of the CYP17 gene is regulated by the peptide hormone adrenocorticotropin via cAMP. Whether the consensus CREB/ATF sequence is associated with the cAMP-mediated transcription of the CYP17 gene remains to be elucidated.
...
PMID:Structural characterization of the bovine CYP17 (17 alpha-hydroxylase) gene. 254 97

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.
...
PMID:Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence 2. 758 16

1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adrenocortical growth and steroidogenesis in the sheep fetus during late gestation. Plasma concentrations of ACTH(1-39) increased between 120-125 and 136-142 days (P < 0.05), but did not change after surgical disconnection of the fetal hypothalamus and pituitary (HPD) at 106-120 days gestation. There was no effect of either gestational age or HPD on the circulating concentrations of the ACTH-containing precursors pro-opiomelanocortin (POMC) and pro-ACTH (the 22 kDa N-terminal portion of POMC). 2. In the fetal sheep adrenal, the relative abundance of the mRNAs of the steroidogenic enzymes CYPIIA1 and CYP21A1 increased between 130-135 and 136-140 days gestation (P < 0.05) and remained high after 141 days, whereas that of CYP17 mRNA increased after 141 days gestation (P < 0.05). The abundance of adrenal 3 beta-HSD mRNA did not change between 130 and 145 days. 3. Hypothalamo-pituitary disconnection significantly reduced the abundance of of CYPIIA1 mRNA, 3 beta-HSD mRNA and CYP17 mRNA by 3.4, 3.1 and 3.7 times, respectively, at 140-142 days gestation (P < 0.05). 4. In the intact group of fetal sheep, adrenal weight increased between 130-135 and 141-145 days (P < 0.05), but there was no change in the abundance of adrenal insulin-like growth factor II (IGF-II) mRNA across this gestational age range. Hypothalamo-pituitary disconnection significantly reduced fetal adrenal weight to 66% that of intact sheep (P < 0.01), but did not alter the abundance of IGF-II mRNA in the fetal adrenal at 140-142 days. 5. Our results suggest that the prepartum changes in adrenal growth and steroidogenesis are under the control of an intact hypothalamo-pituitary axis in late gestation and are dependent on an increase in circulating ACTH(1-39), rather than on ACTH precursors. We have found no evidence, however, for a direct-relationship between fetal adrenal growth or steroidogenesis and adrenal IGF-II mRNA between 130 and 145 days gestation.
...
PMID:The peptide ACTH(1-39), adrenal growth and steroidogenesis in the sheep fetus after disconnection of the hypothalamus and pituitary. 881 18

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11 beta-hydroxylase or 17 alpha-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
...
PMID:Inherited forms of mineralocorticoid hypertension. 895 79

Steroid hormone biosynthesis in the adrenal cortex is controlled by the peptide hormone adrenocorticotropin (ACTH), which acts to increase intracellular cAMP and results in the activation of cAMP-dependent protein kinase A (PKA) and subsequent increase in steroidogenic gene transcription. Protein phosphorylation by PKA activates transcription of genes encoding steroidogenic enzymes; however the precise proteins which are phosphorylated remain to be determined. We have recently shown that phosphoprotein phosphatase (PP) activity is essential for cAMP-dependent transcription of the human CYP17 (hCYP17) gene in H295R adrenocortical cells. The aim of our current studies was to determine if inhibition of PP activity attenuates cAMP-dependent mRNA expression of other steroidogenic genes in H295R cells. Using various inhibitors of serine/threonine and tyrosine PPs, we examined the role of phosphatase activity on cAMP-dependent transcription of steroidogenic genes in the adrenal cortex. CYP11A, CYP11B1/2, CYP21, and adrenodoxin also require PP activity for cAMP-stimulated gene expression. Inhibition of both serine/threonine and tyrosine PP activities suppresses the cAMP-dependent mRNA expression of several steroidogenic genes, suggesting that a dual-specificity PP is essential for conveying ACTH/cAMP-stimulated transcription. We propose that PKA phosphorylates and activates a dual-specificity phosphatase, which mediates steroidogenic gene transcription in response to ACTH/cAMP.
...
PMID:cAMP-dependent transcription of steroidogenic genes in the human adrenal cortex requires a dual-specificity phosphatase in addition to protein kinase A. 1220 Feb 37

Steroid hormone biosynthesis in the adrenal cortex is controlled by adrenocorticotropin (ACTH), which increases intracellular cAMP, resulting in the activation of cAMP-dependent protein kinase(PKA) and subsequent increase in steroidogenic gene transcription. We have found that a dual-specificity phosphatase is essential for conveying ACTH/cAMP-stimulated transcription of several steroidogenic genes in the human adrenal cortex. In the present study, the role of mitogen-activated protein kinase phosphatase-1 (MKP-1), a nuclear dual-specificity phosphatase, in the transcriptional activation of human CYP17 (hCYP17) in H295R human adrenocortical cells is established. Stimulation of H295R cells with dibutyryl-cAMP (Bt(2)cAMP) induces MKP-1 mRNA and protein expression within 30 min of exposure. In transient-transfection studies, transcriptional activity of an hCYP17 promoter-reporter construct was increased by Bt(2)cAMP and by overexpression of PKA or MKP-1. Furthermore, PKA phosphorylated an MKP-1-glutathione S-transferase fusion protein in in vitro assays and Bt(2)cAMP increased (32)P associated with MKP-1 that was immunoprecipitated from H295R cells. Finally, silencing MKP-1 expression using antisense oligonucleotides attenuated cAMP-stimulated hCYP17 expression, whereas silencing of ERK1/2 increased hCYP17 expression. These findings demonstrate integral roles for MKP-1 and ERK1/2 via regulation of the phosphorylation state of steroidogenic factor-1 (SF-1) in mediating ACTH/cAMP-dependent transcription of hCYP17, thereby maintaining the balance between transcriptional activation and repression.
...
PMID:CAMP-dependent protein kinase enhances CYP17 transcription via MKP-1 activation in H295R human adrenocortical cells. 1250 19

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.
...
PMID:Transcriptional complexes at the CYP17 CRS. 1253 Jun 62

Cytochrome P450c17, encoded by the CYP17 gene, is a component of the 17alpha-hydroxylase/17,20-lyase enzyme complex essential for production of adrenal glucocorticoids and androgens as well as gonadal androgens. The expression of CYP17 in adrenocortical cells is stimulated by corticotropin (ACTH) via the signal transduction pathway involving cAMP and protein kinase A (PKA). Thus, in addition to glucocorticoids, ACTH stimulates formation of adrenal androgens, which are known to induce transforming growth factor beta (TGF-beta) secretion. TGF-b in turn inhibits steroid hormone output by attenuating both basal and ACTH-dependent expression of CYP17. The present study revealed that treatment of bovine and human H295R adrenocortical cells with androgens resulted in a decrease in the basal level of CYP17 transcript and cortisol secretion, without affecting forskolin-stimulated levels. We also demonstrated that in H295R cells TGF-beta inhibited both basal and forskolin-stimulated accumulation of CYP17 mRNA. Determination of promoter activity, directing luciferase reporter gene expression in H295R cells transfected with deletion fragments of bovine CYP17 promoter, indicated that the -483 to -433 bp fragment of the promoter was necessary for the inhibitory action of TGF-beta on CYP17 expression. It is concluded that in bovine and human adrenocortical cells, androgens inhibit basal CYP17 expression probably at the transcriptional level and independently of the effect of TGF-beta.
...
PMID:Inhibition of CYP17 expression by adrenal androgens and transforming growth factor beta in adrenocortical cells. 1562 62

Sphingolipids are a diverse family of phospholipids and glycolipids that mediate cell-cell interactions, participate in signal transduction pathways and modulate the activity of various cellular proteins and receptors. The objective of the present studies was to characterize the role of the sphingolipid biosynthetic pathway in adrenocorticotropin (ACTH)-dependent steroidogenic gene expression and cortisol production. H295R human adrenocortical cells were treated with ACTH or dibutyryl cAMP (Bt2cAMP) for various time periods and the content of sphingolipids was quantified by mass spectrometry. Treatment of H295R cells with ACTH and Bt2cAMP activated sphingolipid metabolism within five minutes. Decreases were found in the cellular levels of several sphingolipids, including sphingomyelin (SM) and glucosylceramide. ACTH/cAMP rapidly decreased levels of the signaling molecules ceramide, sphingosine and sphingosine-1-phosphate (S1P). The effect of these bioactive sphingolipids on steroidogenic gene expression was also examined. Both sphingosine and S1P were found to increase endogenous CYP17 mRNA and activate the transcriptional activity of CYP17-luciferase reporter constructs. Further, sphingosine and S1P rapidly increase cortisol biosynthesis in H295R cells. In summary, our studies establish a link between ACTH/cAMP-dependent steroidogenesis and sphingolipid metabolism in the human adrenal cortex. Finally, these findings suggest that sphingolipids may serve as signaling mediators in ACTH-stimulated cortisol biosynthesis.
...
PMID:ACTH regulates steroidogenic gene expression and cortisol biosynthesis in the human adrenal cortex via sphingolipid metabolism. 1566 26

Dioxins and polychlorinated biphenyls (PCBs) have been shown to accumulate in the adrenal glands when incorporated into the body. However, the impacts of exposure on adrenal steroidogenesis have not been thoroughly investigated. In this study, we demonstrated that dioxin-like PCB126 altered androgen, cortisol, and aldosterone biosynthesis differentially in human adrenocortical H295R cells. PCB126 diminished basal and cAMP-induced androstenedione production as well as CYP17 mRNA expression in a dose-dependent and time-dependent manner. The CYP17 repression was accompanied with decreases in the encoded 17 alpha-hydroxylase and 17,20-lyase activities, particularly the latter. In contrast, high concentrations of PCB126 stimulated basal cortisol and aldosterone biosynthesis, including induction of CYP21B, CYP11B1, and CYP11B2 mRNA expression and elevation of the conversion of cortisol from 17-OH-progesterone and aldosterone from progesterone. cAMP abolished the positive effect of PCB126 on cortisol synthesis, while it synergistically enhanced PCB126 stimulation on CYP11B2 expression and aldosterone production. It seemed likely that the downregulation of CYP21B caused by the combination of PCB126 and cAMP counteracted the CYP11B1 induction stimulated by the co-treatment. In addition, high concentrations of PCB126 might sensitize the regulation of adrenocorticotropin (ACTH) on the adrenocortical cells by increasing ACTH receptor levels. Because adrenal steroids have profound influences on glucose tolerance, insulin sensitivity, lipid metabolism, obesity, vascular function, and cardiac remodeling, this article also discusses the potential association of the detected adrenocortical alterations with increased diabetic and cardiovascular risk found among highly exposed people.
...
PMID:PCB126 induces differential changes in androgen, cortisol, and aldosterone biosynthesis in human adrenocortical H295R cells. 1570 66


1 2 Next >>

---