Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid-suppressible hyperaldosteronism (GSH) is an autosomal dominant form of familial hypertension. The biochemical abnormalities seen in this disorder may be remedied by administration of dexamethasone, implying that aldosterone synthesis is being abnormally regulated by corticotropin. The final three steps of aldosterone synthesis, 11 beta- and 18-hydroxylation and 18-oxidation, are mediated by a cytochrome P450 in the zona glomerulosa of the adrenal cortex termed CYP11B2. A related isozyme in the zona fasciculata, CYP11B1, is required for cortisol synthesis; this isozyme, which is normally expressed at much higher levels than CYP11B2, only has 11 beta-hydroxylase activity. These isozymes are encoded by genes on human chromosome 8q22. We have now studied four unrelated patients with GSH. We found that each patient has one chromosome that carries three CYP11B genes instead of two. This has presumably been generated by unequal meiotic crossing-over. The extra gene is a hybrid with 5' regulatory and coding regions corresponding to CYP11B1 and 3' coding regions from CYP11B2. The breakpoint is in intron 2 in two cases, intron 3 in one, and exon 4 in one. Cells transfected with hybrid cDNAs containing up to the first three exons of CYP11B1 synthesized aldosterone at levels near that of cells carrying normal CYP11B2, but cells transfected with hybrids containing the first five or more exons of CYP11B1 could not synthesize detectable amounts of aldosterone. These data demonstrate that GSH is caused by expression of a gene that is regulated like CYP11B1 but that encodes a protein able to synthesize aldosterone.
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PMID:Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. 151 66

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.
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PMID:Inherited forms of mineralocorticoid hypertension. 895 79

To elucidate the mechanism(s) by which adrenocorticotropic hormone (corticotropin) stimulates transcription of the steroid 11beta-monooxygenase gene (CYP11B1) in adrenocortical cells, the 5'-flanking region of rat CYP11B1 was analyzed using transient transfection and protein-binding assays with mouse adrenocortical Y1 cells. The results indicated that both basal and corticotropin-induced transcriptional activation of CYP11B1 required a common regulatory element containing a binding site for activator protein-1 (AP-1) transcription factors (dimers of the Jun and Fos family proteins) in the 5'-flanking region. Other DNA-binding protein(s) such as transcription factor Ad4BP was not required for either basal or corticotropin-induced transcriptional activation. Corticotropin stimuli were found to induce expression of a subset of the jun and fos family gene products in Y1 cells significantly, while total amounts of AP-1 factors capable of binding to its site in the CYP11B1 promoter did not change greatly. Treatment of rats with corticotropin had similar effects on mRNA levels of the jun and fos family genes in the adrenocortical zona fasciculata cells together with an enhancing effect on the level of CYP11B1 mRNA in the tissue. The effects of corticotropin on mRNA levels of the jun and fos family genes as well as transcription of CYP11B1 in Y1 cells were mimicked by treatment of the cells with dibutyryl cAMP. Furthermore, when components of AP-1 factors were overexpressed by transfecting Y1 cells with their expression vectors, a paired expression of AP-1 components such as c-Jun and c-Fos, which were inducible by corticotropin, transactivated the CYP11B1 promoter more strongly in the absence of corticotropin than other combinations such as JunD and Fra-2 expressed constitutively. These results suggest that corticotropin regulates transcription of the CYP11B1 gene by causing compositional changes in AP-1 transcription factors in the adrenocortical cells via a cAMP-dependent pathway.
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PMID:Adrenocorticotropic hormone stimulates CYP11B1 gene transcription through a mechanism involving AP-1 factors. 974 64

1. Because aldosterone is the minority hormone of the adrenal cortex, its proper function depends on protective physiological mechanisms. These include a particular site of aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex as well as a complex multifactorial control system, which adapts aldosterone production to acute and chronic changes in body sodium and potassium content, irrespective of pituitary adrenocorticotropic hormone (ACTH) secretion. 2. Over the past decade, an important element of these mechanisms has been identified in the form of the enzyme involved in the final steps of aldosterone biosynthesis. In species such as the human, rat and mouse, the conversion of deoxycorticosterone to aldosterone is catalysed by an isozyme (CYP11B2) of cytochrome P450(11) beta (CYP11B1). The gene encoding this enzyme is expressed only in the zona glomerulosa. Its transcription is enhanced by sodium deficiency and potassium intake, but is suppressed by long-term administration of high doses of ACTH. 3. In contrast, the gene encoding CYP11B1 (i.e. the major (non-aldosterone-producing) type of the enzyme) is expressed mainly in the zona fasciculata and its expression depends on physiological concentrations of ACTH. 4. In other animal species (cattle, pig, sheep), the major forms of cytochrome P450(11) beta have an inherent aldosterone-synthesizing activity, which is, however, selectively suppressed in mitochondria of zona fasciculata cells. 5. The elucidation of the mechanisms involved in this suppression or of those mediating alterations in CYP11B2 expression in response to physiological stimuli may be important areas of future research on the regulation of aldosterone biosynthesis.
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PMID:Regulation of aldosterone biosynthesis: the end of the road? 980 98

Aldosterone and cortisol are the major mineralocorticoid and glucocorticoid produced by the human adrenal. Circulating levels of angiotensin II and potassium control the adrenal production of aldosterone, while the production of cortisol is controlled mainly by adrenocorticotropin. The capacity of the adrenal cortex to differentially produce aldosterone and cortisol relies to a large degree on the expression of aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1). CYP11B2 catalyzes the final steps in the biosynthesis of aldosterone and is expressed solely in the glomerulosa of the adrenal cortex, while CYP11B1 catalyzes the final steps in the biosynthesis of cortisol and is expressed in the fasciculata/reticularis. The zonal expression of these two isozymes appears to result from transcriptional regulation of the two genes. Herein, the recent progress in defining the cellular mechanisms that regulate transcription of these two isozymes and thus the capacity of the adrenal gland to differentially produce aldosterone and cortisol is discussed.
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PMID:Adrenal zonation: clues from 11beta-hydroxylase and aldosterone synthase. 1041 30

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.
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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

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalyzing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed in high levels in the zona fasciculata and is regulated by adrenocorticotropic hormone (ACTH). CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. The substrate for P450c11 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension and is autosomal recessively inherited. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). Molecular genetic studies of the CYP11B1 gene in 11beta-hydroxylase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. Molecular genetic studies have practical importance for the prenatal diagnosis of virilizing CAH forms.
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PMID:Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency. 1242 5

Salt-inducible kinase (SIK), expressed in Y1 mouse adrenocortical tumor cells at an early stage of adrenocorticotropic hormone (ACTH)-stimulation, represses the cAMP-responsive element (CRE)-dependent gene expression of CYP11A and StAR by acting on bZIP domain of CRE-binding protein. ACTH induced the SIK's nuclear to cytosolic translocation in a PKA-dependent manner. A mutant SIK in which the PKA-dependently phosphorylatable Ser577 had been replaced with Ala could not move out of the nucleus. The degree of CRE-reporter repression by SIK was strong as long as SIK was present in the nucleus. These indicated that intracellular translocation of SIK might be an important factor to determine the time-dependent change in the level of steroidogenic gene expression in ACTH-stimulated cells. Promoter analyses suggested that SIK repressed gene expressions not only of CYP11A and StAR but also of CYP11B1, CYP11B2 and SIK itself. We propose here that SIK is one of important molecule regulating expression of steroidogenic genes in the early phase of ACTH treatment.
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PMID:Salt-inducible kinase-mediated regulation of steroidogenesis at the early stage of ACTH-stimulation. 1294 28

This article reports the case of a boy diagnosed at 1.8 years of age with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. The patient showed salt-wasting episodes during the neonatal period. On molecular analysis, a homozygous deletion hybrid (CYP11B2-CYP11B1) involving the CYP11B locus at 8q24.3 was found. Southern blot analysis showed the break point of the chimera gene to be located before intron 5; sequence analysis identified it at exon 4 between codons 202 and 248. This CYP11B2(5')/B1(3') hybrid should lack aldosterone synthase activity (due to the CYP11B1 residues at exons 5 and 6), and the enzyme it codes for should not be promoted by adrenocorticotropic hormone (ACTH) (CYP11B2 promoter sequences). The patient phenotype - neonatal salt-wasting and 11 beta-hydroxylase deficiency - is in agreement with this hybrid structure. This is the first time a homozygous deletion hybrid generated by unequal crossover has been described in exon 4. This genetic lesion appears to be the reciprocal product from the recombination event that causes glucocorticoid-remediable aldosteronism, a duplication dominant allele (CYP11B2-CYP11B1/B2-CYP11B1) coding for additional aldosterone synthase activity regulated by ACTH. The clinical presentation of the condition in this patient contributes to the in vivo understanding of the regulation of this complex locus in which two 'duplicated' genes have evolved different regulatory and enzymatic activities involved in mineralocorticoid and glucocorticoid synthesis in the adrenal glands. The fact that this allele was first predicted and has now been documented clinically and molecularly in vivo is particularly noteworthy.
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PMID:Neonatal salt-wasting and 11 beta-hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)-CYP11B1 (11 beta-hydroxylase). 1532 22

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.
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PMID:PCB126 induces differential changes in androgen, cortisol, and aldosterone biosynthesis in human adrenocortical H295R cells. 1570 66


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