Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The conversion of androgens to estrogens by CYP19 (cytochrome P450AROM, aromatase) is an important step in the mechanism of androgen action in the brain. CYP19 expression has been demonstrated in the brain of various animal species and in the human temporal lobe. Studies on postnatal CYP19 expression in various other areas of the human brain are rare and carried out in a limited number of post mortem obtained tissue. Therefore, we investigated CYP19 mRNA expression in fresh human frontal and hippocampal tissues and compared them to the expression in temporal neocortex tissues. We studied biopsy materials removed at neurosurgery from 45 women and 54 men with epilepsy. Quantification of CYP19 mRNA was achieved by nested competitive reverse transcription-PCR. CYP19 mRNA concentrations were significantly higher in temporal (2.29+/-0.40 arbitrary units, AU, mean +/- SEM; n = 57) than in frontal neocortex specimens (0.92+/-0.17 AU; n = 18; P<0.04). In hippocampal tissue specimens CYP19 expression (1.41+/-0.18 AU; n = 24) was lower than in temporal neocortex specimens, but the difference did not reach statistical significance. Sex differences were not observed in any of the brain regions under investigation. In conclusion, CYP19 mRNA is expressed in the human temporal and frontal neocortex as well as in the hippocampus. Regardless of sex, CYP19 expression was significantly higher in the temporal than in the frontal neocortex.
J Steroid Biochem Mol Biol
PMID:Expression of CYP19 (aromatase) mRNA in different areas of the human brain. 1062 13

Cytochrome P450 aromatase (P450arom; CYP19) mediates the conversion of androgens to estrogens and its activity has been found in all vertebrates studied to date. This study describes the full-length cDNA encoding the ovarian form of P450arom and the differences in the 5'-untranslated region (5'-UTR) of the extra-gonadal P450arom transcript expressed by the Atlantic stingray (Dasyatis sabina). Elasmobranchs (cartilaginous fishes such as sharks, rays and skates) diverged from the other vertebrates more than 350 million years ago, therefore the stingray P450arom cDNA may represent an ancient form of this gene. Northern blot analysis showed that the ovarian follicle expressed transcripts of 3.1 and 1.7 kb in size which correspond to the clones isolated from a stingray ovarian follicle cDNA library. Both transcripts consisted of an identical 1.5 kb coding region and a 41 bp 5'-UTR, however the 3'-UTRs differed in the use of the most proximate and the most distal of four polyadenylation signals. COS cells transfected with the 1.7 kb cDNA had twice the aromatase activity as cells transfected with the 3.1 kb cDNA. The coding region of the cDNA predicted a 58.5 kDa protein which consisted of 511 residues. Alignment of the stingray protein indicates that the P450arom is equally identical (53-59%) to all other vertebrate forms of P450arom characterized to date, thus indicating a common ancestry. The evolutionary relationship of the stingray form of P450arom clearly predates the other forms and belongs to a unique lineage. Transcripts of P450arom were expressed in ovarian follicles (of all sizes), the testis, the pituitary, in all sections of the brain, and in the kidney. The extra-gonadal transcripts appear to encode a protein identical to the ovarian form, however, the 5'-UTR was 657 bp longer presumably due to the transcription of an untranslated 'first exon' as seen in the mammalian form of this gene.
Mol Cell Endocrinol 2000 Jun
PMID:Characterization of gonadal and extra-gonadal forms of the cDNA encoding the Atlantic stingray (Dasyatis sabina) cytochrome P450 aromatase (CYP19). 1102 68

The human placenta has a remarkable capacity to aromatize C19-steroids, produced by the fetal adrenals, to estrogens. This reaction is catalyzed by aromatase P450 (P450arom), encoded by the CYP19 gene. In placenta, CYP19 gene expression is restricted to the syncytiotrophoblast layer. Cytotrophoblasts isolated from human placenta, when placed in monolayer culture in 20% O2, spontaneously fuse to form syncytiotrophoblast. These morphological changes are associated with a marked induction of aromatase activity and CYP19 gene expression. When cytotrophoblasts are cultured in an atmosphere containing 2% O2, they manifest increased rates of DNA synthesis and fail to fuse and form syncytiotrophoblast. The objective of the present study was to utilize cytotrophoblasts isolated from midterm human placenta to analyze the effects of O2 on CYP19 gene expression and the molecular mechanisms that mediate these effects. We observed that when trophoblast cells were maintained in 2% O2, there was only a modest induction of CYP19 expression as a function of time in culture, and aromatase activity was barely detectable. However, when cytotrophoblasts that had been maintained in 2% O2 for 3 days were placed in a 20% O2 environment, there was a rapid onset of cell fusion and induction of P450arom mRNA and aromatase activity. In addition, mRNAs for the helix-loop-helix factors Mash-2 (mammalian achaete-scute homologous protein-2) and Id1 (inhibitor of differentiation 1) were readily detectable in freshly isolated cytotrophoblasts and were markedly decreased upon differentiation to syncytiotrophoblast in 20% O2. By contrast, when cytotrophoblasts were cultured in 2% O2, mRNA levels for Mash-2 and Id1 remained elevated. Interestingly, overexpression of Mash-2 in primary cultures of human trophoblast cells markedly inhibited cell fusion and the spontaneous induction of P450arom mRNA levels and caused a marked decrease in expression of co-transfected fusion gene constructs containing either 125, 201, 246, or 501 bp of DNA flanking the 5'-end of the placenta-specific exon (exon I.1) of the human CYP19 gene linked to the human GH (hGH) structural gene, as reporter. In studies using BeWo, a human choriocarcinoma cell line, overexpression of Mash-2 also inhibited expression of cotransfected CYP19I.1:hGH fusion gene constructs. The findings that Mash-2 had no effect on the expression of a CYP19I.1(-42):hGH fusion gene in primary cultures of human trophoblast and BeWo cells suggest that Mash-2 exerts its inhibitory effects directly or indirectly though CYP19I.1 5'-flanking sequences that lie between -42 and -125 bp. By contrast, neither Id1 nor Id2 had an effect on CYP19I. 1 promoter activity in the transfected BeWo cells. These findings suggest that Mash-2 may serve as a hypoxia-induced transcription factor that prevents differentiation to syncytiotrophoblast and aromatase induction in human trophoblast cultured under low O2 conditions.
Mol Endocrinol 2000 Oct
PMID:Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription factor Mash-2 (mammalian achaete-scute homologous protein-2). 1104 80

Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C19 androgens to C18 estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin E2 (PGE2) increases intracellular cAMP levels and stimulates estrogen biosynthesis, and our recent studies have shown a strong linear association between CYP19 expression and the sum of COX-1 and COX-2 expression in breast cancer specimens. PGE2 can bind to four receptor subtypes, EP1-EP4, which are coupled to different intracellular signaling pathways. In primary human breast stromal cell cultures, aromatase activity was significantly induced by PGE2, dexamethasone, and agonists for the EP1 and EP2 receptor subtypes. An EP1 antagonist, SC-19220, inhibited the induction of enzyme activity by PGE2 or 17-phenyltrinor-PGE2, an EP1 agonist. Sulprostone, an EP3 agonist, did not alter aromatase activity levels. Investigations are also underway on the regulation of aromatase by exogenous medicinal agents. Selective steroidal and nonsteroidal agents are effective in inhibiting breast tissue aromatase. The benzopyranone ring system is a molecular scaffold of considerable interest, and this scaffold is found in certain flavonoid natural products that have weak aromatase inhibitory activity. Our novel synthetic route for benzopyranones utilizes readily available salicylic acids and terminal alkynes as starting materials. The synthesis of flavones with diversity on the benzopyranone moiety and at the C-2 position occurs with good to excellent yields using these reaction conditions, resulting in an initial benzopyranone library of thirty compounds exhibiting enhanced and differential aromatase inhibition. Current medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents. 1185 Feb 10

Expression of the human CYP19 gene in placental syncytiotrophoblast, ovarian granulosa and luteal cells and adipose stromal cells is regulated by tissue-specific promoters which lie upstream of unique untranslated first exons. In placenta, the majority of CYP19 mRNA transcripts contain 5'-sequences encoded by exon I.1 which lies >35 kb upstream of the translation initiation sequence in exon II. Mononuclear cytotrophoblasts isolated from midterm human placenta spontaneously fuse in culture to form multinucleated syncytiotrophoblast. These morphological changes are associated with a marked induction of CYP19 gene expression. To functionally define genomic regions required for placenta-specific expression, fusion genes containing various amounts of exon I.1 5'-flanking sequence linked to the human growth hormone (hGH) structural gene, as reporter, were introduced into human trophoblast cells in primary monolayer culture and into transgenic mice. Our findings using transfected cells and transgenic mice suggest that sequences between -501 and -42 bp upstream of exon I.1 contain a positive enhancer element(s) that mediates the actions of trophoblast-specific transcription factors, as well as a negative element(s) that binds inhibitory transcription factors in other cell types. Our findings from transgenic studies further indicate that mouse placenta contains the necessary transcription factors required to activate the human CYP19 promoter although mouse placenta does not express endogenous aromatase.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Identification of the regulatory regions of the human aromatase P450 (CYP19) gene involved in placenta-specific expression. 1185 Feb 22

In humans, the CYP19 (aromatase P450) gene is expressed in a number of tissues, including gonads, placenta, adipose tissue, skin and brain. The 5'-untranslated regions (UTR) of CYP19 mRNA transcripts in these tissues are encoded by different tissue-specific first exons, which are alternatively spliced onto a common site just upstream of the start of translation in exon II. In ovary, the 5'-UTR of CYP19 transcripts is encoded by exon IIa, which lies just upstream of exon II, while in adipose, the 5'-UTR of CYP19 transcripts is encoded by exon I.4, which lies >20 kb upstream of exon II. To map genomic sequences required for ovary- and adipose-specific CYP19 expression, fusion genes containing 2700, 278 and 43 bp of DNA flanking the 5'-end of ovary-specific exon IIa, or 348 bp of 5'- flanking DNA and 170 bp of adipose-specific exon I.4 were linked to the human growth hormone (hGH) gene, as reporter, and introduced into transgenic mice. We observed that CYP19(IIa):hGH fusion genes containing as little as 278 bp of exon IIa 5'-flanking sequence were expressed at high levels in an ovary-specific manner in transgenic mice, while the CYP19(IIa)(-43):hGH fusion gene was not expressed in any tissue. These results suggest that sequences between -43 and -278 bp upstream of exon IIa mediate ovary-specific CYP19 gene expression. In mice carrying the CYP19(I.4)(-348):hGH fusion gene, transgene expression was detected in skin and in mammary adipose, but not in any of the other tissues examined. These results indicate that genomic elements within -348 and +170bp of adipose-specific exon I.4 mediate adipose- and skin-specific CYP19 gene expression. Studies are in progress using transgenic mice to further define the response elements that mediate ovary and adipose-specific hCYP19 gene expression.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Tissue-specific expression of the human CYP19 (aromatase) gene in ovary and adipose tissue of transgenic mice. 1185 Feb 25

We investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line and also in human ovarian granulosa cells, using each selective ligand for retinoic acid receptor, RAR (TTNPB), retinoid X receptor, RXR (LG100268), PPARgamma (troglitazone), and vitamin D3 receptor (cholecalciferol). In MCF-7 cells, the combined treatment with TTNPB and LG100268 caused a dramatic stimulation of the aromatase activity. The combined treatment with other ligand and LG100268 had little or no effect on the aromatase activity. The increase in the aromatase activity by TTNPB plus LG100268 was accompanied by an increase in the P450arom mRNA levels, which was also found to be related to the specific usage of promoter 1a of the CYP19 gene. These results suggest that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells. In cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization, troglitazone or LG100268 alone decreased the aromatase activity, while the combined treatment caused an even greater reduction in this activity. Little effect of other specific ligands for RXR heterodimer partners may support the notion that the effects of troglitazone and/or LG100268 in human granulosa cells may be mediated through the specific activation of PPARgamma:RXR heterodimer system. Since similar manners of effects of several PPARgamma ligands and/or LG100268 on the aromatase activity were observed in a newly established human ovarian granulosa cancer cell line, KGN, we performed the detailed analysis of the mechanisms of these effects using this cell line. As a result, the inhibitory effect of aromatase activity by troglitazone plus LG100268 was accompanied by the decrease of P450arom mRNA level. Furthermore, the loss of P450arom expression was considered to be due to both the decreased transcription and rapid degradation of its RNA based on the studies of nuclear run-on assay and RNA stability assay. In conclusion, RAR:RXR and PPARgamma:RXR heterodimer nuclear receptor systems may be other important modulators of estrogen production in human breast cancer cells and ovarian granulosa cells, respectively.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Regulation of aromatase by nuclear receptors. 1185 Feb 24

In adult male primates, estrogens play a role in both gonadotropin feedback and sexual behavior. Inhibition of aromatization in intact male monkeys acutely elevates serum levels of luteinizing hormone, an effect mediated, at least partially, within the brain. High levels of aromatase (CYP19) are present in the monkey brain and regulated by androgens in regions thought to be involved in the central regulation of reproduction. Androgens regulate aromatase pretranslationally and androgen receptor activation is correlated with the induction of aromatase activity. Aromatase and androgen receptor mRNAs display both unique and overlapping distributions within the hypothalamus and limbic system suggesting that androgens and androgen-derived estrogens regulate complimentary and interacting genes within many neural networks. Long-term castrated monkeys, like men, exhibit an estrogen-dependent neural deficit that could be an underlying cause of the insensitivity to testosterone that develops in states of chronic androgen deficiency. Future studies of in situ estrogen formation in brain in the primate model are important for understanding the importance of aromatase not only for reproduction, but also for neural functions such as memory and cognition that appear to be modulated by estrogens.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance. 1185 Feb 31

Cytochrome P450arom, a key enzyme in the hormonal steroidogenic pathway, mediates the conversion of androgens to estrogens. This work describes the molecular cloning of the cDNA encoding the European sea bass (Dicentrarchus labrax L.) cytochrome P450arom by means of reverse transcriptase and polymerase chain reaction (RT-PCR) and 5' and 3'-rapid amplification of cDNA ends (RACE) analyses. The cDNA is 1822bp in length and encodes a putative protein of 517 amino acids. Northern blot analysis revealed that the ovary expressed a transcript of about 2.2kb in size. Analysis of the deduced amino acid sequence indicated 62-86% identity with ovarian P450arom of other teleost fish, the highest identity being found with the Japanese flounder, Paralichthys olivaceous. Identity was lower (56-65%) with the P450arom forms first reported in teleost brain. Only 52% identity was observed with the corresponding fragment of the cartilaginous fish, Dasyatis sabina. RT-PCR revealed that the sea bass P450arom mRNA was also expressed, at low levels, in testis and brain. Between the 5' and 3'-untranslated terminal regions (UTR), the sea bass CYP19 gene contains eight introns. All introns conform to the GT/AG rule for RNA splicing and are inserted in exactly the same positions as those found in Oryzias latipes and the human CYP19 gene.
J Steroid Biochem Mol Biol 2002 Jan
PMID:European sea bass (Dicentrarchus labrax L.) cytochrome P450arom: cDNA cloning, expression and genomic organization. 1186 61

Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C(19) androgens to C(18) estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin PGE(2) increases intracellular cAMP levels and stimulates estrogen biosynthesis, and our recent studies have shown a strong linear association between CYP19 expression and the sum of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression in breast cancer specimens. Knowledge of the signaling pathways that regulate the expression and enzyme activity of aromatase and cyclooxygenases (COXs) in stromal and epithelial breast cells will aid in understanding the interrelationships of these two enzyme systems and potentially identify novel targets for regulation. The effects of epidermal growth factor (EGF), transforming growth factor-beta (TGFbeta), and tetradecanoyl phorbol acetate (TPA) on aromatase and COXs were studied in primary cultures of normal human adipose stromal cells and in cell cultures of normal immortalized human breast epithelial cells MCF-10F, estrogen-responsive human breast cancer cells MCF-7, and estrogen-unresponsive human breast cancer cells MDA-MB-231. Levels of the constitutive COX isozyme, COX-1, were not altered by the various treatments in the cell systems studied. In breast adenocarcinoma cells, EGF and TGFbeta did not alter COX-2 levels at 24h, while TPA induced COX-2 levels by 75% in MDA-MB-231 cells. EGF and TPA in MCF-7 cells significantly increased aromatase activity while TGFbeta did not. In contrast to MCF-7 cells, TGFbeta and TPA significantly increased activity in MDA-MB-231 cells, while only a modest increase with EGF was observed. Untreated normal adipose stromal cells exhibited high basal levels of COX-1 but low to undetectable levels of COX-2. A dramatic induction of COX-2 was observed in the adipose stromal cells by EGF, TGFbeta, and TPA. Aromatase enzyme activity in normal adipose stromal cells was significantly increased by EGF, TGFbeta and TPA after 24h of treatment. In summary, the results of this investigation on the effects of several paracrine and/or autocrine signaling pathways in the regulation of expression of aromatase, COX-1, and COX-2 in breast cells has identified more complex relationships. Overall, elevated levels of these factors in the breast cancer tissue microenvironment can result in increased aromatase activity (and subsequent increased estrogen biosynthesis) via autocrine mechanisms in breast epithelial cells and via paracrine mechanisms in breast stromal cells. Furthermore, increased secretion of prostaglandins such as PGE(2) from constitutive COX-1 and inducible COX-2 isozymes present in epithelial and stromal cell compartments will result in both autocrine and paracrine actions to increase aromatase expression in the tissues.
J Steroid Biochem Mol Biol 2002 Feb
PMID:Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells. 1189 4


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