Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens are synthesized from C19 steroids by a unique form of cytochrome P450, aromatase cytochrome P-450 (P-450AROM; the product of the CYP19 gene). We have shown that tissue-specific expression of human P-450AROM is determined, in part, by the use of alternative promoters. Previous methods of analysis for determining the specific 5'-termini of the different transcripts included S1 nuclease protection, primer extension, and Northern analysis. In the present study we have used the RACE procedure (rapid amplification of cDNA ends) to amplify and clone the 5' termini of P-450AROM transcripts expressed in human corpus luteum (CL). Sequencing of the resulting clones supports the results of the previously performed studies. Specifically, the proximal promoter, PII, is the predominant promoter utilized in CL, such that the start of transcription occurs 26 bp downstream of the putative TATA sequence. A minority of the clones possess an alternative 5'-end, namely I.3. Exon-specific Northern analysis confirms that the majority of the P-450AROM transcripts in CL tissue contain sequence specific for promoter II. Similarly, exon-specific Northern analysis indicates that transcripts in human follicles, as well as granulosa cells in culture, contain primarily sequence specific for promoter II.
Mol Cell Endocrinol 1993 Nov
PMID:Exon-specific northern analysis and rapid amplification of cDNA ends (RACE) reveal that the proximal promoter II (PII) is responsible for aromatase cytochrome P450 (CYP19) expression in human ovary. 814 90

Prolactin (PRL) gene expression is regulated through a complex network of signal transduction pathways activated by various hormones and growth factors. Estrogens regulate PRL gene transcription in vivo through both direct and indirect, protein synthesis-dependent, mechanisms. Therefore, we hypothesized that other stimulators of PRL gene transcription might also act via protein synthesis-dependent mechanisms. To test this hypothesis, we examined, in GH4C1 rat pituitary tumor cells, the effects of protein synthesis inhibitors on the induction of PRL mRNA by known stimulators of PRL gene transcription. Whereas induction by epidermal growth factor (EGF) was abolished by cycloheximide and puromycin, increases in PRL mRNA caused by thyrotropin releasing hormone, 12-O-tetradecanoylphorbol 13-acetate, forskolin, or dibutyryl cyclic AMP were unaffected. These data suggest that the induction of PRL mRNA by EGF may require the induced synthesis of an intermediary regulatory protein.
Mol Cell Endocrinol 1993 Apr
PMID:Epidermal growth factor induces prolactin mRNA in GH4C1 cells via a protein synthesis-dependent pathway. 839 91

Estrogens are considered to act as promoters in a multistep process of hormonal carcinogenesis, although the molecular mechanisms by which these hormones act in tumorigenesis are unclear at present. Estradiol is known to induce expression of certain proto-oncogenes, and this led us to examine potential regulatory regions of the cellular c-fos oncogene. The 5'-flanking region of the murine c-fos contains a 13-bp palindromic sequence (GGTCTnnnAGACC) with striking homology to the consensus estrogen-responsive element (ERE) GGTCAnnnTGACC. However, the c-fos sequence did not bind the human estrogen receptor or confer hormonal responsiveness in a yeast-based transcriptional test system. Importantly, a single base change in the fifth position of the c-fos sequence (GGTCTnnnAGACC to GGTCA/GnnnAGACC) produced an element that bound the estrogen receptor and conferred estrogen-dependent transcriptional activation of a reporter gene. This suggests a specific hypothesis by which estrogens could act as tumor promoters. In this paradigm, the regulatory region of the cellular oncogenes, tumor suppressor genes, and growth-factor genes contain inactive sequences with close homologies to hormone-responsive elements. Initiation occurs when some agent (e.g., a chemical carcinogen) causes a mutation in such a sequence to create a functional hormone-responsive element. Estrogens, acting through their receptors and the mutated element, can then activate the target gene to stimulate cell proliferation and increase the population of initiated cells.
Mol Carcinog 1993
PMID:Creation of an active estrogen-responsive element by a single base change in the flanking sequence of a cellular oncogene: a possible mechanism for hormonal carcinogenesis? 845 91

Estrogens are required for both the organization of the brain in early development and adult behavior. Two approaches have been used in our laboratory to study the behavioral role of brain aromatase. First, brain metabolism of testosterone (T) has been related to behavior in the same individual using a well established neuroendocrine model, the ring dove, in which estradiol-17 beta (E2) has specific effects on brain mechanisms of male behavior. Aromatase in preoptic area (POA) (a) has a high activity (Vmax) and strong substrate binding affinity (Km < 5 nM), (b) is regulated by both androgens and estrogens, and the type of regulation differs according to brain area, (c) is influenced by products of an endogenous inactivating pathway, 5 beta-reduction; 5 beta-dihydrotestosterone and other 5 beta-reduced metabolites appear to be non-genomic regulators of the brain aromatase. Preoptic aromatase activity is also influenced by photoperiod and socio-sexual stimuli. The codistribution of regulated aromatase activity and estrogen receptor cells is found to be T-dependent. Our second approach has been to relate the aromatase system to developmental sex differences in brain structure and behavior of the Mongolian gerbil. Neonatal gerbil aromatase is relatively active in the POA, but has a weaker T substrate-binding affinity (Km = 30 nM) than the dove. T acting via its metabolite, E2, masculinizes the sexually dimorphic area of the hypothalamus; the differentiating effect is asymmetric. We suggest that the regulation of the brain aromatase system may be lateralized during steroid-sensitive periods of development.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Aromatase: neuromodulator in the control of behavior. 847 65

The effects of the constant infusion with mini-osmotic pumps of several steroid hormones on body weight, energy balance and protein/lipid/water composition in young female rats has been studied for a period of 15 days. Despite unchanged food consumption, progesterone strongly induced fat deposition, with higher protein accrual efficiency coupled with lowered energy losses through thermogenesis. Estrogens lowered body weight but maintained higher protein levels and protein accrual rates; beta-estradiol induced the loss of lipid and diminished food intake. Heat production was unchanged or lower in all estrogen-treated animals; beta-estradiol had a more marked effect on body weight (through food intake, heat production and lipid mobilization/storage combined) than estrone. Testosterone and 5-androstenediol increased the proportion of protein, but none of them had a significant effect on lipid deposition or heat production. Nortestosterone, increased energy expenditure, fuelled in part by a higher food ingestion, a trait shared by 4-androstenedione, but not by the other androgens. The effect of androgens on body weight may thus be a combination of their actions on a) food intake, b) efficiency of protein deposition and c) activation of heat production or of lipid (energy) storage. Practically all increased the efficiency of protein deposition. Nortestosterone increased heat production. Androstenedione increased lipid storage. Dehydroepiandrosterone did not decrease body weight or metabolic rate. Cortisol depressed heat production and food intake, with a net loss of weight. Cortisol and cortisone did not increase protein deposition, but corticosterone did; deoxycorticosterone showed a high efficiency of protein deposition and increased the size of fat stores, also increasing the metabolic rate by a mean 26% versus controls, compared with a reduction of about the same magnitude induced by cortisol. The data presented suggest that cortisol-cortisone and corticosterone may represent two distinct groups of glucocorticoids.
Biochem Mol Biol Int 1993 Feb
PMID:Effect of chronic intravenous injection of steroid hormones on body weight and composition of female rats. 849 17

Estrogens regulate the in vivo expression of the c-fos proto-oncogene in rat uterus, and this regulation appears to occur at the transcriptional level. This system thus provides the ability to study the in vivo effects of antiestrogens on specific gene expression in normal estrogen target tissue. Immature rats were treated with estradiol, tamoxifen, or other nonsteroidal antiestrogens, total uterine RNA was isolated, and c-fos transcript levels were monitored by blot analysis. Tamoxifen increases the 2.2-kilobase c-fos transcript approximately 20-fold in 6 hr. This effect is comparable in magnitude to that produced by estradiol, but the maximum response to the hormone occurs in 3 hr. c-fos induction is observed at doses of 0.1-10 mg/kg tamoxifen. The nonsteroidal antiestrogens nafoxidine, Cl-628, and 4-hydroxytamoxifen also induce c-fos expression. The induction of c-fos by both estradiol and tamoxifen is blocked by the progestin medroxyprogesterone acetate. In addition to effects on c-fos mRNA, tamoxifen also increases uterine levels of c-jun, jun-B, and c-myc mRNAs. These results indicate that tamoxifen acts in vivo as an estrogen agonist for activating expression of cellular oncogenes in normal uterine tissue.
Mol Pharmacol 1993 May
PMID:Tamoxifen stimulates expression of the c-fos proto-oncogene in rodent uterus. 850 28

The enzyme aromatase converts testosterone (T) into 17 beta-estradiol and plays a pivotal role in the control of reproduction. In particular, the aromatase activity (AA) located in the preoptic area (POA) of male Japanese quail is a limiting step in the activation by T of copulatory behavior. Aromatase-immunoreactive (ARO-ir) cells of the POA are specifically localized within the cytoarchitectonic boundaries of the medial preoptic nucleus(POM), a sexually dimorphic and steroid-sensitive structure that is a necessary and sufficient site of steroid action in the activation of behavior. Stereotaxic implantation of aromatase inhibitors in but not around the POM strongly decreases the behavioral effects of a systemic treatment with T of castrated males. AA is decreased by castration and increased by aromatizable androgens and by estrogens. These changes have been independently documented at three levels of analysis: the enzymatic activity measured by radioenzymatic assays in vitro, the enzyme concentration evaluated semi-quantitatively by immunocytochemistry and the concentration of its messenger RNA quantified by reverse transcription-polymerase chain reaction (RT-PCR). These studies demonstrate that T acting mostly through its estrogenic metabolites regulates brain aromatase by acting essentially at the transcriptional level. Estrogens produced by central aromatization of T therefore have two independent roles: they activate male copulatory behavior and they regulate the synthesis of aromatase. Double label immunocytochemical studies demonstrate that estrogen receptors(ER) are found in all brain areas containing ARO-ir cells but the extent to which these markers are colocalized varies from one brain region to the other. More than 70% of ARO-ir cells contain detectable ER in the tuberal hypothalamus but less than 20% of the cells display this colocalization in the POA. This absence of ER in ARO-ir cells is also observed in the POA of the rat brain. This suggests that locally formed estrogens cannot control the behavior and the aromatase synthesis in an autocrine fashion in the cells where they were formed. Multi-neuronal networks need therefore to be considered. The behavioral activation could result from the action of estrogens in ER-positive cells located in the vicinity of the ARO-ir cells where they were produced (paracrine action). Alternatively, actions that do not involve the nuclear ER could be important. Immunocytochemical studies at the electron microscope level and biochemical assays of AA in purified synaptosomes indicate the presence of aromatase in presynaptic boutons. Estrogens formed at this level could directly affect the pre-and post-synaptic membrane or could directly modulate neurotransmission namely through their metabolization into catecholestrogens (CE) which are known to be powerful inhibitors of the catechol- omicron - methyl transferase (COMT). The inhibition of COMT should increase the catecholaminergic transmission. It is significant to note, in this respect, that high levels of 2-hydroxylase activity, the enzyme that catalyzes the transformation of estrogens in CE, are found in all brain areas that contain aromatase. On the other hand, the synthesis of aromatase should also be controlled by estrogens in an indirect, transynaptic manner very reminiscent of the way in which steroids indirectly control the production of LHRH. Fibers that are immunoreactive for tyrosine hydroxylase (synthesis of dopamine), dopamine beta-hydroxylase (synthesis of norepinephrine) or vasotocine have been identified in the close vicinity of ARO-ir cells in the POM and retrograde tracing has identified the origin of the dopaminergic and noradrenergic innervation of these areas. A few preliminary physiological experiments suggest that these catecholaminergic inputs regulate AA and presumably synthesis.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Effects of testosterone and its metabolites on aromatase-immunoreactive cells in the quail brain: relationship with the activation of male reproductive behavior. 860 40

Estrogens have a pivotal role in the growth and development of hormone-dependent breast cancers. In postmenopausal women, the hydrolysis of the conjugate estrone sulphate (E1S) to estrone (E1) by the enzyme estrone sulphatase is the major source of breast tumour estrogen. Inhibitors of estrone sulphatase should therefore have considerable therapeutic potential for the treatment of hormone-dependent tumours of the breast, either as the sole agent or in conjunction with aromatase inhibitors. Several inhibitors of estrone sulphatase have now been developed of which estra-1,3,5(10)-trien-17-one-3-sulphamate (EMATE) is the most potent and also inhibits the enzyme in a time- and concentration-dependent manner, showing that it acts as an irreversible inhibitor. Analogues of EMATE in which the 3-O-atom is replaced by other heteroatoms (S and N) were synthesized and tested for inhibition against estrone sulphatase. 4-Methoxyphenylsulphamide (1), 4-chlorothiophenyl-S-(N,N-dimethyl)sulphamate (2), estra-1,3,5(10)-trien-17-one-3-sulphamide (3), estra-1,3,5(10)-trien-17-one-3-S-sulphamate (4) and estra-1,3,5(10)-trien-17-one-3-S-(N,N-dimethyl)sulphamate (5) were found to inhibit estrone sulphatase weakly, but none of these compounds appears to behave as a time-dependent inhibitor. A model of the mechanism of enzyme inhibition by EMATE is proposed and we conclude that the sulphamate bridging oxygen atom of EMATE is essential for active site-directed inhibition of estrone sulphatase.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Heteroatom-substituted analogues of the active-site directed inhibitor estra-1,3,5(10)-trien-17-one-3-sulphamate inhibit estrone sulphatase by a different mechanism. 864 20

Estrogens play an important role in breast cancer and the effect of estrogen on growth of breast cancer cells has been extensively studied. However, only little information is available about the response of normal breast epithelial cells to estrogen, mainly due to the difficulties in establishing estrogen receptor (ER)-positive human breast epithelial cells in culture. We have stably transfected the human estrogen receptor (hER) wt cDNA into the ER-negative, spontaneously immortalized human breast epithelial cell line, HMT-3522S1, in order to develop a model for studying the effect of estrogen on nonmalignant human breast epithelial cells. Characterization of the transfected clone F9 confirmed incorporation of the estrogen receptor gene in the genome, expression of hER mRNA and hER protein. However, proliferation of F9 cells was inhibited by both estradiol (E2) and tamoxifen, whereas the pure antiestrogen ICI 182,780 had no effect on cell proliferation. This seems paradoxical since E2 stimulated the expression of the endogenous genes, TGF-alpha, cathepsin D, and alpha1-antitrypsin. In breast cancer cell lines, high expression of these genes is correlated to estrogen-stimulated cell proliferation. The spontaneously immortalized HMT-3522S1 cells transfected with wt ER cDNA behave similarly to cell lines from nonmalignant breast tissue immortalized by carcinogens and transfected with mutated ER cDNA as described by others. The discrepancy between growth inhibition and induction of positive growth factors by E2 indicates that either ER-positive nonmalignant breast epithelial cells are growth-inhibited by E2 in contrast to malignant cells or that introduction of the ER into ER-negative cells is not sufficient for restoring "normal' estrogen responsiveness.
Mol Cell Endocrinol 1996 May 17
PMID:Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor (ER) cDNA. 879 53

Retinoids modulate gene activity, cell growth and differentiation by binding to a series of nuclear receptors, i.e., retinoic acid receptors (RARs) or retinoid X receptors. Retinoic acid (RA) inhibition of estrogen receptor (ER)-positive breast carcinoma seems to be mediated through RAR alpha. Estrogens upregulate RAR alpha in ER-positive breast carcinoma cell lines. In this study we examined RAR alpha expression in the ER-positive MCF7 and ER-negative MDA-MB-231 human breast carcinoma cell lines as well as in 10 ER-negative and 9 ER-positive infiltrating ductal breast carcinoma specimens using immunohistochemistry and quantitation by image cytometry. MCF7 cells expressed twofold higher levels of RAR alpha protein than MDA-MB-231 cells. RAR alpha expression, as detected by immunostaining and quantitated by image cytometry, was upregulated in these cells by estradiol. ER-positive breast carcinoma specimens also exhibited approximately two-fold higher RAR alpha levels than their ER-negative counterparts. Thus, RAR alpha expression is significantly elevated in ER-positive breast tumors as assessed by detection and quantitation using immunohistochemical staining and image cytometry, respectively. Whether the decrease in RAR alpha protein levels and loss of RA-mediated growth inhibition in ER-negative tumor plays a role in the increased metastatic potential of ER-negative tumors remains to be determined.
Diagn Mol Pathol 1997 Feb
PMID:Elevated expression of retinoic acid receptor-alpha (RAR alpha) in estrogen-receptor-positive breast carcinomas as detected by immunohistochemistry. 902 36


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