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

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) by converting active glucocorticoid to an inactive metabolite confers specificity upon the mineralocorticoid receptor (MR) and regulates ligand access to the glucocorticoid receptor (GR). Factors which influence 11 beta-HSD activity seem likely to be of considerable importance in the modulation of both mineralocorticoid and glucocorticoid hormone action. The administration of tri-iodothyronine (T3) to rats has previously been shown to reduce 11 beta-HSD activity in liver but not in kidney. We have studied the effect of T3 on 11 beta-HSD gene expression in vivo in rat liver, kidney, distal colon and pituitary. In addition the effects of T3 on 11 beta-HSD gene expression in vitro in the rat pituitary GH3 cell line have been studied. T3 administration to normal adult rats (40 micrograms/day, s.c. for 1, 3 and 7 days) resulted in a marked decline in liver and pituitary 11 beta-HSD mRNA levels and activity following 3 and 7 days of treatment. These reduced levels were maintained for 3 days following withdrawal of T3 treatment, but returned to control levels after 7 days. In contrast 11 beta-HSD mRNA and activity in kidney and distal colon were unaffected by T3 treatment at each time point studied. In vitro, levels of 11 beta-HSD mRNA and activity in GH3 cells were unchanged following 8, 24 and 72 h treatment with T3 (10(-8) to 10(-6) M). T3 bio-activity was confirmed by a marked dose-dependent decline in the expression of the T3 and glucocorticoid responsive gene, prolactin. T3 inhibits 11 beta-HSD gene expression in both liver and pituitary at a pre-translational level. This effect is absent in the predominantly mineralocorticoid target tissues, kidney and distal colon, i.e. it is tissue specific and as such is consistent with the existence of multiple differentially regulated isoforms of 11 beta-HSD. The time course of the T3 effect in liver and pituitary in vivo and the lack of any effect in vitro suggests that this action is indirect, and not as a result of interaction between the T3 receptor and the putative thyroid hormone response element on the rat 11 beta-HSD gene.
J Steroid Biochem Mol Biol 1993 Nov
PMID:Tissue specific effects of thyroid hormone on 11 beta-hydroxysteroid dehydrogenase gene expression. 824 Sep 75

Previous studies have revealed that human breast fibroblasts secrete the cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF-7 human breast carcinoma cells to convert estrone (E1) to the biologically more active 17 beta-estradiol (E2). This is mediated by an increase in reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity. In the studies described here, we have extended our observations using the anti-estrogen, tamoxifen, to demonstrate that in a steady state, endogenous intracellular concentrations of E2 have no effects on reductive 17-HSD activity (E1-->E2), but are already maximally inhibitory for the oxidative reaction (E2-->E1). Increasing intracellular concentrations of E2, however, stimulated the reductive 17-HSD in a dose-dependent manner. IL-6 stimulated the reductive pathway and was synergistic with E2. IL-6 is most likely acting through an E2-dependent mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observations suggest that tamoxifen may reduce intratissular levels of E2 by directly increasing oxidative 17-HSD activity and by blocking the actions of paracrine factors such as IL-6 which increase reductive 17-HSD activity.
J Steroid Biochem Mol Biol 1993 Nov
PMID:The anti-estrogen tamoxifen blocks the stimulatory effects of interleukin-6 on 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. 824 Sep 83

The essential amino acids lysine and threonine are synthesized in higher plants by two separate branches of a common pathway. This pathway is primarily regulated by three key enzymes, namely aspartate kinase (AK), dihydrodipicolinate synthase (DHPS) and homoserine dehydrogenase (HSD), but how these enzymes operate in concert is as yet unknown. Addressing this issue, we have expressed in transgenic tobacco plants high levels of bacterial AK and DHPS, which are much less sensitive to feedback inhibition by lysine and threonine than their plant counterparts. Such expression of the bacterial DHPS by itself resulted in a substantial overproduction of lysine, whereas plants expressing only the bacterial AK overproduced threonine. When both bacterial enzymes were expressed in the same plant, the level of free lysine exceeded by far the level obtained by the bacterial DHPS alone. This increase, however, was accompanied by a significant reduction in threonine accumulation compared to plants expressing the bacterial AK alone. Our results suggested that in tobacco plants the synthesis of both lysine and threonine is under a concerted regulation exerted by AK, DHPS, and possibly also by HSD. We propose that the balance between lysine and threonine synthesis is determined by competition between DHPS and HSD on limiting amounts of their common substrate 3-aspartic semialdehyde, whose level, in turn, is determined primarily by the activity of AK. The potential of this molecular approach to increase the nutritional quality of plants is discussed.
Plant Mol Biol 1993 Nov
PMID:Concerted regulation of lysine and threonine synthesis in tobacco plants expressing bacterial feedback-insensitive aspartate kinase and dihydrodipicolinate synthase. 825 29

3 beta-Hydroxysteroid dehydrogenase (3 beta HSD) in human placenta converts 3 beta-hydroxy-5-ene steroids producing progesterone, whereas 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) mediates the interconversion of estrone and estradiol. We first showed that the expression of type I 17 beta HSD (17 beta HSD-I) gene was undetectable in human JEG-3 cells. We then studied the effects of cAMP- and protein kinase-C-dependent pathways on the expression of 3 beta HSD-I and 17 beta HSD-II genes using an analog of cAMP [8-(4-chlorophenylthio)cAMP (8CPTcAMP)] and a protein kinase-C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), in JEG-3 cells. Novel inhibitors of protein kinase-A (PKA) and PKC were also used. The 3 beta HSD cDNA probe hybridized to a single 1.7-kilobase (kb) 3 beta HSD mRNA species corresponding to the transcript of the 3 beta HSD-I gene. The 17 beta HSD cDNA probe hybridized to two 17 beta HSD transcripts of 1.3 and 2.2 kb. The 1.3-kb 17 beta HSD mRNA species was regulated, whereas the 2.2-kb species was constitutively expressed in JEG-3 cells. When JEG-3 cells were exposed to 8CPTcAMP or PMA, 3 beta HSD-I and 17 beta HSD-II gene transcriptions were increased in a dose- and time-dependent manner. Moreover, the combined effects of PMA and 8CPTcAMP on 3 beta HSD-I mRNA levels was additive and synergistic on 17 beta HSD-II mRNA levels. The mechanism by which cAMP activated accumulation of 3 beta HSD-I and 17 beta HSD-II mRNAs involved an activation of the cyclase. The effects of a cAMP-dependent kinase inhibitor and a diacylglycerol-dependent kinase inhibitor in JEG-3 cells indicated that cAMP acts on 3 beta HSD-I mRNA via a PKA-dependent mechanism, but on 17 beta HSD-II mRNA via another nonclassical cAMP-dependent mechanism. Finally, the effect of activation of both signaling pathways on expression of the 17 beta HSD-II gene as well as the effect of PMA on the 3 beta HSD-I gene did not require protein synthesis. These data provide strong evidence for the regulation of the 3 beta HSD-I and 17 beta HSD-II genes by cAMP and PKC and, thus, indicate an important endocrine and/or paracrine regulation of steroid hormone production in human placenta.
Mol Endocrinol 1993 Mar
PMID:Regulation of 3 beta-hydroxysteroid dehydrogenase and 17 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels by cyclic adenosine 3',5'-monophosphate and phorbol myristate acetate in human choriocarcinoma cells. 838 58

The human estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II) gene has been assigned by somatic cell hybridization to chromosome 17q11-q21, near the region of assignment of the gene BRCA1, which is involved in hereditary breast-ovarian cancer. The nucleotide sequence of 17 beta-HSD II was completely determined in four unrelated individuals. Direct sequencing of PCR fragments that span the complete 17 beta-HSD II gene revealed a total of 11 allelic variants which were due to single base substitutions. The presence of these variants was then studied in twenty six additional unrelated individuals. There were nine frequent and two rare polymorphisms. Seven of the 11 polymorphisms were in complete linkage disequilibrium. These polymorphisms in the 17 beta-HSD II gene provide markers that can be used for the genetic mapping of this locus, and may be used to establish whether 17 beta-HSD II is a candidate gene for hereditary breast-ovarian cancer.
Hum Mol Genet 1993 Apr
PMID:Detection of polymorphisms in the estradiol 17 beta-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21. 838 26

It has been demonstrated that reductive 17 beta-hydroxysteroid dehydrogenase activity (17-HSD) in the human breast cancer cell line MCF-7 can be stimulated by 17 beta-estradiol (E2), progesterone (P) and interleukin-6 (IL-6). We have examined the interactive effects of these factors on growth and reductive 17-HSD activity of MCF-7 cells cultured under defined conditions in phenol red-free medium. E2 stimulated growth of MCF-7 cells in a dose-dependent manner, while IL-6 had a growth inhibitory effect and in combination with E2, it reduced or abolished the stimulatory effects of the steroid. Both E2 and IL-6 stimulated 17-HSD activity by a maximum of 2- to 5-fold, but, in combination, the stimulatory effects ranged from 7- to 10-fold, indicating a strong synergism between the 2 factors. P had growth stimulatory effects on MCF-7, but when combined with IL-6 had no further positive or negative growth effects. Both factors stimulated reductive 17-HSD activity and simultaneous treatment with P and IL-6 indicated a synergy between the 2 factors. These results provide evidence of powerful interactive effects between steroidal and paracrine control of human breast epithelial cells in vitro.
J Steroid Biochem Mol Biol 1993 Jul
PMID:Interactive effects of interleukin-6, 17 beta-estradiol and progesterone on growth and 17 beta-hydroxysteroid dehydrogenase activity in human breast carcinoma cells. 839 37

A susceptibility gene for hereditary breast-ovarian cancer, BRCA1, has been assigned by linkage analysis to chromosome 17q21. Candidate genes in this region include EDH17B2, which encodes estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II), and RARA, the gene for retinoic acid receptor alpha. We have typed 22 breast and breast-ovarian cancer families with eight polymorphisms from the chromosome 17q12-21 region, including two in the EDH17B2 gene. Genetic recombination with the breast cancer trait excludes RARA from further consideration as a candidate gene for BRCA1. Both BRCA1 and EDH17B2 map to a 6 cM interval (between THRA1 and D17S579) and no recombination was observed between the two genes. However, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in four unrelated affected women did not uncover any sequence variation, other than previously described polymorphisms. Mutations in the EDH17B2 gene, therefore do not appear to be responsible for the hereditary breast-ovarian cancer syndrome. Single meiotic crossovers in affected women suggest that BRCA1 is flanked by the loci RARA and D17S78.
Hum Mol Genet 1993 Aug
PMID:Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. 840 1

An abundant 37-kDa protein, which comprises up to 30% of the soluble proteins of the ovary, has been found to have 20 alpha-hydroxysteroid dehydrogenase (20 alpha HSD) activity. The steroidogenic enzyme 20 alpha HSD regulates the conversion of progesterone to 20 alpha-hydroxyprogesterone in many mammalian species. Complimentary DNA clones encoding a unique and abundant 20 alpha HSD were isolated from a mature rabbit ovary library using guinea pig antisera generated to the purified 37-kDa protein and from a 5' EcoRI fragment from the initial positive clone. A full-length cDNA clone of 1217 basepairs encoding a 323-amino acid protein with an estimated mol wt of 37 kilodaltons was obtained. Amino acid sequence data indicate a similarity to human chlordecone reductase, bovine lung prostaglandin F synthase, human aldose reductase, human aldehyde reductase, and frog lens rho-crystallin, placing rabbit ovarian 20 alpha HSD in the aldo-keto reductase family of proteins. Northern blot analysis demonstrated a 1.2-kilobase mRNA in the interstitial tissue of mature rabbit ovaries and, to a lesser extent, in corpora luteal tissue. 20 alpha HSD was expressed in bacteria as a recombinant protein and was shown to possess enzymatic activity, preferring NADP as a cofactor. These studies demonstrate that an abundant ovarian protein belonging to the superfamily of NADP-dependent aldo-keto reductases has 20 alpha HSD activity. This is the first example of an abundant crystallin-related protein with known enzymatic activity in a tissue other than the lens.
Mol Endocrinol 1993 Jan
PMID:Molecular cloning and expression of an abundant rabbit ovarian protein with 20 alpha-hydroxysteroid dehydrogenase activity. 824 25

In this review, we consider the relationship between the structure and function of 11 beta-hydroxysteroid dehydrogenase (11-HSD) purified from rat liver. The rat liver enzyme is a single domain glycoprotein with a unique active site and belongs to the short chain alcohol dehydrogenase family. Evidence supporting the presence in other tissues of 11-HSD isoforms is discussed.
J Steroid Biochem Mol Biol 1993 Apr
PMID:The forms and functions of 11 beta-hydroxysteroid dehydrogenase. 848 41

In vitro conversion in human endometrial tissue of Org OD 14 [17 alpha-hydroxy-7 alpha-methyl-19-norpregn-5(10)-en-20-yn-3-one, a 3-keto-delta 5-10-19-nortestosterone derivative structurally related to norethynodrel] to its 4-ene isomer was demonstrated and measured spectrophotometrically and by chromatographic separation of the labeled metabolite from the tritiated precursor. The endometrial isomerase catalyzing this conversion is the 3 beta-hydroxy-steroid dehydrogenase/isomerase (3 beta HSD/isomerase), detected by Western blotting as a 42 kDa band, as confirmed by the inhibition of Org OD 14 isomerization with an antibody against this enzyme. The endometrial isomerase activity was found to be higher in secretory than in proliferative tissue and to be influenced by progestins, as suggested by the small but significant increase in activity resulting from exposure of proliferative endometrium to medroxyprogesterone acetate under organotypic culture conditions. In addition to the expected physiologic importance of endometrial 3 beta HSD/isomerase in the local metabolism of circulating steroids of adrenal origin, its presence in the endometrium is likely to have pharmacologic relevance, as illustrated by the local conversion of Org OD 14 to the 4-ene isomer, a metabolite with higher progestagenic and lower estrogenic potencies than those of its precursor. The local, tissue-specific, modification of the precursor would yield intracellular concentration ratios of Org OD 14 to 4-ene isomer in the endometrium significantly lower than those in blood. As a result, the estrogenic effects of Org OD 14 or of its 3-hydroxy metabolites on endometrial cell proliferation are minimized by the local formation of the progestagenic 4-ene isomer. This is a favorable feature of Org OD 14 since it selectively prevents undesirable proliferative stimulation of the endometrium in postmenopausal users while preserving its beneficial effects on other tissues, including bone.
J Steroid Biochem Mol Biol 1993 May
PMID:Human endometrial 3 beta-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). 849 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>