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

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Query: EC:3.1.21.1 (DNase)
7,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear and cytoplasmic binding sites for estradiol (E2-17 beta) in granulosa cells of immature rats were characterized. These binding sites for estrogen were high affinity, low capacity with an affinity constant (Kd) of 1.9 X 10(-10)M (binding capacity, Ro = 80 pM) for nuclear sites and a Kd = 3.5 X 10(-10) M (Ro = 45 pM) for cytosol sites. Binding was specific for biologically active estrogens. The estrogen receptor in granulosa cells is a protein and heat-labile as treatment with protease or pre-incubation at 37 degrees C for 1 h significantly diminished binding. RNase and DNase had no effect on estrogen binding. Sedimentation coefficients for nuclear and cytosol binding components were 5S and 8S respectively, similar to values obtained with uteri. Finally, translocation was demonstrated after a s.c. injection of E2-17 beta. Forty-five minutes post-injection, cytosol binding sites for estradiol were depleted concomitant with accumulation of nuclear binding sites. We concluded that granulosa cells of immature rats have binding sites specific for estradiol which have characteristics similar to the classical estrogen receptor in uteri.
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PMID:Identification of estrogen receptors in granulosa cells of immature rats. 667 47

Cytosols of whole testicular homogenates from the Syrian golden hamster contained specific binding sites for [3H]triamcinolone acetonide that exhibited limited capacity and high affinity binding characteristic of glucocorticoid receptors in other target tissues. The receptor complex sedimented as an 8.6S binder in low salt 5-20% linear sucrose gradients and as 6.2S and 4.0S moieties in 0.15M and 0.4 M KCl, respectively. The Ka at equilibrium was 3.1-3.3 X 10(9) M-1 at 4 C in intact and adrenalectomized males. The testicular glucocorticoid binder was vulnerable to proteolytic degradation while being completely resistant to the action of RNase and DNase. In addition the binding protein exhibited the usual steroid specificities for type I glucocorticoid receptor: triamcinolone acetonide greater than dexamethasone greater than cortisol greater than corticosterone greater than progesterone greater than aldosterone greater than prednisone greater than 5 alpha-dihydrotestosterone greater than diethylstilbestrol. Unexpectedly, 17 beta-estradiol competed for receptor binding to the same extent as prednisone. A 3.2 S nuclear receptor was extracted from purified testicular nuclei after incubation of whole suspensions in culture media containing 5 nm radiolabeled triamcinolone acetonide at 32 C. Although the glucocorticoid receptor concentrations in prepubertal, adrenalectomized, and hypophysectomized animals were markedly higher in the testis compared to the concentration in the normal adult hamster (52 +/- 4 fmol/mg cytosol protein), the greatest total amount of receptor per testis was found in the mature intact animal. Moreover, under the conditions studied, the concentration of glucocorticoid receptor substantially exceeded the levels of either androgen or estrogen receptor when determined simultaneously. In contrast, no measurable cytoplasmic [3H]triamcinolone acetonide binding was detected in adjacent urogenital organs such as the epididymis and seminal vesicle. It is therefore unlikely that the testicular glucocorticoid receptor is associated with the spermatid or present as a secretory product in the seminiferous tubule lumen.
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PMID:Characterization of specific glucocorticoid receptor in the Syrian hamster testis. 729 80

Partial purification and characterization of a cytoplasmic component of cow uterus, which specifically binds with native "4S" estrogen receptor (ER) to give "8S" ER was carried out. The component was designated as "8S" ER-forming factor [("8S"ER)-FF]. ("8S"ER)-FF did not bind estradiol by itself. The Stokes radius of ("8S"ER)-FF was estimated to be approximately 51 A. ("8S"ER)-FF sedimented at around 6.9S in sucrose gradient centrifugation under hypotonic conditions. The molecular weight and frictional ratio of ("8S"ER)-FF were calculated to be 145,000 and 1.47, respectively. ("8S"ER)-FF was degraded by trypsin treatment, but was not affected by DNase or RNase. The Stokes radius of "8S" ER was estimated to be approximately 68 A. The molecular weight and frictional ratio of "8S" ER were calculated to be 225,000 and 1.69, respectively. "8S" ER was estimated to be a 1 : 1 complex between native "4S" ER and ("8S"ER)-FF. It was estimated that in the cow uterine cytosol, there was at least a 3-fold molar excess of ("8S"ER)-FF over the amount of "4S" ER. ("8S" ER)-FF inhibited both the Ca2+-dependent and -independent modifications of native "4S" ER by the cytoplasmic protease.
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PMID:Estrogen receptor of cow uterus. II. Characterization of a cytoplasmic factor which binds with native "4S" estrogen receptor to give "8S" estrogen receptor. 745 23

Cytosol from MTW9 rat mammary tumor contains a high molecular weight inhibitor of estrogen receptor binding to DNA. RNase treatment of crude preparations destroys inhibitory activity, whereas DNase or trypsin treatment are without affect, suggesting that some RNA molecule might be involved; in addition, RNA extracted from tumor cytosol was an effective inhibitor of estrogen receptor binding to DNA. A number of synthetic and natural RNA species were analyzed for inhibitory activity; a definite specificity was observed, with poly(G) > poly(U) > poly(A) or poly(C).
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PMID:RNA inhibits estrogen receptor binding to DNA. 745 96

Progesterone receptor gene expression is induced by estrogen in MCF-7 human breast cancer cells. Although it is generally thought that estrogen responsiveness is mediated through estrogen response elements (EREs), the progesterone receptor gene lacks an identifiable ERE. The progesterone receptor A promoter does, however, contain a half-ERE/Sp1 binding site comprised of an ERE half-site upstream of two Sp1 binding sites. We have used in vivo deoxyribonuclease I (DNase I) footprinting to demonstrate that the half-ERE/Sp1 binding site is more protected when MCF-7 cells are treated with estrogen than when cells are not exposed to hormone, suggesting that this region is involved in estrogen-regulated gene expression. The ability of the half-ERE/Sp1 binding site to confer estrogen responsiveness to a simple heterologous promoter was confirmed in transient cotransfection assays. In vitro DNase I footprinting and gel mobility shift assays demonstrated that Sp1 present in MCF-7 nuclear extracts and purified Sp1 protein bound to the two Sp1 sites and that the estrogen receptor enhanced Sp1 binding. In addition to its effects on Sp1 binding, the estrogen receptor also bound directly to the ERE half-site. Taken together, these findings suggest that the estrogen receptor and Sp1 play a role in activation of the human progesterone receptor A promoter.
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PMID:Sp1 binding sites and an estrogen response element half-site are involved in regulation of the human progesterone receptor A promoter. 1089 48

Antiestrogen resistance is frequently observed in patients after longterm treatment with tamoxifen, a nonsteroidal antiestrogen widely used for endocrine therapy of breast cancer. In vitro studies in resistant cells showed that the expression of natural estrogen-responsive genes is frequently altered. Using MVLN cells, an MCF-7-derived cell model, we previously demonstrated that 4-hydroxytamoxifen (OHT) treatment irreversibly inactivated an estrogen-regulated chimeric luciferase response by a direct effect of the drug and not through a cell selection process (E. Badia et al., Cancer Res., 54: 5860-5866, 1994). In the present study, we present tamoxifen-resistant but still estrogen-dependent clones isolated after long-term treatment of MVLN cells with OHT and show that progesterone receptor (PR) expression was irreversibly decreased in some of these clones, whereas the PRA:PRB ratio of residual PR remained unchanged. The irreversible inactivation of both chimeric luciferase gene and PR gene expression was associated with the disappearance of DNase 1-hypersensitive sites. In the case of the chimeric gene, at least one of these sites was close to the estrogen responsive element. Genomic sequencing analysis of a clone with very low PR content did not reveal any methylation on CpG dinucleotides or any mutation in the PR gene promoter region. In all of the resistant clones tested and independently of their PR content, estrogen receptor expression was only lowered by half and remained functional, whereas pS2 expression was not modified. We also observed that the residual luciferase activity level (1-2%) of the MVLN clones, the luciferase expression of which had been irreversibly inactivated, was raised 4-fold by trichostatin A treatment. We conclude that long-term OHT treatment may modify the chromatin structure and thus could contribute to differentially silencing natural target genes.
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PMID:Long-term hydroxytamoxifen treatment of an MCF-7-derived breast cancer cell line irreversibly inhibits the expression of estrogenic genes through chromatin remodeling. 1094 20

Estrogen-regulated gene expression is dependent on interaction of the estrogen receptor (ER) with the estrogen response element (ERE). We assessed the ability of the ER to activate transcription of reporter plasmids containing either the consensus vitellogenin A2 ERE or the imperfect pS2, vitellogenin B1, or oxytocin (OT) ERE. The A2 ERE was the most potent activator of transcription. The OT ERE was significantly more effective in activating transcription than either the pS2 or B1 ERE. In deoxyribonuclease I (DNase I) footprinting experiments, MCF-7 proteins protected A2 and OT EREs more effectively than the pS2 and B1 EREs. Limited protease digestion of the A2, pS2, B1, or OT ERE-bound receptor with V8 protease or proteinase K produced distinct cleavage products demonstrating that individual ERE sequences induce specific changes in ER conformation. Receptor interaction domains of glucocorticoid receptor interacting protein 1 and steroid receptor coactivator 1 bound effectively to the A2, pS2, B1, and OT ERE-bound receptor and significantly stabilized the receptor-DNA interaction. Similar levels of the full-length p160 protein amplified in breast cancer 1 were recruited from HeLa nuclear extracts by the A2, pS2, B1, and OT ERE-bound receptors. In contrast, significantly less transcriptional intermediary factor 2 was recruited by the B1 ERE-bound receptor than by the A2 ERE-bound receptor. These studies suggest that allosteric modulation of ER conformation by individual ERE sequences influences the recruitment of specific coactivator proteins and leads to differential expression of genes containing divergent ERE sequences.
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PMID:Allosteric modulation of estrogen receptor conformation by different estrogen response elements. 1143 12

The progesterone receptor (PR) gene is activated by estrogen in MCF-7 human breast cancer cells. Although the human PR gene does not contain an estrogen response element (ERE), we have identified a putative activating protein-1 (AP-1) site at +90 in the PR gene that was hypersensitive to deoxyribonuclease I cleavage in genomic Southern analysis, bound purified Fos and Jun, formed a complex with Fos/Jun heterodimers present in MCF-7 nuclear extracts in gel mobility shift assays, and functioned as an estrogen-responsive enhancer in transient cotransfection assays. When the +90 AP-1 site was mutated in the context of the PR gene, estrogen responsiveness was significantly decreased. Purified estrogen receptor (ER) enhanced binding of Fos and Jun to the +90 AP-1 site and bound to an adjacent imperfect ERE half-site. Mutating this ERE half-site diminished the binding of ER, Fos, and Jun and decreased transcription. Chromatin immunoprecipitation assays demonstrated that the ER, Fos, and Jun were present at the +90 AP-1 site in the endogenous PR gene only after treatment of MCF-7 cells with estrogen. These studies suggest that the cooperative interaction of the ER with Fos and Jun proteins helps confer estrogen responsiveness to the endogenous PR gene.
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PMID:Estrogen receptor alpha and activating protein-1 mediate estrogen responsiveness of the progesterone receptor gene in MCF-7 breast cancer cells. 1244 85

Interleukin-6 (IL-6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes the response to hormones and to chemotherapeutics. We explored transcription mechanisms involved in differential IL-6 gene expression in breast cancer cells with different metastatic properties. In weakly metastatic MCF7 cells, histone H3 K9 methylation, HP1 binding, and weak recruitment of AP-1 Fra-1/c-Jun, NF-kappaB p65 transcription factors, and coactivators is indicative of low chromatin accessibility and gene transcription at the IL-6 gene promoter. In highly metastatic MDA-MB231 cells, strong DNase, MNase, and restriction enzyme accessibility, as well potent constitutive transcription of the IL-6 gene promoter, coincide with increased H3 S10 K14 phosphoacetylation and promoter enrichment of AP-1 Fra-1/c-Jun and NF-kappaB p65 transcription factors and MSK1, CBP/p300, Brg1, and Ezh2 cofactors. Complementation, silencing, and kinase inhibitor experiments further demonstrate involvement of AP-1 Fra-1/c-Jun and NF-kappaB p65/RelB members, but not of the alpha estrogen receptor in promoting chromatin accessibility and transcription across the IL-6 gene promoter in metastatic breast cancer cells. Finally, the natural withanolide Withaferin A was found to repress IL-6 gene transcription in metastatic breast cancer cells upon dual inhibition of NF-kappaB and AP-1 Fra-1 transcription factors and silencing of IL-6 promoter chromatin accessibility.
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PMID:Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. 1968 1

Bisphenol A (BPA) is an environmental endocrine disruptor which has been detected in human bodies. Many studies have implied that BPA exposure is harmful to human health. Previous studies mainly focused on BPA effects on estrogen receptor (ER)-positive cells. Genome-wide impacts of BPA on gene expression in ER-negative cells is unclear. In this study, we performed RNA-seq to characterize BPA-induced cellular and molecular impacts on ER-negative HEK293 cells. The microscopic observation showed that low-dose BPA exposure did not affect cell viability and morphology. Gene expression profiling analysis identified a list of differentially expressed genes in response to BPA exposure in HEK293 cells. These genes were involved in variable important biological processes including ion transport, cysteine metabolic process, apoptosis, DNA damage repair, etc. Notably, BPA up-regulated the expression of ERCC5 encoding a DNA endonuclease for nucleotide-excision repair. Further electrochemical experiment showed that BPA induced significant DNA damage in ER-positive MCF-7 cells but not in ER-negative HEK293 cells. Collectively, our study revealed that ER-negative HEK293 cells employed mechanisms in response to BPA exposure different from ER-positive cells.
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PMID:Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells. 2490 Dec 18


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