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: DrugBank:BIOD00001 (DNase I)
8,324 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse mammary tumor virus (MMTV) promoter, that responds to glucocorticoids and progestins, contains a complex hormone response element (HRE) in the long terminal repeat (LTR) region covered by a phased nucleosome. Hormone treatment leads to alterations in chromatin structure that make the HRE region more accessible to digestion by DNase I and permit binding of transcription factors, including nuclear factor I (NFI), immediately downstream of the HRE. NFI acts as a basal transcription factor on the MMTV promoter in vitro but competes with the hormone receptors in terms of binding to free DNA. In uninduced chromatin, the precise positioning of the DNA double helix on the surface of the histone octamer precludes binding of NFI to its cognate sequence while still allowing recognition of the HRE by the hormone receptors. We postulate that receptor binding to the nucleosomally organized MMTV promoter disrupts the chromatin structure enabling NFI binding and subsequent formation of a stable transcription complex. Whether the receptor remains bound to DNA during induction or is displaced by NFI is not conclusively known, but our evidence supports a "hit and run" mechanism. NFI is not the only factor involved in hormonally induced transcription of the MMTV promoter. Two degenerated octamer motifs located immediately upstream of the TATA box are recognized by the ubiquitous transcription factor OTF-1 (Oct-1, NFIII), and are also important. In vitro, mutations in these motifs do not influence basal transcription, but completely abolish the stimulatory effect of purified progesterone receptor. Progesterone receptor bound to the HRE facilitates binding of OTF-1 to the two octamer motifs. Thus, OTF-1 is a natural mediator of progesterone induction of the MMTV promoter and acts through cooperation with the hormone receptor for binding to DNA.
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PMID:Interplay of steroid hormone receptors and transcription factors on the mouse mammary tumor virus promoter. 132 70

A DNA fragment containing glucocorticoid receptor binding sites in the mouse mammary tumor virus promoter was reconstituted in vitro with histones to form nucleosome cores, which become positioned on the DNA fragment in a sequence-specific manner. Glucocorticoid receptor binding to specific DNA sequences was analyzed by quantitative DNase I footprinting. The receptor interacted with surprisingly high affinity with one of the binding sites in the reconstituted promoter, although it was reduced by a factor of approximately 2 compared with the same site in protein-free DNA. By contrast, the affinity for random genomic nucleosomal sites was drastically reduced compared with histone-free DNA. Thus, reconstituting the promoter in vitro resulted in a 60- to 70-fold increase in binding specificity. Such an increase in selective binding may help to explain the ability of glucocorticoid receptor to effectively locate its target sites in chromatin.
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PMID:Glucocorticoid receptor DNA-binding specificity is increased by the organization of DNA in nucleosomes. 157 Mar 8

The mouse mammary tumor virus (MMTV) promoter is positively regulated by glucocorticoid hormone via binding of glucocorticoid receptor to a specific response element. Upon addition of hormone, a nucleosome containing the glucocorticoid response element is removed or structurally altered, suggesting that the nucleosome interferes with transcription. Accordingly, inhibition of chromatin assembly should relieve the repression and result in an increased constitutive activity. We have tested this hypothesis by injecting nonspecific competitor DNA into Xenopus laevis oocytes to titrate endogenous histones. The coinjection of competitor DNA altered chromatin structure: nucleosomal ladders produced by micrococcal nuclease were disrupted, and the unique helical setting of the MMTV promoter in a nucleosome was lost, as shown by in situ DNase I footprinting. Basal MMTV transcription was drastically increased by competitor DNA, whereas a coinjected, constitutively active adenovirus 2 major late promoter was not stimulated. These results show that the uninduced MMTV promoter is under negative control and provide direct support for the theory that the nucleosomal organization maintains the repression of this promoter in its uninduced state.
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PMID:Inhibition of chromatin assembly in Xenopus oocytes correlates with derepression of the mouse mammary tumor virus promoter. 165 27

The steroid hormone-inducible promoter from mouse mammary tumor virus is associated with a distal negative regulatory element that represses its inherent basal activity. Deletion analysis localized the sequences required for repression to 64 base pairs of DNA between -427 and -364 with respect to the transcription initiation site. Transient transfection experiments with a series of linker scanning and small internal deletion mutations revealed two mutation-sensitive domains separated by a region of relative resistance to sequence alterations. DNase I footprinting and gel electrophoresis mobility shift experiments with crude nuclear extracts identified at least one protein-binding site within each of the two mutation-sensitive regions. An oligonucleotide corresponding to one of these sites is able to repress transcription, but only when linked to the promoter in multiple copies. This negative regulatory element functions synergistically with a promoter proximal negative element to mediate efficient promoter repression, selectively affecting basal relative to steroid hormone-induced transcription and thus increasing the ratio of promoter activity observed in the presence and absence of hormone.
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PMID:Multipartite structure of a negative regulatory element associated with a steroid hormone-inducible promoter. 166 Aug 91

Although receptors for most steroid hormones are present in the heart, few cardiac-specific target genes have been identified and studied at the molecular level. Transcription of the atrial natriuretic factor (ANF) gene, which encodes the major secretory product of the heart, is induced by glucocorticoids. In both atrial and ventricular cardiac cells in primary cultures, ANF mRNA levels are increased 3-4-fold after dexamethasone treatment in a time- and dose-dependent manner. This response to glucocorticoids is completely abolished by the antagonist RU486. Interestingly, ventricular myocytes appear to be more sensitive to glucocorticoids than atrial myocytes. DNA-mediated gene transfer studies indicate that glucocorticoids affect ANF gene transcription via a glucocorticoid response element located in the distal 5'-flanking sequences of the rat ANF gene between -697 and -1,029 base pairs. In vitro DNase I footprinting experiments reveal the presence of two binding sites for purified glucocorticoid receptor within this region. Mobility shift assays and competition experiments show that binding of the glucocorticoid receptor to both ANF sites results in a DNA-protein complex similar in affinity and specificity to that of the well characterized mammary tumor virus glucocorticoid response element. Since glucocorticoid activation of the ANF promoter appears specific to cardiac cells, the interaction between the glucocorticoid receptor binding sites and cardiac-specific regulatory elements of this promoter could provide a model to study a mechanism of hormone-dependent signal transduction in the heart.
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PMID:Distal cis-acting promoter sequences mediate glucocorticoid stimulation of cardiac atrial natriuretic factor gene transcription. 183 78

Activation of mouse mammary tumor virus transcription by the hormone-bound glucocorticoid receptor results in disruption of a nucleosome that is specifically positioned on the promoter. Limited treatment of cells with the histone deacetylase inhibitor sodium butyrate prevents receptor-dependent promoter activation and nucleosome disruption [Bresnick, E. H., John, S., Berard, D. S., LeFebvre, P., & Hager, G. L. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3977-3981]. On the basis of this observation, we undertook a series of experiments to compare the structure of normal and hyperacetylated mouse mammary tumor virus chromatin. Although butyrate prevents hormone-induced restriction enzyme cutting specifically in the B nucleosome region, chromatin containing hyperacetylated histones does not differ from normal chromatin in general sensitivity to restriction enzymes. Indirect end-labeling analysis of micrococcal nuclease digested chromatin reveals that nucleosomes are identically phased on the mouse mammary tumor virus long terminal repeat in normal and hyperacetylated chromatin. A synthetic DNA fragment spanning the B nucleosome region was reconstituted into a monosome by using core particles containing normal or hyperacetylated histones. Analysis of the structure of reconstituted monosomes by nondenaturing polyacrylamide gel electrophoresis, salt stability, thermal stability, restriction enzyme accessibility, and exonuclease III or DNase I footprinting reveals no effect of histone hyperacetylation on monosome structure. These observations suggest that histone hyperacetylation does not induce a major change in the structure of mouse mammary tumor virus chromatin, such as nucleosome unfolding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histone hyperacetylation does not alter the positioning or stability of phased nucleosomes on the mouse mammary tumor virus long terminal repeat. 184 27

Transcriptional activation by steroid hormones is often associated with the appearance of a DNase I hypersensitive site resulting from a local alteration of the nucleoprotein structure of the promoter. For the mouse mammary tumor virus long terminal repeat, a viral promoter under glucocorticoid control, a model has been proposed: the appearance of the hormonodependent DNase I hypersensitive site reflects the displacement of a single precisely positioned nucleosome associated with the glucocorticoid responsive elements. To determine if such a mechanism is of general relevance in transcriptional activation by steroid hormones, we have investigated the nucleosomal organization of the rat tyrosine aminotransferase promoter over a 1-kilobase region that contains the glucocorticoid regulatory target. This region displays a hormonodependent DNase I hypersensitive site. In the absence of hormone, micrococcal nuclease digestion of nuclei demonstrates the presence of positioned nucleosomes, with cutting sites centered around positions -3080, -2900, -2700, -2800, -2255, and -2040. Treatment of the cells with dexamethasone induces a disruption of the chromatin structure over a relatively short stretch of DNA (approximately positions -2400 to -2650) that overlaps two nucleosomes. These observations suggest a strong similarity in the role of chromatin structure in glucocorticoid-dependent transcriptional activation of mouse mammary tumor virus and tyrosine aminotransferase promoters.
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PMID:Glucocorticoids locally disrupt an array of positioned nucleosomes on the rat tyrosine aminotransferase promoter in hepatoma cells. 197 70

A fragment of the rat androgen receptor (amino acids 533-637) containing the DNA-binding domain was produced in Escherichia coli as a fusion product with protein A of Staphylococcus aureus. The fusion protein was purified on IgG-Sepharose, a method that does not involve the use of denaturing agents. Approximately 4 mg of fusion protein was obtained from 500 ml of bacterial culture. In gel shift assays, the recombinant DNA-binding domain displays an affinity for a fragment of the long terminal repeat of mouse mammary tumor virus and for an intronic fragment of the gene coding for the C3 component of the androgen-regulated rat prostatic binding protein. In a DNase I footprinting assay, the fusion protein protects a sequence in the C3 fragment that has previously been shown to act as a functional androgen response element. Interestingly, a single base pair mutation in the response element, which abolishes androgen inducibility, also destroys the ability to interact with the recombinant androgen receptor DNA-binding domain.
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PMID:Interaction of androgen response elements with the DNA-binding domain of the rat androgen receptor expressed in Escherichia coli. 199 8

Several steroid hormones induce transcription of the mouse mammary tumor virus (MMTV) promoter, through an interaction of their respective receptors with the hormone responsive elements (HREs) in the long terminal repeat (LTR) region. The molecular mechanism underlying transcriptional activation is not known, but binding of nuclear factor I (NFI) to a site adjacent to the HRE appears to be required for efficient transcription of the MMTV promoter. In JEG-3 choriocarcinoma cells the MMTV promoter is transcribed inefficiently, even after transfection of the receptor cDNA and treatment with glucocorticoids or progestins. These cells contain low levels of NFI as cotransfection of NFI cDNA enhances MMTV transcription and this effect is inhibited by mutation of the NFI binding site. In DNA binding experiments with purified NFI from pig liver, the glucocorticoid and progesterone receptors do not co-operate but rather compete with NFI for binding to their respective sites on the LTR. Similar results are obtained with a functional recombinant NFI synthesized in vitro. Competition for DNA binding is probably due to steric hindrance as the DNase I footprints of the hormone receptors and NFI do overlap. These results suggest that, though NFI acts as a transcription factor on the MMTV promoter, transcriptional activation does not take place through a direct facilitation of DNA binding of NFI by steroid hormone receptors.
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PMID:Nuclear factor I acts as a transcription factor on the MMTV promoter but competes with steroid hormone receptors for DNA binding. 216 64

The interaction of partially purified calf uterine estradiol-charged estrogen receptor ([3H]ER) with rat nuclei was studied in vitro. We previously observed a significantly greater number of [3H]ER binding sites (at saturation) in nuclei of R3230AC mammary tumors from intact vs ovariectomized (ovex) rats with no difference in the affinity of [3H]ER binding for these nuclei. We now report on the nuclease sensitivity of [3H]ER binding sites in nuclei from these tumors and from normal rat tissues. Digestion of tumor nuclei with deoxyribonuclease I (DNase I) prior to incubation with [3H]ER in vitro resulted in a progressive loss of [3H]ER binding capacity, which was not accompanied by alterations in the affinity of [3H]ER for the nuclei (Kd = 1-3 nM). A significantly lower concentration (P less than 0.005) of DNase I eliminated 50% of the [3H]ER binding sites in nuclei of tumors from intact hosts (8 unit.min/ml) compared to tumors from ovex hosts (22 unit.min/ml). These results indicate that DNA regions capable of binding ER are more susceptible to DNase I digestion in tumors from intact rats than those from ovex hosts, suggesting that the endogenous hormonal milieu is responsible, at least in part, for maintenance of nuclease-sensitive DNA conformations in this hormone-responsive mammary tumor. The amount of DNase I required to eliminate 50% of [3H]ER binding to nuclei from lactating mammary gland, liver, and kidney ranged from 14 to 56 unit.min/ml. Therefore, accessibility of [3H]ER binding sites to nuclease digestion in normal rat tissue is generally less than that of R3230AC tumors.
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PMID:Nuclease sensitivity of estradiol-charged estrogen receptor binding sites in nuclei isolated from normal and neoplastic rat mammary tissues. 219 77


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