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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Characterization of a mutant T7 RNA polymerase (RNAP) that is active on non-promoter templates but has lost the ability to selectively utilize the T7 promoter led to the finding that wild-type T7 RNAP initiates transcription at a high rate on non-promoter templates but that most (approximately 90%) of these initiation events lead to synthesis of dinucleotides only. The anomalously high activity of T7 RNAP on poly(dC) templates (relative to other non-promoter templates) is due to a reduction in the rate of transcription abortion after dinucleotide synthesis rather than an increase in initiation. Evidence is presented that the transition from abortive to processive transcription is associated with a conformational change in T7 RNAP. The stability of the nascent chain in a ternary complex is shown to increase with increasing chain length in the 2 to 14 base range even when the size of the complementary RNA-DNA hybrid remains constant and small (2 to 3 base-pairs). Two mutant polymerases that show increased release of transcripts during abortive transcription and a proteolytically nicked polymerase that exhibits reduced RNA binding are shown to have reduced ability to read-through a T7 RNAP hairpin U-stretch transcription terminator. Single-stranded nucleic acids are shown to bind more tightly than double-stranded nucleic acids to T7 RNAP. These observations and a large set of published studies on T7 RNAP structure and mechanism are accommodated in a relatively simple model of T7 RNAP transcription initiation and termination in which a T7 RNAP that has initiated transcription is proposed to be capable of assuming two functionally distinct conformations: an abortive conformer characterized by a loose association with the nascent RNA and an inability to translocate along the template; and a processive conformer characterized by the stable retention of the nascent RNA and the ability to process stably along the template. The equilibrium between these two conformations is shifted towards the processive form when the nascent chain binds at a site located at least partly on the T7 RNAP N-terminal domain. The interaction requires that the RNA be more than approximately nine bases and this RNAP-RNA interaction plays a primary role in retaining the RNA within the ternary complex.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1992 Mar 20
PMID:Model for the mechanism of bacteriophage T7 RNAP transcription initiation and termination. 156 Apr 55

We have demonstrated previously that the administration of dihydrotestosterone (DHT) decreases plasma progesterone levels within 24 h and thus, results in abortion during the first half of pregnancy (Am. J. Physiol. 241 (1981) E444-E448). The purpose of this study was to determine (a) if the administration of DHT suppresses plasma prolactin levels or its nocturnal surge within 24 h after the treatment, (b) how soon after the commencement of treatment do the concentrations of DHT increase and progesterone levels decrease in the circulation, (c) the ultrastructural changes that occur in corpora lutea, and (d) the changes in luteal P-450 side-chain cleavage (P-450scc) enzyme and mRNA content upon DHT treatment. Within 24 h after the commencement of DHT treatment, the nocturnal surge of prolactin, detected in both groups on day 10 at 03.30 h, was inhibited in DHT-treated rats as compared to controls. The non-surge levels of prolactin at 05.00 and 06.00 h were not different between groups. The intraovarian DHT pellet increased plasma levels of the steroid 3-fold within 2 h (blood samples were taken at 2-hourly intervals) when compared to controls. By 24 h DHT levels were decreased but were still higher than controls. Plasma progesterone levels began to fall 6 h after the commencement of treatment. Luteal tissue from animals treated with DHT appeared steroidogenic, and contained more lipid droplets than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1991 May
PMID:Effects of in vivo dihydrotestosterone treatment on changes in nocturnal surge of prolactin, luteal ultrastructure and P-450scc mRNA and protein content in pregnant rats. 181 5

A survey of the research on gossypol, the lipophilic agent derived from cotton seed already being used as male oral contraceptive in China and Brazil, leaves many questions unanswered as to its mode of action and safety. Gossypol is a polyphenolic dialdehyde, occurring in 2 racemic isomers with different biological activities. It is soluble in lipids, binds to membranes, inhibits several enzymes including arachidonate lipoxygenases, and is an antioxidant. It has been used traditionally to treat bronchitis and to induce abortion and menses, but was only recognized as a male antifertility agent in the 1970s. It is spermicidal, it inhibits sperm motility, and causes azoospermia, at different doses and with marked species variability. There is evidence from China for regional variation in effect, possibly related to genetic factors, or even more likely due to dietary intake. Whether infertility induced by gossypol is reversible is in dispute. The most common toxic side effect is hypokalemia, which is severe enough to cause temporary paralysis in 1% of 8806 volunteers in a study conducted in China. Whether potassium loss can be reversed by supplementation, or by taking potassium-sparing diuretics, has been questioned. Similarly, the extent and permanence of renal damage presumed responsible for potassium loss is uncertain. A suitable animal model for studies on gossypol, either in vivo or in vitro, is unavailable. Studies on the mechanism of action of gossypol suggest structural alterations of cell membranes, inhibition of enzymes and energy metabolism may be affected, but this type of work needs to be refined to pinpoint the site of action.
Mol Reprod Dev 1990 Apr
PMID:Effects of gossypol on the motility of mammalian sperm. 218 32

The use of antiprogestins as abortifacients is more effective when antiprogestin priming is followed by the administration of a small dose of synthetic prostaglandin. This increased myometrial sensitivity towards PG has not been explained and experiments in the guinea-pig where no myometrial activity is observed after 48 h of antiprogestin administration together with measurements of PG metabolites in uterine vein blood have given rise to the suggestion that prostaglandin synthesis is inhibited by antiprogestins. We have treated groups of 50 day pregnant guinea-pigs with 10 mg RU486 or vehicle alone and examined the ability of homogenised uterine tissues (myometrium/decidua, cervix, chorion and amnion) to metabolize PGE when given a large excess of substrate and sufficient cofactors. In addition we have examined the ability of these homogenates to synthesis PG. Antiprogestin treatment in vivo resulted in a 9-fold reduction in metabolic activity in chorion (P less than 0.02) and a 4-fold reduction in myometrium/decidua (P less than 0.02). Reduction in activity seen in amnion and cervix was not significant. The maximum metabolism was seen in the chorion and minimal metabolism in the amnion. Maximum PG production was seen in the amnion and minimum in the chorion. These results show that the effect of antiprogestin in reducing prostaglandin catabolism would reduce the threshold above which PG production would cause contractions which would in turn stimulate PG production. Thus an explanation is provided of how low doses of exogenous PGs or transient synthesis of endogenous PG within an antiprogestin treated uterus can led to a self sustaining cycle of stimulation which will lead to abortion.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Antiprogestagenic inhibition of uterine prostaglandin inactivation: a permissive mechanism for uterine stimulation. 224 56

pBR322 DNA, linearized by lysis of an oxolinic acid-treated culture of Escherichia coli strain DK6recA- (pBR322) with sodium dodecyl sulfate, was purified, treated with DNA polymerase in the presence of the four deoxynucleoside triphosphates, and ligated to DNA linkers containing the XhoI recognition sequence. Most of the drug-resistant colonies resulting from transformation of E. coli with this material bore plasmids that appeared by restriction enzyme analysis to differ from pBR322 only by the introduction of an XhoI site. The XhoI sites in plasmids from 93 transformants were distributed unevenly around the pBR322 map. Maxam-Gilbert DNA sequence analysis of 36 of these plasmids, labeled at the 5' termini of the XhoI sites, revealed that 29 of them contained, in addition to the XhoI linker, a duplication of four base-pairs of the pBR322 sequence surrounding the linker. Therefore, oxolinic acid-induced linearization must have resulted in 5'-terminal extensions of four bases, the configuration known to result from oxolinic acid-induced DNA cleavage by DNA gyrase in vitro. The sequence data thus allowed the determination of the precise point at which linearization occurred, apparently by the abortion of a gyrase-DNA covalent intermediate that existed in vivo. When the 19 different sites of the 29 plasmids were compared, the following set of rules could be derived: (formula; see text) where N is any nucleotide, R is a purine, and Y is a pyrimidine. Cleavage occurred at the line between the eighth and ninth positions from the left. The parenthetical G and T were preferred secondarily to T and G, respectively, whereas T and G in the 13th position from the left were equally preferred. Several of these rules are similar to those proposed previously based on several in vitro gyrase cleavage sites. Some of our rules show dyad symmetry around the axis midway between the cleavage points in the two strands, while others are distinctly asymmetric.
J Mol Biol 1985 Jan 05
PMID:Sites of reaction of Escherichia coli DNA gyrase on pBR322 in vivo as revealed by oxolinic acid-induced plasmid linearization. 298 30

The importance of inherited mutations as a cause of human disease has been established clearly through examples of well-defined genetic anomalies, such as Down syndrome and retinoblastoma. Furthermore, it is suspected that environmental contaminants induce mutations resulting in increased risk for such defects in subsequent generations of persons exposed. The present lack of direct evidence for induced inherited genetic disorders in human beings hampers the development of risk estimation techniques for extrapolation from animal models. The most extensive prospective epidemiologic studies of inherited genetic effects have involved survivors of atomic bomb detonations and patients treated with cancer chemotherapy. In neither case has a significant elevation in inherited genetic effects or cancer been detected in the offspring of exposed individuals. Epidemiologic studies of subjects receiving chronic exposure may be confounded by the effect of maternal exposure during pregnancy. Consideration of only paternal exposure can minimize the confounding influence of teratogenicity, enhancing the resolving power of studies for inherited effects. Using this approach, retrospective (case-control) studies of childhood cancer patients have provided limited but suggestive evidence for inheritance of induced effects. Endpoints, such as congenital malformations and spontaneous abortion following paternal exposure, can also be considered as indicators of heritable mutagenic effects. For example, there is limited evidence suggesting that paternal exposure to anaesthetic gases may cause miscarriage and congenital abnormalities as a result of induced male germ cell mutations. By comparing male-exposure endpoints for which there are human data, as described above, with parallel or similar animal endpoints, such as dominant lethal, inherited cancer and "male teratogenic" effects, it is possible that suitable models for extrapolating to human risk can be developed. In order to establish a clearer relationship between induced mutation and genetic disease, the current surveillance systems should be expanded to include endpoints relevant to genetic study. The relaxation of regulations regarding access to census data could improve the chances of documenting such an association.
Environ Mol Mutagen 1988
PMID:Human mutagens: evidence from paternal exposure? 328 30

Genetical analysis of two-spored asci formed by interrupted sporulation offers a novel procedure for mapping of centromere-linked genes in Saccharomyces cerevisiae. Unlike the two-spored asci encountered under normal sporulation conditions, these asci are produced by a nonrandom mechanism. They fall into three categories (+ +), (+ -) and (- -) with respect to any marker. The percentage of (+ -) asci varies directly as a function of centromere-linkage of a gene. It is observed that almost 100% asci are of the (+ -) type in case of very tightly linked genes like trp-1 and cdc-10, while in case of markers unlinked to the centromere, e.g, trp-5 and met-8, the (+ -) asci constitute 50% of the total number of asci. Other markers with varying degrees of linkage, e.g. ura-3 and lys-1 show corresponding numbers of (+ -) asci between 50% and 100% of the total asci. These findings are in contrast to the results expected from a random abortion of two spores, in which case the (+ -) asci would constitute 67% of the total number of asci irrespective of the degree of centromere linkage of a marker. The linkage-dependent segregation of markers in these new kind of two-spored asci permits a rapid and accurate estimate of centromere linkage of a gene.
Mol Gen Genet 1983
PMID:Two-spored asci produced by interrupted sporulation: a novel approach to linkage analysis in yeast. 635 Aug 24

Epoxide formation from drugs, chemicals, food additives and environmental pollutants is catalyzed by cytochrome P-450 dependent monooxygenase(s). Epoxides are converted to glycols or dihydrodiols by epoxide hydrolase (EH). These enzymes are known to be present in the microsomes of different mammalian tissues and in the hepatic nuclei from rats and humans. The balance between the epoxide forming (AHH) and metabolizing (EH) enzyme activities may provide information about the "epoxide exposure" of a tissue. We thus investigated AHH and EH in the nuclear and microsomal fractions from six livers, four kidneys, four lungs, and two adrenals from human fetuses (gestational age between 15 and 24 weeks). Tissues were obtained at legal abortion for sociomedical reasons. AHH activity was measured according to van Cantfort et al (Biochem Biophys Res Commun 79: 505, 1977) using beno (a)pyrene as substrate. EH was measured as described by Jerina et al (Mol Pharmacol 13:342, 1977) using both styrene oxide (SO) and benzo(a)pyrene-4,5-oxide (BPO) as substrate. The nuclear fraction was isolated by a multistep procedure including centrifugation in high density sucrose ( Pacifici et al, unpublished). The hepatic AHH activity (pmole/min/mg; mean +/- SEM) was 11.5 +/- 2.2 in the nuclear fraction and 34.7 +/- 1.7 in the microsomes. In adrenals it was 6.0 (nuclei) and 4.4 (microsomes). The nuclear fraction from kidneys and lungs did not catalyze this reaction at a measurable rate, whereas microsomal AHH activity was 1.3 +/- 0.3 and 5.3 +/- 1.1, respectively, in these tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Epoxide hydrolase and aryl hydrocarbon hydroxylase in human fetal tissues: activities in nuclear and microsomal fractions and in isolated hepatocytes. 667 72

The effect of the synthetic antiprogestin RU486 on luteal function in late pregnant rats was studied by evaluating the activities of the enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD). RU486 (2 mg/kg) administered to rats on day 18 of pregnancy at 10.00 h induced preterm delivery 26.4 +/- 0.35 h (n = 8) after treatment. Luteal 3 beta-HSD activity increased 24 and 34 h after RU486 injection, but a significant and progressive decrease started at 48 h with the maximal reduction 72 h after RU486 treatment, when compared with controls. Serum progesterone concentration decreased at the time of 3 beta-HSD activity reduction. Interestingly, 20 alpha-HSD activity started to increase 58 h after RU486 injection. The administration of the cyclooxygenase inhibitor, diclofenac (1.3 mg/kg), on days 17-19 of pregnancy to RU486-treated rats, delayed abortion and the duration of delivery, and prevented the decrease in 3 beta-HSD and the increase in 20 alpha-HSD activities observed 58 h after antiprogesterone treatment. RU486 administered intrabursally (1 microgram per ovary) on day 20 (14.00-15.00 h) increased 3 beta-HSD and decreased 20 alpha-HSD luteal activities at 18.00 h on day 21 of pregnancy, without modifying serum progesterone concentration, when compared with normal pregnant rats. In conclusion, the luteolytic process after preterm delivery induced by RU486 administration in late pregnant rats is characterized by a decrease in luteal 3 beta-HSD activity and circulating progesterone, which may trigger the increase in luteal 20 alpha-HSD activity. Prostaglandins seems to be involved in the increase of 20 alpha-HSD activity and therefore, in the demise of corpora lutea.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Luteolytic action of RU486: modulation of luteal 3 beta-hydroxysteroid dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase activities in late pregnant rats. 777 60

Endotoxin is abortifacient. Abortion may be due to maternal, fetal or combined endotoxemia. The present study was performed to evaluate if fetal rat endotoxemia was induced by maternal endotoxemia in late gestation. An intraperitoneal injection of smooth lipopolysaccharide (Escherichia coli LPS and Shigella flexneri LPS) or rough LPS (Rc mutant Escherichia coli LPS) induced Limulus activity in maternal plasma, but not fetal plasma. These results suggest that fetal rat endotoxemia is not induced during maternal endotoxemia. Thus, the abortion may not be due to fetal endotoxemia.
Res Commun Mol Pathol Pharmacol 1994 Jul
PMID:LPS injected into the pregnant rat late in gestation does not induce fetal endotoxemia. 795 89


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