Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA polymerase activity was measured in vitro in soluble cytoplasmic and nuclear fractions of chick oviduct, after in vivo hormone stimulation. By twelve hours after a subcutaneous injection of oestradiol, cytosolic and nuclear DNA polymerase activity had increased 2 to 5 fold over control levels ane continued to increase until 24 hours after the injection. Progesterone induced a slight rise in DNA polymerase activity and dihydrotestosterone had no effect. When oestradiol + progesterone were given together, the stimulating effect of oestradiol was cancelled for approximately 14 hours, contrasting with their synergist-c effect on transcription in this system. Various quantities and various sequences of hormone administration were studied, and some of the physico chemical parameters of the enzymes were determined after the different hormone stimulations. The demonstration of a sex steriod dependent regulation of chick oviduct DNA polymerases and the opposite effects of the oestradiol + progesterone combination on replication and on transcription can represent a new approach in the study of the mechanism of action of steroid sex hormones.
 ...
PMID:[Regulation of chick oviduct DNA polymerases by steroid hormones (author's transl)]. 100 13

Microtubule-associated protein 2 (MAP2) isolated from porcine brains stimulated the activity of DNA polymerase alpha immunopurified from calf thymus or human lymphoma cells, in a dose-dependent manner. This stimulation was pronounced when activated DNA or poly(dA).(dT)10 was used as the template-primer. DNA polymerase alpha bound to a MAP2-immobilized column, whereas preincubation of the enzyme with unbound MAP2 prevented binding to the column. These events suggested that a physical binding occurred between the polymerase and MAP2. Kinetic analyses revealed that MAP2 decreased the Km value of the polymerase for deoxyribonucleotides, irrespective of the species of template-primer. A concomitant increase in Vmax was observed; however, the extent of the increase depended on the species of template-primer. MAP2 also decreased the Km value of the polymerase for template-primers when activated DNA of poly(dA).(dT)10 was used as the template-primer. Product analyses showed that MAP2 did not significantly alter the processivity of the polymerase and the increment of Vmax is considered to be due to an increase in the frequency of initiation of DNA synthesis. The stimulation by MAP2 occurred specifically in the activity of DNA polymerase alpha, but not DNA polymerases beta, gamma, and I from Escherichia coli. Other MAPs, tau and 190-kDa MAP, could substitute for MAP2. Thus, the specific stimulation of DNA polymerase alpha by MAPs supports the notion of a possible involvement of MAPs or MAP-like proteins in DNA replication, in vivo.
 ...
PMID:Stimulation of DNA polymerase alpha activity by microtubule-associated proteins. 174 79

Cytosols of human breast tumours have been assayed for DNA dependent DNA polymerase alpha activity. DNA polymerase alpha activity in benign tumours was found to be significantly lower than in untreated malignant tumours. Biopsy samples removed surgically before and after endocrine therapy showed reduced DNA polymerase alpha activity in 6 out of 9 patients treated with 4-hydroxyandrostenedione, and in 6 out of 7 patients treated with MPA. DNA polymerase alpha activity in malignant breast tumours was higher in oestrogen receptor negative than oestrogen receptor positive tumours.
 ...
PMID:Analysis by DNA polymerase alpha activity of human breast tumour proliferation and the effect of endocrine therapy. 214 78

Endometrial hyperplasia (EH) was found to coexist in 13 of 21 patients (cystic glandular hyperplasia, 13; adenomatous hyperplasia, 9) with endometrial adenocarcinoma (EC), but in only 44 of 940 patients with other than EC. In this study, blood type (A, B, H), c-myc translation products, estrogen receptor and DNA polymerase alpha were examined on endometrium of proliferative phase (EPP), EH and EC. Patient blood type products were shown in EH surrounding EC, and yet they were detected in only small portion or none of EC itself. H products were detected in EC of other than O type. c-myc translation products were shown in only a small portion of cancer cells. EPP had many ER positive cells and a few proliferating cells as they were shown by staining with anti-DNA polymerase alpha monoclonal antibody. EC can be divided into two types, one has few ER positive cells and many proliferating cells, other many ER positive cells and a few proliferating cells. In EH, the numbers of ER positive cells and DNA polymerase alpha positive cells were between those of EPP and EC. In a patient with atypical hyperplasia, high dose Medroxyprogesterone acetate (MPA) therapy induced that stratification and papillary growth of gland lining epithelia disappeared, and that cytoplasmic enlargement and vacuolation appeared. These findings were important histopathological changes in high dose MPA administration to EH and EC.
 ...
PMID:[Diagnosis and treatment of endometrial hyperplasia]. 252 3

The effects of estradiol on DNA polymerase alpha activity were investigated in an estrogen-responsive human endometrial cancer cell line (Ishikawa) derived from a well differentiated endometrial adenocarcinoma. These cells are known to respond to estradiol by increasing progesterone receptor levels, alkaline phosphatase activity, and cell density. Four- to 5-fold increases in DNA polymerase alpha activity occurred when estradiol was added to cultures of Ishikawa cells in medium containing charcoal-treated fetal bovine serum. Maximal stimulation was achieved at 18 h during incubations with 10(-8) M estradiol, but significant effects also were found with 10(-9) and 10(-6) M. These effects were almost completely counteracted by a 100-fold excess of 4-hydroxytamoxifen. At 10(-6) M, the antiestrogen had no influence on the basal levels of DNA polymerase alpha. Medroxyprogesterone acetate (10(-6) M) was ineffective as either an enhancer of enzymatic activity or an antiestrogen when tested in combination with 10(-8) M estradiol, even in the presence of appreciable levels of specific progesterone binders. The responsiveness of the Ishikawa cells to estrogen contrasts with the lack of effects of estradiol on DNA polymerase alpha activity in another human endometrial adenocarcinoma cell line (HEC-50).
 ...
PMID:Effects of estradiol on deoxyribonucleic acid polymerase alpha activity in the Ishikawa human endometrial adenocarcinoma cell line. 294 47

The effects of the antiprogestin RU 486 on the human endometrium were investigated. Seventeen postmenopausal women were injected with estradiol (E2) benzoate (0.625 mg/day) for 15 days. Progesterone (P) (25 mg/day) and/or RU 486 (100 or 200 mg/day) were given to groups of 2-3 women during the last 6 days of E2 benzoate treatment. Serial blood samples were drawn for the measurement of plasma E2, P, and LH and FSH. An endometrial biopsy was performed on the last day of treatment, and processed for histology or for assays of DNA polymerase alpha, E2-dehydrogenase (E2DH), and P receptor (PR). Treatment with E2 benzoate alone resulted in a marked decrease of plasma gonadotropins; in those patients who received either P, RU 486, or both, in addition to E2 benzoate, the concentrations of plasma LH and FSH were further decreased to premenopausal levels. In absence of glycerol, the affinity of RU 486 for the endometrial PR (Kd = 0.8 nM) was higher than that of P (Kd = 1.2 nM). Glycerol decreased markedly the affinity of RU 486, whereas the affinity of P for the PR was unchanged. RU 486 had negligible affinity for plasma transcortin. Either P or RU 486, but not both together, induced secretory changes in the endometrium as determined from histologic sections of tissue biopsies. Either P or RU 486 decreased DNA polymerase alpha and increased E2-DH activities in the endometrium. Unexpectedly, when P and RU 486 were given together. E2-DH activity remained at the level found in E2-treated women. In vitro cultures of proliferative endometrium treated with the synthetic progestagen R 5020 or with RU 486 also had increased E2-DH activity; RU 486 counteracted R 5020 effects. We conclude that, contrary to previous results with experimental animals, the anti-P RU 486 has some progestomimetic activity in humans under specific conditions. Paradoxically, when given together with P, RU 486 lost most of its progestomimetic activity in the endometrium and behaved as a pure antagonist.
 ...
PMID:Endometrial and pituitary responses to the steroidal antiprogestin RU 486 in postmenopausal women. 396 88

After a single injection of oestradiol benzoate (1.5 mg/kg) to oestrogen-withdrawn chickens, there was an increase in magnum wet weight, DNA polymerase alpha activity, adenosine-3',5'-monophosphate-dependent protein-kinase activity and estrogen-receptor concentration, as measured over 36 h. Besides these intracellular proteins, the secretory proteins ovalbumin and conalbumin were also augmented, and detailed time-course studies were performed. Early induction kinetics for ovalbumin and conalbumin synthesis, which differed for each protein, were independent of the dose of oestradiol benzoate injected if it exceeded 0.1 mg/kg. After 6 h for ovalbumin and 2 h for conalbumin, the induction curves diverged according to the dose of hormone administered and in correlation with the persistence of elevated nuclear oestrogen-receptor concentrations, a result confirmed with 11 beta-methoxy-17 alpha-ethynyloestradiol (R 2858), a powerful synthetic oestrogen. When oestradiol benzoate (1 mg/kg) and progesterone (3 mg/kg) were injected simultaneously, the rate of conalbumin sythesis, during the first 6-8 h, was lower than that observed in animals injected with oestradiol benzoate alone. However at later times conalbumin synthesis was greater in animals receiving both hormones than with oestradiol alone. In contrast, the rate of ovalbumin synthesis after the combined injection was higher than that induced by either hormone alone throughout the entire experimental period. In order to study further the synergistic and antagonistic activities of these two hormones, a single injection of progesterone (3 mg/kg) was administered 6, 12 or 18 h after 1.5 mg/kg oestradiol benzoate. Progesterone administration resulted in a reduction in cytoplasmic, nuclear and total oestrogen receptor concentration for at least 6 h when compared with the values in birds treated with oestrogen alone. DNA polymerase and protein kinase activities were also reduced during this period. Subsequently, all parameters increased, and by 18-24 h after progesterone treatment, reached values higher than those observed in animals receiving oestrogen alone.
 ...
PMID:Steroid receptors and effects of oestradiol and progesterone on chick oviduct proteins. 624 83

Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed drugs for endocrine therapy of metastatic breast cancer. In this study, the serum MPA concentration was measured by high-performance liquid chromatography (HPLC) and evaluated for its usefulness in predicting the response in 79 cases of advanced or recurrent breast cancers. Overall, 29 patients (37%) achieved an objective response. The response rate correlated significantly with the oestrogen receptor (ER) status (P = 0.03), proliferative activity determined by DNA polymerase alpha (P = 0.04), the disease-free interval (DFI) (P = 0.05) and the serum MPA concentration (P < 0.001). Patients with ER-positive tumours, lower proliferative activity, a longer (DFI) or a higher serum MPA concentration responded more frequently. The mean serum MPA concentration in the responders with ER-positive tumours (P = 0.01) or tumours with a lower proliferative activity (P = 0.008) were significantly lower than in cases with ER-negative tumours or tumours with a higher proliferative activity, respectively. Cases with soft tissue metastases showed responses at significantly lower MPA concentrations (P = 0.003) than those with bone or visceral metastases. Furthermore, there was a dramatic decrease in the MPA concentration when a responder with a high concentration became unresponsive to the therapy. Thus, the serum MPA concentration is a determining factor for the response to treatment.
 ...
PMID:Predictive value of serum medroxyprogesterone acetate concentration for response in advanced or recurrent breast cancer. 933 82

MPA [the active metabolite of the immuno-suppressive agent CellCept] and ribavirin markedly potentiate the anti-HBV activity of the guanine-based nucleoside analogue entecavir (ETV) against both wild-type HBV and a lamivudine-resistant variant. Ribavirin (in its 5'-monophosphate form) and MPA are inhibitors of IMP-dehydrogenase and cause depletion of intracellular dGTP pools. The active triphosphorylated form of ETV may inhibit more efficiently the priming reaction, reverse transcription and DNA-dependent DNA polymerase activity of the HBV polymerase in the presence of reduced levels of dGTP. The potential for enhanced ETV activity is supported by the observation that exogenously added deoxyguanosine reversed the potentiating effect of ribavirin and MPA. Our observations may have important implications for those (liver) transplant recipients that receive MMF as part of their immunosuppressive regimen and who, because of a de novo or a persistent infection with HBV need antiviral therapy such as ETV. Further studies will need to be conducted to determine if combining ribavirin (a compound used for the treatment of HCV infections) with ETV could have an advantage for the treatment of HBV infections, in particular in patients co-infected with HCV.
 ...
PMID:Ribavirin and mycophenolic acid markedly potentiate the anti-hepatitis B virus activity of entecavir. 1709 96