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)

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.
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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.
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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.
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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).
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PMID:Effects of estradiol on deoxyribonucleic acid polymerase alpha activity in the Ishikawa human endometrial adenocarcinoma cell line. 294 47

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.
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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.
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PMID:Ribavirin and mycophenolic acid markedly potentiate the anti-hepatitis B virus activity of entecavir. 1709 96