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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cell proliferation is of interest since abnormal cell proliferation appears to be a precursor of tumorigenesis and also because the quantitative description of cell proliferation in tumors can be used to predict the biological behavior of a particular neoplasia. 2. There are several reliable methods of studying cell proliferation in tissues. One of the most important is the detection of the Ki67 defined antigen in frozen sections. The number of cells expressing Ki67 correlates with histological grades of tumors and can also be predictive of clinical outcome. The Ki67 can be localized in tissue sections using monoclonal antibodies in association with the immunoperoxidase technique. 3. Proliferating cell nuclear antigen (PCNA) is a component of DNA polymerase-delta and is another important cell proliferation marker manifesting a striking increase in concentration during the S phase of the cell cycle. 19A2 and PC10 are two different monoclonal antibodies which can be employed to detect PCNA in paraffin-embedded tissues. 4. Molecular biology has also been making a great contribution to the study of cell proliferation. The most recent innovation in tissue identification of proliferating cells is the use of in situ hybridization for the localization of histone H3 and/or H4 mRNA. H3 mRNA-positive cells appear to be present in basal cells of the skin and in crypt cells of the intestine which are sites with high proliferation rate.
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PMID:Detection of cell proliferation in tissue sections. 790 73

Proliferating cell nuclear antigen (PCNA) is an auxiliary protein for DNA polymerase delta and is required for both DNA replication and DNA repair. PCNA forms complexes with D-type cyclins, candidate G1 cyclins in mammalian cells. To better understand the functions of the complexes, we examined interactions between PCNA and D-type cyclins, using in vitro-translated mouse PCNA and mouse cyclin D1 or D3 fused to glutathione S-transferase (GST). Analysis of a set of deletion mutants of PCNA revealed that either the N-terminal (residues 2-64) or the C-terminal (residues 197-228) region is necessary for association with D-type cyclins. The cyclin binding of the chimeric protein of the N-terminal (residues 1-68) or the C-terminal (residues 195-261) region of PCNA and rat DNA polymerase beta which does not bind to the cyclins by itself supports this notion. The purified recombinant mouse PCNA expressed in Escherichia coli bound to the D-type cyclin-GST fusion proteins, thereby suggesting that PCNA binds directly to D-type cyclins, without the requirement of other cellular factors. This is apparently the first report on the structure-function relationship of PCNA which may link DNA replication and DNA repair with cell cycle control.
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PMID:D-type cyclin-binding regions of proliferating cell nuclear antigen. 790 6

Cellular proliferation is being evaluated as an independent prognostic indicator in a variety of tumors, including non-Hodgkin's lymphomas (NHL). Although the labeling index (LI), using either tritiated thymidine or monoclonal antibodies to bromodeoxyuridine, is considered to be the gold standard of cell kinetic measurements, recent advances in the use of antibodies specific to cellular proliferating antigens and computer-based image analysis have potentially established a new technology for evaluating the growth fraction of NHL. Proliferating cell nuclear antigen (PCNA), a protein associated with DNA polymerase that is expressed only in the nuclei of cells actively synthesizing DNA, was quantitated in 46 formalin-fixed, paraffin-embedded samples of various types of NHL using the Cell Analysis Systems 200 image analyzer. The results were expressed as the percentage of nuclear area (%NA) positive for PCNA. These results were compared with the bromodeoxyuridine LI, and a correlation coefficient of 0.78 was calculated using first-order linear regression. An average positive NA of 8.2% for low-grade NHL, 32% for intermediate-grade, and 43% for high-grade NHL was observed. The potential advantages PCNA quantitation by image analysis may offer over LI are discussed.
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PMID:Proliferative activity in non-Hodgkin's lymphomas. A comparison of the bromodeoxyuridine labeling index with PCNA immunostaining and quantitative image analysis. 810 Jun 80

Proliferating cell nuclear antigen (PCNA), also known as cyclin, is an auxiliary protein of DNA polymerase-delta and is found only in the nuclei of proliferating cells in the late G1 and S phases. The proliferation of hepatocellular carcinoma (HCC) by immunohistochemical staining for PCNA using paraffin sections of 20 surgically resected HCC specimens was analysed. The mean percentage of PCNA-positive nuclei in the HCC tissue was 10.3% in grade I of Edmondson and Steiner's classification, 25.5% in grade II, 28.4% in grade III and 41.5% in grade IV. In early HCC, we observed only a few PCNA-positive tumour cells. However, PCNA-positive nuclei were numerous in the tumour thrombi found in portal vein branches, in regions of extracapsular tumour growth, and in the inner nodules of tumours with a nodule-in-nodule formation. Proliferating cell nuclear antigen positivity was correlated with an increase of the nucleocytoplasmic ratio of tumour cells as determined by image analysis. Our findings showed that PCNA positivity was correlated with the histological grade and invasiveness of HCC, suggesting that this antigen may be used as an indicator to predict tumour invasion in patients with HCC.
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PMID:Immunohistochemical detection of proliferating cell nuclear antigen in hepatocellular carcinoma: relationship to histological grade. 810 98

Proliferating cell nuclear antigen (PCNA) is a 36-kD nuclear protein that functions as a cofactor of delta DNA polymerase which is regulated in a cell cycle-dependent fashion. PCNA expression also increases when cells are actively engaged in DNA repair. We used Western blotting (WB) to measure the level of expression of PCNA in peripheral blasts of 36 adult acute myelogenous leukemia (AML) patients treated with Ara-C based induction regimens. PCNA levels correlated positively with the percentage of cells in S+G2M of the cell cycle. Logistic regression analysis revealed PCNA (beta = 4.5162; p = 0.0260) together with age (beta = 0.1777; p = 0.0364) as independent variables for remission induction: high PCNA levels were associated with poor response to induction therapy. PCNA expression was not, however, a predictor of survival in this subset of patients. We conclude that PCNA levels in this disease may be important for predicting response to Ara-C based remission induction chemotherapy.
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PMID:Quantitative expression of proliferating cell nuclear antigen by western blot (PCNAWB) in peripheral blasts correlates with remission induction in patients with acute myelogenous leukemia. 853 14

It is well known that the histological appearance of meningiomas often fails to predict accurately the clinical behavior of the tumor. Therefore, attention has turned from tumor histology to tumor biology. Proliferating cell nuclear antigen (PCNA), a cell cycle-regulated protein, has been recently characterized as the cofactor of DNA polymerase-delta, an enzyme required for DNA replication. The rate of synthesis of PCNA directly correlates with the proliferative state of cells. Immunohistochemical labeling of this antigen is now possible with monoclonal antibodies that allow for its demonstration in routinely fixed, paraffin-embedded specimens. In this study, the PCNA labeling index (LI) was determined for 83 meningiomas, including tumors with both benign and malignant clinical courses and with benign, atypical, and malignant histologies, apparent after total or subtotal resections. No statistical difference was found between the LI on recurrence and that found at initial presentation. In addition, stepwise multivariate regression analysis failed to identify any combination of factors (age, gender, race, age of specimen, tumor histology, Simpson grade of resection) that contributes to the predictive strength of the PCNA LI for tumor recurrence. However, for LIs less than 2%, only one of 26 gross totally resected tumors recurred (mean follow up 53 months); for LIs more than 7%, five of 13 gross totally resected tumors recurred (mean follow up 55 months). The difference in recurrence rates between gross totally resected meningiomas with PCNA LIs less than 2% and those with PCNA LIs more than 7% achieved statistical significance with a Fisher's exact probability equaling 0.011. The authors conclude that quantitative PCNA labeling of meningiomas is a promising technique that can provide meaningful prognostic information.
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PMID:Significance of proliferating cell nuclear antigen in predicting recurrence of intracranial meningioma. 861 41

Replication factor C (RFC, also called Activator I) is part of the processive eukaryotic DNA polymerase holoenzymes. The processive elongation of DNA chains requires that DNA polymerases are tethered to template DNA at primer ends. In eukaryotes the ring-shaped homotrimeric protein, proliferating cell nuclear antigen (PCNA), ensures tight template-polymerase interaction by encircling the DNA strand. Proliferating cell nuclear antigen is loaded onto DNA through the action of RFC in an ATP-dependent reaction. Human RFC is a protein complex consisting of five distinct subunits that migrate through SDS/polyacrylamide gels as protein bands of 140, 40, 38, 37, and 36 kDa. All five genes encoding the RFC subunits have been cloned and sequenced. A functionally identical RFC complex has been isolated from Saccharomyces cerevisiae and the deduced amino acid sequences among the corresponding human and yeast subunits are homologous. Here we report the expression of the five cloned human genes using an in vitro coupled transcription/translation system and show that the gene products form a complex resembling native RFC that is active in supporting an RFC-dependent replication reaction. Studies on the interactions between the five subunits suggest a cooperative mechanism in the assembly of the RFC complex. A three-subunit core complex, consisting of p36, p37, and p40, was identified and evidence is presented that p38 is essential for the interaction between this core complex and the large p140 subunit.
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PMID:In vitro reconstitution of human replication factor C from its five subunits. 869 48

The development of head and neck cancer has been proposed to be a multistep process, with accumulation of genetic and phenotypic alterations resulting from carcinogen exposure. Proliferating cell nuclear antigen (PCNA), also called cyclin, is a 36-KD auxiliary protein of DNA polymerase-delta, that has been found to be a useful marker in immunocytochemical studies of cell proliferation because its expression correlates with the proliferative state of the cell. PCNA expression was analyzed in 10 samples of normal mucosa, 23 benign oral lesions (18 hyperplasia and 5 oral lichen plani), 10 oral lesions with epithelial dysplasia, and 10 dysplastic epithelia adjacent to tumors. Immunocytochemical stained sections were scored for the presence or absence of suprabasal PCNA positivity regardless of location. The results indicate that the PCNA expression in the suprabasal layers increased with the degree of epithelia dysplasia and in the samples of histological dysplastic epithelium adjacent to the tumors, while the percentage of suprabasal PCNA expression was insignificant in the samples of normal oral mucosa and benign oral lesions. The authors conclude that suprabasal PCNA expression could be a marker of dysplasia in oral mucosa, indicating a special proliferative cellular state in those lesions.
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PMID:Proliferating cell nuclear antigen (PCNA) as a marker of dysplasia in oral mucosa. 898 50

Proliferating cell nuclear antigen (PCNA) plays an essential role in nucleic acid metabolism as a component of the replication and repair machinery. This toroidal-shaped protein encircles DNA and can slide bidirectionally along the duplex. One of the well-established functions for PCNA is its role as the processivity factor for DNA polymerase delta and epsilon. PCNA tethers the polymerase catalytic unit to the DNA template for rapid and processive DNA synthesis. In the last several years it has become apparent that PCNA interacts with proteins involved in cell-cycle progression which are not a part of the DNA polymerase apparatus. Some of these interactions have a direct effect on DNA synthesis while the roles of several other interactions are not fully understood. This review summarizes the structural features of PCNA and describes the diverse functions played by the protein in DNA replication and repair as well as its possible role in chromatin assembly and gene transcription. The PCNA interactions with different cellular proteins and the importance of these interactions are also discussed.
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PMID:PCNA: structure, functions and interactions. 903 70

Proliferating cell nuclear antigen (PCNA) is a DNA polymerase accessory factor that is required for DNA replication during S phase of the cell cycle and for resynthesis during nucleotide excision repair of damaged DNA. PCNA binds to flap endonuclease 1 (FEN-1), a structure-specific endonuclease involved in DNA replication. Here we report the direct physical interaction of PCNA with xeroderma pigmentosum (XP) G, a structure-specific repair endonuclease that is homologous to FEN-1. We have identified a 28-amino acid region of human FEN-1 (residues 328-355) and a 29-amino acid region of human XPG (residues 981-1009) that contains the PCNA binding activity. These regions share key hydrophobic residues with the PCNA-binding domain of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), and all three competed with one another for binding to PCNA. A conserved arginine in FEN-1 (Arg339) and XPG (Arg992) was found to be crucial for PCNA binding activity. R992A and R992E mutant forms of XPG failed to fully reconstitute nucleotide excision repair in an in vivo complementation assay. These results raise the possibility of a mechanistic linkage between excision and repair synthesis that is mediated by PCNA.
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PMID:The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. 930 16


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