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

---

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

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.
...
PMID:Immunohistochemical detection of proliferating cell nuclear antigen in hepatocellular carcinoma: relationship to histological grade. 810 98

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.
...
PMID:Proliferating cell nuclear antigen (PCNA) as a marker of dysplasia in oral mucosa. 898 50

Cyclins A and B1 activate cyclin-dependent kinases CDK2 and CDC2, which regulate cell progression through S and G2. Expression of these cyclins is generally measured in populations of synchronized cells, by immunoblotting. Such studies neither provide information regarding intercellular variability in cyclin expression nor yield precise data on a time relationship between initiation and termination of DNA replication in relation to cyclin expression. Furthermore, cell synchronization by DNA polymerase inhibitors or excess of thymidine induces cell growth imbalance and alters expression of cyclins, thereby introducing an experimental bias. Using a novel flow cytometric method of detection of incorporated bromodeoxyuridine (BrdUrd) in the present study, we have been able to correlate expression of immunocytochemically discerned cyclins A and B1 with incorporation of BrdUrd and the cell cycle position of individual MOLT-4 cells. On the basis of differences in amount of incorporated BrdUrd and DNA content, the following cohorts of cells in narrow windows of the cell cycle were identified: (a) cells initiating and (b) terminating DNA replication during a 1-h pulse of BrdUrd; (c) cells replicating DNA throughout the duration of BrdUrd pulse; (d) G1 cells; and (e) G2 cells that remained in G2 for at least 1 h after exiting S phase. These populations were characterized with respect to expression of cyclins A and B1. Expression of cyclin A was an early event of S phase, and 84% of cells entering S phase during 1 h of exposure to BrdUrd were already cyclin A positive. More than 95% of S-phase cells, as well as the cells exiting S during BrdUrd pulse, were also cyclin A positive. The maximal rate of accumulation of cyclin A was seen during the first hour of progression through S phase. In contrast, the maximal accumulation rate of cyclin B1 showed cells during the first hour of progression through G2. A strong correlation between expression of cyclin A and the rate of DNA replication, estimated by the degree of BrdUrd incorporation (r = 0.99), was observed.
...
PMID:Correlation between DNA replication and expression of cyclins A and B1 in individual MOLT-4 cells. 904 Nov 74

During the past few years, several categories of cyclin-dependent kinase inhibitors (CDKIs), which negatively regulate cyclin/cyclin-dependent kinase (CDK) activities, were cloned. The p21WAF1, also known as CIP1 or SDI1, was the first reported CDKI: it's expression is induced by wild-type p53. The p21WAF1 is a potent inhibitor of most cyclin/CDK complexes and also inhibits the ability of the proliferating cell nuclear antigen (PCNA) to activate DNA polymerase d. Alterations of the cell-cycle can cause cellular transformation. We analysed 471 primary samples from 15 types of human malignancies and 36 cell lines for structural alterations of the p21WAF1 gene. No changes were found in the coding region of p21WAF1 gene by polymerase-chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. Many of these tumors had a normal p53 gene. Other investigators showed that p21WAF1 knockout mice did not have an increased incidence of cancer, while p53 knock-out mice did. Taken together, the absence of alterations of p21WAF1 in a series of malignancies suggests that p21WAF1 may not have a role in either onset or progression of most human cancers. Furthermore, p53 probably activates additional, critical tumor suppressor pathways.
...
PMID:p21WAF1 mutations and human malignancies. 925 Jul 85

Epidemiological studies strongly suggest that a newly discovered herpesvirus, Kaposi's sarcoma associated-herpesvirus (KSHV/HHV8), is the likely infectious cause of Kaposi's sarcoma (KS). Identification of this agent suggests the possibility that existing anti-herpesvirus chemotherapeutics have activity against KSHV. Using KSHV/Epstein-Barr virus (EBV)-coinfected cell line BC-1 and KSHV-infected/EBV-negative cell line BC-3, the effect of DNA polymerase inhibitors in the presence of virus-inducing agents was examined. The phorbol ester TPA induced 8.2-fold EBV replication in BC-1 cells with only minimal concurrent KSHV genome replication in BC-1, but induced fourfold KSHV in BC-3 cells. TPA, however, induced transcripts encoded by the lytic cycle major capsid protein gene that were inhibited by both phosphonoacetic acid and phosphonoformic acid either in the KSHV/EBV-infected cell line or in the EBV-negative/KSHV-infected cell line. Transcripts hybridizing to a KSHV-encoded cyclin gene were unaffected by either TPA or DNA polymerase inhibitors in both cell lines. These results show in vitro activity of DNA polymerase inhibitors on KSHV lytic transcript accumulation and may provide a simple assay for evaluating the efficacy of potential anti-KSHV chemotherapeutics.
...
PMID:Effect of DNA synthesis inhibitors on Kaposi's sarcoma-associated herpesvirus cyclin and major capsid protein gene expression. 931 Feb 90

p21cip1/waf1/sdi1 is a universal cyclin-Cdk kinase inhibitor that has two functional domains; one binds and inhibits cyclin-Cdk activity and the other binds PCNA and thereby inhibits elongation by DNA polymerase. When transiently expressed in hamster BHK21 cells we found that human p21 was able to cause cell cycle arrest in G1 phase; this arrest was counteracted by coexpression of E2F-1 or SV40 large T antigen. To study the effect of p21 overexpression in vivo, BHK21 cell clones inducibly expressing human p21 (Tet-p21) driven by the tetracycline (Tet)-repressible promoter were established. The maximum induced p21 levels in the absence of Tet were estimated to be ten times that of endogenous hamster p21. As p21 levels rose following removal of Tet, p21-associated histone H1 kinase activity was increased and concomitantly cell growth and DNA synthesis were reduced. Tet-p21 BHK21 cells became arrested in G1 phase and lost colony forming ability irreversibly 2-4 days after removal of Tet. The induction of cyclin E- and cyclin A-associated kinase activities was diminished when G0-synchronized Tet-p21 BHK21 cells were serum stimulated in the absence of Tet. Increased binding of p21 to PCNA and cyclin D1-Cdk4 was detected in induced cells. Overexpression of p21 led to cell death in BHK21 cells at 39.5 degrees C within 4 days.
...
PMID:Induction of growth arrest and cell death by overexpression of the cyclin-Cdk inhibitor p21 in hamster BHK21 cells. 946 62

Eukaryotic DNA replication is limited to once per cell cycle because cyclin-dependent kinases (cdks), which are required to fire origins, also prevent re-replication. Components of the replication apparatus, therefore, are 'reset' by cdk inactivation at the end of mitosis. In budding yeast, assembly of Cdc6p-dependent pre-replicative complexes (pre-RCs) at origins can only occur during G1 because it is blocked by cdk1 (Cdc28) together with B cyclins (Clbs). Here we describe a second, separate process which is also blocked by Cdc28/Clb kinase and, therefore, can only occur during G1; the recruitment of DNA polymerase alpha-primase (pol alpha) to chromatin. The recruitment of pol alpha to chromatin during G1 is independent of pre-RC formation since it can occur in the absence of Cdc6 protein. Paradoxically, overproduction of Cdc6p can drive both dephosphorylation and chromatin association of pol alpha. Overproduction of a mutant in which the N-terminus of Cdc6 has been deleted is unable to drive pol alpha chromatin binding. Since this mutant is still competent for pre-RC formation and DNA replication, we suggest that Cdc6p overproduction resets pol alpha chromatin binding by a mechanism which is independent of that used in pre-RC assembly.
...
PMID:Evidence for a Cdc6p-independent mitotic resetting event involving DNA polymerase alpha. 967 28

The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth. In this communication, we present evidence to show that these proteins inhibit tumor cell proliferation by participating in the activation of tumor cell differentiation. The ML-1 human myeloblastic leukemia cells used in this study proliferate when treated with insulin-like growth factor I and transferrin but differentiate to monocytes when exposed to tumor necrosis factor alpha or transforming growth factor beta1, or to macrophage-like cells when treated with both these cytokines. Initiation of proliferation but not of differentiation was followed by a 20- to 25-fold increase in the nuclear level of the DNA polymerase-associated processivity factor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation but not of proliferation was followed by a 25- to 30-fold increase in the nuclear level of the tumor suppressor proteins p53 (wild type), pRb, and p130/Rb2 and of the p53-dependent cyclin kinase inhibitor p21/Cip1. p53 and p21/Cip1, respectively, inhibit the expression and activation of PCNA, whereas p130 and pRb, respectively, inhibit the expression and activation of E2F1. As a result, G1-S-associated DNA and mRNA synthesis is inhibited, growth uncoupled from differentiation, and maturation enabled to proceed. Where this function of the tumor suppressor proteins is impaired, the capacity for differentiation is lost, which leads to the sustained proliferation that is characteristic of the cancer cell.
...
PMID:Tumor suppressor proteins as regulators of cell differentiation. 976 53

The p21Cdn1 protein (cip1/waf1/sdi1) plays an important role as an inhibitor of mammalian cell proliferation in response to DNA damage. By interacting with and inhibiting the function of cyclin-Cdk complexes, p21 can block entry into S phase. p21 can also directly inhibit replicative DNA synthesis by binding to the DNA polymerase sliding clamp factor PCNA. When cells are damaged and p21 is induced, DNA nucleotide excision repair (NER) continues, even though this pathway is PCNA-dependent. We investigated features of p21-resistant NER using human cell extracts. A direct end-labelling approach was used to measure the excision of damaged oligonucleotides by NER and no inhibition by p21 was found. By contrast, filling of the approximately 30 nt gaps created by NER could be inhibited by pre-binding p21 to PCNA, but only when gap filling was uncoupled from incision. Binding p21 to PCNA could also inhibit filling of model 30 nt gaps by both purified DNA polymerases delta and epsilon. When p21 was incubated in a cell extract before addition of PCNA, inhibition of repair synthesis was gradually relieved with time. This incubation gives p21 the opportunity to associate with other targets. As p21 blocks association of DNA polymerases with PCNA but does not prevent loading of PCNA onto DNA, repair gap filling can occur rapidly as soon as p21 dissociates from PCNA. A synthetic PCNA-binding p21 peptide was an efficient inhibitor of NER synthesis in cell extracts.
...
PMID:Resistance of human nucleotide excision repair synthesis in vitro to p21Cdn1. 987 89

In Saccharomyces cerevisiae, replication origins are activated with characteristic timing during S phase. S-phase cyclin-dependent kinases (S-CDKs) and Cdc7p-Dbf4p kinase are required for origin activation throughout S phase. The activation of S-CDKs leads to association of Cdc45p with chromatin, raising the possibility that Cdc45p defines the assembly of a new complex at each origin. Here we show that both Cdc45p and replication protein A (RPA) bind to Mcm2p at the G(1)-S transition in an S-CDK-dependent manner. During S phase, Cdc45p associates with different replication origins at specific times. The origin associations of Cdc45p and RPA are mutually dependent, and both S-CDKs and Cdc7p-Dbf4p are required for efficient binding of Cdc45p to origins. These findings suggest that S-CDKs and Cdc7p-Dbf4p promote loading of Cdc45p and RPA onto a preformed prereplication complex at each origin with preprogrammed timing. The ARS1 association of Mcm2p, but not that of the origin recognition complex, is diminished by disruption of the B2 element of ARS1, a potential origin DNA-unwinding element. Cdc45p is required for recruiting DNA polymerase alpha onto chromatin, and it associates with Mcm2p, RPA, and DNA polymerase epsilon only during S phase. These results suggest that the complex containing Cdc45p, RPA, and MCMs is involved in origin unwinding and assembly of replication forks at each origin.
...
PMID:Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase. 1075 93


<< Previous 1 2 3 4 5 6 Next >>

---