Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA polymerase delta, and is expressed at high levels in growing normal and tumor cells. To clarify the relationship between cell proliferation and PCNA expression, we generated NIH-3T3 cells that overexpress PCNA and analyzed the phenotype of these cells. The resulting 3T3-PCNA cells, which overexpressed PCNA, were found to proliferate beyond the saturation density of the parental NIH-3T3 cells. Although NIH-3T3 cell proliferation is arrested under serum starvation conditions, 3T3-PCNA cell proliferation is not arrested by serum starvation. The expression levels of cdk2, cdk4 and cdk6 were the same in 3T3-PCNA and NIH-3T3 cells. The activity of cdk4 was identical for both cell types. However, the activity of cdk2 was higher in serum-starved 3T3-PCNA cells than in NIH-3T3 cells, although the expression of cyclin E decreased in both types of cells, suggesting that increases in cdk2 activity are related to negation of growth arrest in 3T3-PCNA cells. These results indicate that increases in PCNA expression lead to the disruption of growth control and may lead to malignant transformation.
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PMID:Overexpression of proliferating cell nuclear antigen in mammalian cells negates growth arrest by serum starvation and cell contact. 1035 43

Proliferating cell nuclear antigen is best known as a DNA polymerase accessory protein but has more recently also been shown to have different functions in important cellular processes such as DNA replication, DNA repair, and cell cycle control. PCNA has been found in quaternary complexes with the cyclin kinase inhibitor p21 and several pairs of cyclin-dependent protein kinases and their regulatory partner, the cyclins. Here we show a direct interaction between PCNA and Cdk2. This interaction involves the regions of the PCNA trimer close to the C termini. We found that PCNA and Cdk2 form a complex together with cyclin A. This ternary PCNA-Cdk2-cyclin A complex was able to phosphorylate the PCNA binding region of the large subunit of replication factor C as well as DNA ligase I. Furthermore, PCNA appears to be a connector between Cdk2 and DNA ligase I and to stimulate phosphorylation of DNA ligase I. Based on our results, we propose the model that PCNA brings Cdk2 to proteins involved in DNA replication and possibly might act as an "adaptor" for Cdk2-cyclin A to PCNA-binding DNA replication proteins.
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PMID:A direct interaction between proliferating cell nuclear antigen (PCNA) and Cdk2 targets PCNA-interacting proteins for phosphorylation. 1093 Apr 25

Proliferating cell nuclear antigen (PCNA) is an essential protein in both DNA replication and DNA damage repair. A novel 15 kD protein, p15(PAF), was identified as a PCNA-associated factor in a yeast two-hybrid screen using PCNA as the bait. p15(PAF) is localized primarily in the nucleus. p15(PAF) shares the conserved PCNA binding motif with several other PCNA binding proteins including CDK inhibitor p21. Overexpression of p15(PAF) competes with p21-PCNA binding. Mutation of this motif in p15(PAF) abolished its PCNA-binding activity. Notably, p15(PAF) expression in several types of tumor tissues was significantly increased, especially in esophageal tumors. Like PCNA, p15(PAF) may possess prognostic significance in a broad array of human cancers.
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PMID:p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues. 1131 79

While the pesticide methoxychlor (MXC) has a variety of adverse effects on the female reproductive system, the effects of MXC on the ovarian surface epithelium (OSE) are unknown. Thus, this study tested the hypothesis that MXC alters the growth of the OSE. Mouse OSE cells were isolated by enzymatic digestion and cultured with vehicle, 3 microM of MXC, or 3 microM of 2,2-bis[p-hydroxyphenyl]-1,1,1,-trichloroethane (HPTE) for 14 days. After culture, proliferation and apoptosis were assessed by measurement of cell density, immunohistochemistry, and real-time polymerase chain reaction. Cell density was 66% greater for MXC-treated cells and 95% greater for HPTE-treated cells than controls (p < or = 0.05). The estrogen receptor blocker ICI 182,780 abolished MXC- and HPTE-induced increases in cell density. Proliferating cell nuclear antigen (PCNA) staining was positive in only 22 +/- 2.3% of controls, compared to 35 +/- 2.4% of MXC-treated cells and 40 +/- 2.4% of HPTE-treated cells (p < or = 0.05). The cell cycle regulators, cyclinD2 and cdk4, were significantly increased in MXC- and HPTE-treated cells compared to controls. The ApopTag assay demonstrated apoptotic cells in 4.8 +/- 0.45% of controls, 2.2 +/- 0.56% of MXC-treated cells, and 2.1 +/- 0.33% of HPTE-treated cells (p < or = 0.005). Expression of bcl-2 was significantly increased in MXC- and HPTE-treated cells, while bax was decreased in MXC- and HPTE-treated cells compared to controls. Collectively, these data indicate that MXC and HPTE stimulate OSE cell growth by increasing proliferation and inhibiting apoptosis. Further, since ICI 182,780 blocked MXC- and HPTE-induced OSE growth, these data suggest that the effects of MXC and HPTE on the OSE are mediated by estrogen receptors.
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PMID:Methoxychlor induces proliferation of the mouse ovarian surface epithelium. 1552 93

Chagas' disease caused by the parasite, Trypanosoma cruzi, is accompanied by an acute myocarditis which can be fatal. Mice (A/J strain) infected with T. cruzi (Tulahuen strain) develop an acute myocarditis associated with high parasitemia and uniform mortality. Examination of the myocardium demonstrated myonecrosis, vasculitis and parasite pseudocysts. Immunoblot analysis and quantitative real time PCR of heart lysates demonstrated an increased expression of cell cycle regulatory proteins such as cyclins B1, D1, A1 and E1 and an increased expression of cdk2 when compared with uninfected controls. Extracellular signal-regulated kinase (ERK) was activated. Proliferating cell nuclear antigen (PCNA), endothelin-1, endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) expression were increased. Caveolin-1 is important in the regulation of ERK and cyclin D1. The expression of caveolin-1 as well as caveolin-2 and caveolin-3 was reduced. These data suggest that acute fatal T. cruzi myocarditis is accompanied by changes in cell cycle proteins such as the cyclins and caveolin and that the upregulation of the endothelin pathway may be important in the myocardial abnormalities and mortality observed in this mouse model.
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PMID:Cyclin and caveolin expression in an acute model of murine Chagasic myocarditis. 1631 33