Disease relevance of Pcna

• Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors [1].
• We found that in myotubes infected with the adenovirus mutant dl520, 12S E1A bypasses the early G1 phase and activates the expression of late-G1 genes, such as the cyclin E and cyclin A genes, cdk2, PCNA, and B-myb [2].
• Disruption of the FEN-1/PCNA Interaction Results in DNA Replication Defects, Pulmonary Hypoplasia, Pancytopenia, and Newborn Lethality in Mice [3].
• Cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by the primary mitogen TCPOBOP and suggests that a direct effect of the mitogen on this cyclin may be responsible for the rapid onset of DNA synthesis observed in TCPOBOP-induced hyperplasia [4].
• The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy [5].

Psychiatry related information on Pcna

• In cell extracts, we found that complementary strand synthesis was inhibited by the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and rescued by the addition of proliferating cell nuclear antigen, arguing for the involvement of DNA polymerase (Pol) delta in the conversion reaction [6].
• Proliferating cell nuclear antigen immunohistochemistry in astrocytes in experimental Creutzfeldt-Jakob disease and in human kuru, Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome [7].

High impact information on Pcna

• We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia [8].
• These results indicate that D-type cyclin-dependent kinases are not essential for cell cycle entry and suggest the existence of alternative mechanisms to initiate cell proliferation upon mitogenic stimulation [9].
• Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts [10].
• When separately overexpressed in mammalian cells, the CDK and PCNA inhibitory domains prevent DNA replication, demonstrating a dual function of p21 as a cell-cycle inhibitor in vivo [11].
• Tumour cell proliferation, as measured by bromodeoxyuridine incorporation and immunohistochemical staining proliferating cell nuclear antigen, was not significantly different in dormant and growing metastases [12].

Chemical compound and disease context of Pcna

• Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice) [13].
• The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases [14].
• Greater expression of transforming growth factor alpha and proliferating cell nuclear antigen staining in mouse hepatoblastomas than hepatocellular carcinomas induced by a diethylnitrosamine-sodium phenobarbital regimen [15].
• The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found [16].
• High glucose-induced hypertrophy of mesangial cells requires p27(Kip1), an inhibitor of cyclin-dependent kinases [17].

Biological context of Pcna

• Together with evidence accumulated in vitro, these results strongly support the idea that the Pcna-dependent pathway predominantly acts in BER of radiation-induced DNA damage in vivo [18].
• The structural gene for proliferating cell nuclear antigen (Pcna) has been mapped to mouse Chromosome (Chr) 2 by use of a PCR-based assay [19].
• The determined gene order is we-0.09 +/- 0.09-Itp-0.62 +/- 0.23-D2Mit77-0.26 +/- 0.15-[Evi-4, Pcna, Prn-p]-0.26 +/- 0.15-Scg-1-0.44 +/- 0.19-[Bmp2a, D2Mit70]-0.09 +/-. 0.09-[D2Mit19, D2Mit46]-1.59 +/- 0.36-D2Mit28-0.97 +/- 0.28-D2Ler1-1.50 +/- 0.35-H-3b-0.26 +/- 0.15-un (% recombination +/- 1 SE) [20].
• The orderly progression through the cell cycle is mediated by the sequential activation of several cyclin/cyclin-dependent kinase (cdk) complexes [21].
• Here we show that in noncycling developing thymocytes, the cyclin- dependent kinase Cdk2 is activated in response to all specific and nonspecific apoptotic stimuli tested, including peptide-specific thymocyte apoptosis [22].

Anatomical context of Pcna

• Similar levels of chromatin-bound Pcna were observed immediately after irradiation in non-S-phase cells of both cell lines and disappeared by 4 h after irradiation [18].
• With somatic cell hybrids, Pcna was mapped between the T(2;4)13H and T(2;4)1Sn breakpoints [19].
• Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity [23].
• Cyclin D1 overexpression resulted in a concomitant increase in CDK4 levels in the adult myocardium, as well as modest increases in proliferating cell nuclear antigen and CDK2 levels [24].
• Hepatocyte mitosis was evaluated by either mitotic figures or proliferating cell nuclear antigen staining [25].

Associations of Pcna with chemical compounds

• In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2'-deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated [26].
• Inhibition of mitogenesis in Balb/c-3T3 cells by Trichostatin A. Multiple alterations in the induction and activation of cyclin-cyclin-dependent kinase complexes [27].
• Our data further suggest that the modulation of cki-cyclin-cdk network by resveratrol may be associated with inhibition of the MAPK pathway [28].
• We also evaluated expression of proliferating cell nuclear antigen (PCNA), of cyclin D1 and the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress [29].
• DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point) [13].

Physical interactions of Pcna

• Collectively, our data demonstrate the importance of the FEN-1/PCNA complex in DNA replication and in the embryonic development of mice [3].
• The Delta3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity [30].
• D-type cyclin/cyclin-dependent kinase (CDK) complexes regulate transit through the restriction point of the cell cycle, and thus are required for the initiation of DNA synthesis [24].
• Our data show that active G1 cyclin/cdk complexes are both necessary and sufficient for induction of cyclin A by Myc [31].
• We show that both the cyclin and cdk2 binding motifs of p21 are crucial for the disruption of this endogenous complex of E2F-p130-cyclin-cdk2 [32].

Enzymatic interactions of Pcna

• Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2-58 mice [33].

Regulatory relationships of Pcna

• Our data provide evidence that p21 regulates the PCNA protein level in adult cardiomyocytes, which has implications for cardiomyocyte growth control [34].
• These results demonstrate that TGF-beta stimulates cyclin D(1) expression at least in part through activation of beta-catenin signaling [35].
• Unlike the earlier expression of Ras(Asn17) at the border between G0 and G1, its delayed expression did not compromise the EGF-stimulated transient activation of extracellular signal-regulated kinases or inhibit the stimulated expression of a principal D-type cyclin, cyclin D1, until close to the border between G1 and S [36].
• Thus, the redundant pathways consisting of cyclin proteolysis and CKIs control CDK activity during mitotic exit and contribute to maintenance of genome stability in mammalian cells [37].
• Tyr-Phe and Met limitation in vitro inhibited cell proliferation and proliferating cell nuclear antigen (PCNA) expression to a greater extent than serum limitation [38].

Other interactions of Pcna

• Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes [21].
• Transgenic mice which overexpress cyclin D1 in the heart were produced to determine if D-type cyclin deregulation would alter myocardial development [24].
• A role for the cyclin kinase inhibitor p27(Kip1) (p27) in limiting proliferation has been shown [39].
• Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis [31].
• p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity [26].

Analytical, diagnostic and therapeutic context of Pcna

• Pancreata were studied by routine histological examination and electron microscopy and were immunostained for proliferating cell nuclear antigen (PCNA) [40].
• Immunohistochemistry with antibody reactive with PCNA revealed increased cellular proliferation in the neural tube and the brain, and decreased proliferation in the heart [41].
• In addition, microinjection of recombinant cyclin A2-CDK2 protein increased transcriptional activity [42].
• Alpha-smooth muscle actin, desmin and proliferating cell nuclear antigen were assessed by immunohistochemical testing of whole bladders and Western blot analysis of dissected detrusor layers [43].
• As it has been reported that nuclei undergoing active gene transcription can be TUNEL positive, we evaluated the percentage of PCNA-positive cells, which proved to be 45.2 +/- 4.68% along the endothelium and 22.3 +/- 2.7% in the intima [44].

References