Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4097-4103 ◽  
Author(s):  
Yasuhito Ide ◽  
Daisuke Tsuchimoto ◽  
Yohei Tominaga ◽  
Manabu Nakashima ◽  
Takeshi Watanabe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Proliferating Cell Nuclear Antigen ◽  
Cell Cycle Progression ◽  
Immunoglobulin M ◽  
Nuclear Antigen ◽  
Wild Type ◽  
Cycle Progression ◽  
Class Switch ◽  
M Phase ◽  
Proliferating Cell

Abstract APEX2/APE2 is a secondary mammalian apurinic/apyrimidinic endonuclease that associates with proliferating cell nuclear antigen (PCNA), and the progression of S phase of the cell cycle is accompanied by its expression. To determine the biologic significance of APEX2, we established APEX2-null mice. These mice were about 80% the size of their wild-type littermates and exhibited a moderate dyshematopoiesis and a relatively severe defect in lymphopoiesis. A significant accumulation of both thymocytes and mitogen-stimulated splenocytes in G2/M phase was seen in APEX2-null mice compared with the wild type, indicating that APEX2 is required for proper cell cycle progression of proliferating lymphocytes. Although APEX2-null mice exhibited an attenuated immune response against ovalbumin in comparison with wild-type mice, they produced both antiovalbumin immunoglobulin M (IgM) and IgG, indicating that class switch recombination can occur even in the absence of APEX2. (Blood. 2004;104: 4097-4103)

scholarly journals The distribution pattern of proliferating cell nuclear antigen in the nuclei of Leishmania donovani

Microbiology ◽  
2009 ◽  
Vol 155 (11) ◽  
pp. 3748-3757 ◽  
Author(s):  
Devanand Kumar ◽  
Neha Minocha ◽  
Kalpana Rajanala ◽  
Swati Saha
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Proliferating Cell Nuclear Antigen ◽  
Cell Cycle Progression ◽  
Leishmania Donovani ◽  
Systemic Disease ◽  
S Phase ◽  
Nuclear Antigen ◽  
M Phase ◽  
Proliferating Cell

DNA replication in eukaryotes is a highly conserved process marked by the licensing of multiple origins, with pre-replication complex assembly in G1 phase, followed by the onset of replication at these origins in S phase. The two strands replicate by different mechanisms, and DNA synthesis is brought about by the activity of the replicative DNA polymerases Pol δ and Pol ϵ. Proliferating cell nuclear antigen (PCNA) augments the processivity of these polymerases by serving as a DNA sliding clamp protein. This study reports the cloning of PCNA from the protozoan Leishmania donovani, which is the causative agent of the systemic disease visceral leishmaniasis. PCNA was demonstrated to be robustly expressed in actively proliferating L. donovani promastigotes. We found that the protein was present primarily in the nucleus throughout the cell cycle, and it was found in both proliferating procyclic and metacyclic promastigotes. However, levels of expression of PCNA varied through cell cycle progression, with maximum expression evident in G1 and S phases. The subnuclear pattern of expression of PCNA differed in different stages of the cell cycle; it formed distinct subnuclear foci in S phase, while it was distributed in a more diffuse pattern in G2/M phase and post-mitotic phase cells. These subnuclear foci are the sites of active DNA replication, suggesting that replication factories exist in Leishmania, as they do in higher eukaryotes, thus opening avenues for investigating other Leishmania proteins that are involved in DNA replication as part of these replication factories.

Demonstration of cell cycle kinetics in thyroid primary culture by immunostaining of proliferating cell nuclear antigen: differences in cyclic AMP-dependent and -independent mitogenic stimulations

1993 ◽  
Vol 105 (1) ◽  
pp. 69-80 ◽  
Author(s):  
M. Baptist ◽  
J.E. Dumont ◽  
P.P. Roger
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Primary Culture ◽  
Proliferating Cell Nuclear Antigen ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Major Influence ◽  
Cell Cycle Kinetics ◽  
Experimental Conditions ◽  
Proliferating Cell

In this study, experimental conditions are described that allowed us to follow the fate of the DNA polymerase delta-associated proliferating cell nuclear antigen (PCNA), by immunolabeling during the overall cell cycle. Differences in subcellular localization or the presence of PCNA allowed us to identify each phase of the cell cycle. Using these cell cycle markers in dog thyroid epithelial cells in primary culture, we found unexpected differences in cell cycle kinetics, in response to stimulations through cAMP-dependent and cAMP-independent pathways. These provide a new dimension to the view that the two pathways are largely separate, but co-operate on DNA synthesis initiation. More precisely, thyrotropin (TSH), acting via cAMP, exerts a potent triggering effect on DNA synthesis, associated with a precocious induction of PCNA appearance. This constitutes the major influence of TSH (cAMP) in determining cell cycle progression, which is only partly moderated by TSH-dependent lengthening of S- and G2-phases.

scholarly journals bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)

2020 ◽  
Vol 117 (11) ◽  
pp. 5791-5800 ◽  
Author(s):  
Shuhui Lim ◽  
Regina Khoo ◽  
Khong Ming Peh ◽  
Jinkai Teo ◽  
Shih Chieh Chang ◽  
...  
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Cycle Progression ◽  
E3 Ligases ◽  
Affinity Ligands ◽  
Complementary Approach ◽  
Target Binding ◽  
Traditional Approaches ◽  
Proliferating Cell

Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)—engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates, we show that there is considerable flexibility in both the choice of substrate binders (binding positions, scaffold-class) and the E3 ligases. We then identified a highly effective bioPROTAC against an oncology target, proliferating cell nuclear antigen (PCNA) to elicit rapid and robust PCNA degradation and associated effects on DNA synthesis and cell cycle progression. Overall, bioPROTACs are powerful tools for interrogating degradation approaches, target biology, and potentially for making therapeutic impacts.

scholarly journals Varicella-Zoster Virus ORF12 Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway To Regulate Cell Cycle Progression

2012 ◽  
Vol 87 (3) ◽  
pp. 1842-1848 ◽  
Author(s):  
XueQiao Liu ◽  
Jeffrey I. Cohen
Keyword(s):  
Cell Cycle ◽  
Deletion Mutant ◽  
Cell Cycle Progression ◽  
Phase Cell ◽  
Akt Pathway ◽  
Wild Type ◽  
Cycle Progression ◽  
Varicella Zoster ◽  
M Phase ◽  
Regulate Cell Cycle Progression

ABSTRACTVaricella-zoster virus (VZV) activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and alters cell cycle progression, but the viral protein(s) responsible for these activities is unknown. We previously reported that the VZV open reading frame 12 (ORF12) protein triggers phosphorylation of ERK. Here, we demonstrate that the VZV ORF12 protein also activates the PI3K/Akt pathway to regulate cell cycle progression. Transfection of cells with a plasmid expressing the ORF12 protein induced phosphorylation of Akt, which was dependent on PI3K. Infection of cells with wild-type VZV triggered phosphorylation of Akt, while infection with an ORF12 deletion mutant induced less phosphorylated Akt. The activation of Akt by ORF12 protein was associated with its binding to the p85 subunit of PI3K. Infection of cells with wild-type VZV resulted in increased levels of cyclin B1, cyclin D3, and phosphorylated glycogen synthase kinase 3β (GSK-3β), while infection with the ORF12 deletion mutant induced lower levels of these proteins. Wild-type VZV infection reduced the G1phase cell population and increased the M phase cell population, while infection with the ORF12 deletion mutant had a reduced effect on the G1and M phase populations. Inhibition of Akt activity with LY294002 reduced the G1and M phase differences observed in cells infected with wild-type and ORF12 mutant viruses. In conclusion, we have found that the VZV ORF12 protein activates the PI3K/Akt pathway to regulate cell cycle progression. Since VZV replicates in both dividing (e.g., keratinocytes) and nondividing (neurons) cells, the ability of the VZV ORF12 protein to regulate the cell cycle is likely important for VZV replication in various cell types in the body.

scholarly journals Effect of Surface Coating of Gold Nanoparticles on Cytotoxicity and Cell Cycle Progression

Nanomaterials ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 1063 ◽  
Author(s):  
Qian Li ◽  
Chun Huang ◽  
Liwei Liu ◽  
Rui Hu ◽  
Junle Qu
Keyword(s):  
Cell Cycle ◽  
Gold Nanoparticles ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Biocompatible Polymers ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Microtubule Stabilization ◽  
Lysosomal Accumulation ◽  
Proliferating Cell

Gold nanoparticles (GNPs) are usually wrapped with biocompatible polymers in biomedical field, however, the effect of biocompatible polymers of gold nanoparticles on cellular responses are still not fully understood. In this study, GNPs with/without polymer wrapping were used as model probes for the investigation of cytotoxicity and cell cycle progression. Our results show that the bovine serum albumin (BSA) coated GNPs (BSA-GNPs) had been transported into lysosomes after endocytosis. The lysosomal accumulation had then led to increased binding between kinesin 5 and microtubules, enhanced microtubule stabilization, and eventually induced G2/M arrest through the regulation of cadherin 1. In contrast, the bare GNPs experienced lysosomal escape, resulting in microtubule damage and G0/G1 arrest through the regulation of proliferating cell nuclear antigen. Overall, our findings showed that both naked and BSA wrapped gold nanoparticles had cytotoxicity, however, they affected cell proliferation via different pathways. This will greatly help us to regulate cell responses for different biomedical applications.

Modulation of the nuclear antigen p105 as a function of cell-cycle progression

1987 ◽  
Vol 130 (3) ◽  
pp. 336-343 ◽  
Author(s):  
Charles V. Clevenger ◽  
Alan L. Epstein ◽  
Kenneth D. Bauer
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Cycle Progression

scholarly journals Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

2014 ◽  
Vol 58 (6) ◽  
pp. 2997-3007 ◽  
Author(s):  
Rati Tandon ◽  
Sharat Chandra ◽  
Rajendra Kumar Baharia ◽  
Sanchita Das ◽  
Pragya Misra ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Proliferating Cell Nuclear Antigen ◽  
Leishmania Donovani ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Nuclear Antigen ◽  
Wild Type ◽  
Content Type ◽  
Sensitive Isolate ◽  
Proliferating Cell

ABSTRACTPreviously, through a proteomic analysis, proliferating cell nuclear antigen (PCNA) was found to be overexpressed in the sodium antimony gluconate (SAG)-resistant clinical isolate compared to that in the SAG-sensitive clinical isolate ofLeishmania donovani. The present study was designed to explore the potential role of the PCNA protein in SAG resistance inL. donovani. For this purpose, the protein was cloned, overexpressed, purified, and modeled. Western blot (WB) and real-time PCR (RT-PCR) analyses confirmed that PCNA was overexpressed by ≥3-fold in the log phase, stationary phase, and peanut agglutinin isolated procyclic and metacyclic stages of the promastigote form and by ∼5-fold in the amastigote form of the SAG-resistant isolate compared to that in the SAG-sensitive isolate.L. donovaniPCNA (LdPCNA) was overexpressed as a green fluorescent protein (GFP) fusion protein in a SAG-sensitive clinical isolate ofL. donovani, and modulation of the sensitivities of the transfectants to pentavalent antimonial (SbV) and trivalent antimonial (SbIII) drugs was assessedin vitroagainst promastigotes and intracellular (J774A.1 cell line) amastigotes, respectively. Overexpression of LdPCNA in the SAG-sensitive isolate resulted in an increase in the 50% inhibitory concentrations (IC50) of SbV(from 41.2 ± 0.6 μg/ml to 66.5 ± 3.9 μg/ml) and SbIII(from 24.0 ± 0.3 μg/ml to 43.4 ± 1.8 μg/ml). Moreover, PCNA-overexpressing promastigote transfectants exhibited less DNA fragmentation compared to that of wild-type SAG-sensitive parasites upon SbIIItreatment. In addition, SAG-induced nitric oxide (NO) production was found to be significantly inhibited in the macrophages infected with the transfectants compared with that in wild-type SAG-sensitive parasites. Consequently, we infer that LdPCNA has a significant role in SAG resistance inL. donovaniclinical isolates, which warrants detailed investigations regarding its mechanism.

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