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PubMed2002

Bcl-2 can promote p53-dependent senescence versus apoptosis without affecting the G1/S transition.

With the aim to identify events involved in the determination of p53-dependent apoptosis versus growth arrest, we used rat embryo fibroblasts expressing a temperature-sensitive mutant (tsA58) of the SV40 large tumour antigen (LT). Heat-inactivation of LT leads to p53 activation and commitment to a senescent-like state (REtsA15 cell line) or apoptosis (REtsAF cell line). We report that senescence is associated with high levels of the anti-apoptotic Bcl-2 protein and a cell cycle arrest in G1 phase, whereas apoptosis is associated with low levels of Bcl-2 and a cell cycle arrest in G2 phase. Here we show that Bcl-2, which can inhibit apoptosis and proliferation, turns the apoptotic phenotype into a senescent-like phenotype in G2 phase. This result suggests that Bcl-2-dependent inhibition of apoptosis could be crucial for the commitment to replicative senescence, whereas its ability to inhibit G1 progression would not be required.

Animals↗

PubMed2006

Aquatic herbicides and herbicide contaminants: In vitro cytotoxicity and cell-cycle analysis.

Concerns have arisen about the possible effects of herbicide contamination in aquatic ecosystems. Crop herbicides are introduced into the aquatic environment both inadvertently through runoff events and intentionally through the use of those registered for use in waterways. Acetochlor and atrazine are two agricultural crop herbicides that have often been reported to contaminate waters. Diquat and fluridone are both registered aquatic management herbicides. In this study, a mammalian in vitro cell cytotoxicity assay was used to evaluate the cytotoxicity of these four commonly used herbicides. The ranked order of the cytotoxicity was: diquat (C(1/2) = 0.036 mM +/- 0.011) > acetochlor (C(1/2) = 0.060 mM +/- 0.010) > fluridone (C(1/2) = 0.172 mM +/- 0.029) atrazine (C(1/2) = 0.581 mM +/- 0.050). In addition, flow cytometric analysis was conducted on CHO cells to investigate the potential impact of these four herbicides on the cell cycle. Acetochlor and diquat had the greatest impact on the cell cycle. Acetochor exposure resulted in a decreased number of cells in the G1 phase of the cell cycle, whereas diquat exposure resulted in a decreased number of cells in both the G1 and G2 phases. Both atrazine and fluridone resulted in a decrease in cells in the G2 phase. The agricultural crop herbicides and aquatic management herbicides gave similar results in cytotoxicity and in the cell-cycle assay at the end points tested.

Agriculture↗

PubMed1994

Characterization of a DNA-binding nuclear autoantigen mainly associated with S phase and G2 cells.

During analysis of autoimmune sera showing reactivity to nuclear antigens a serum producing a previously undescribed cell cycle-specific nuclear immunofluorescence pattern was observed. By indirect immunofluorescence the serum generated a densely speckled nucleoplasmic staining pattern of varying intensity with relative sparing of the nucleoli. The staining pattern could be abolished by treating cells with DNase but was not affected by RNase treatment. By flow cytometric dual parameter analysis the antigen expression was shown to increase during S phase with a maximum in G2 cells, whereas G1 and M cells expressed low levels. The cell cycle-specific expression of the target antigen was similar in some aspects to the expression of cyclin A but clearly not identical. The serum recognized a 68/60 kDa doublet in immunoblotting of soluble MOLT-4 cell extract. Antibodies eluted separately from either of the two bands produced the cell cycle-specific staining pattern as well as the doublet in immunoblotting. DNA-cellulose was used for analysis of DNA-binding property and the higher band was found to be DNA-binding, whereas the lower band was not. In summary, this serum reacts with a DNA-binding and cell cycle-specific nuclear antigen which might be a novel protein involved in cell cycle progression.

Aged↗

PubMed1993

X-ray-induced chromatid damage in relation to DNA repair and cancer incidence in family members.

The cytogenetic response to G2-phase X-irradiation was examined in phytohemagglutinin-stimulated peripheral-blood lymphocytes from 69 individuals, a few of whom were cancer patients. The cancer patients had not received radiation or chemotherapy. The responses of cells arrested by Colcemid 30 to 90 min after X-irradiation (58R) could be divided into 2 distinct categories: 51 individuals had aberration frequencies typical of normal individuals in previous studies, while 18 others had a 2- to 3-fold higher frequency of chromatid breaks and gaps. Because chromatid breaks and gaps result from unrepaired DNA strand breaks, the first category may represent an efficient DNA repair phenotype, while the second may represent a deficient repair phenotype. The individuals with the deficient G2 response reported having first- and second-degree relatives with a 3.6- and 2.2-fold higher mean frequency of cancer, respectively. The present results, together with those from earlier studies of families with a genetic disorder predisposing to cancer, suggest that this deficient cytogenetic response to G2 phase X-irradiation is associated with a high risk of cancer.

Adolescent↗

PubMed2006

Variations in cyclin D1 levels through the cell cycle determine the proliferative fate of a cell.

We present evidence that variations in cyclin D1 levels through the cell cycle are essential for continuing proliferation. Cyclin D1 levels must be high during G1 phase for a cell to initiate DNA synthesis, but then must be suppressed to low levels during S phase to allow for efficient DNA synthesis. This suppression during S phase is apparently regulated by cell cycle position alone and occurs automatically during each cell cycle. If the cell is to continue proliferating, cyclin D1 levels must be induced once again during G2 phase. This induction depends upon the activity of proliferative signaling molecules, and ensures that the extracellular environment continues to be conducive for growth. We propose that the suppression of cyclin D1 levels during each S phase ensures that the subsequent induction during G2 phase, and the resulting commitment to continuing proliferation, is closely linked to the cellular growth environment.

Journal Article↗

PubMed1994

The action of the DNA intercalating agents 4'-(9-acridinylamino) methanesulphon-m-anisidide and 1,4-bis(butylamino) benzo[g]phthalazine in U-937 human promonocytic cells: relationship between cell cycle and differentiation.

The action of two structurally related DNA intercalating agents has been studied and compared, namely 4'-(9-acridinylamino) methanesulphon-m-anisidide (amsacrine, mAMSA) and 1,4-bis(butylamino)benzo[g]phthalazine (ABP) on the cell cycle and differentiation of U-937 human promonocytic leukemia cells. mAMSA (0.1 microM) and ABP (4 microM) reduced the proliferation activity to a similar extent and caused little cell mortality. At these subcytotoxic concentrations mAMSA induced the cells to accumulate at the G2 phase of the cycle, while cycle inhibition provoked by ABP was not phase specific. In addition, mAMSA caused an increase in the cell mass while ABP provoked cell shrinkage. This was consistent with the fact that ABP considerably inhibited protein synthesis, while mAMSA did not significantly affect this activity. SDS/K+DNA precipitation assays indicated that mAMSA, but not ABP, stimulated protein-DNA covalent complex formation. Finally, it was found that mAMSA, but not ABP, elicited the expression of differentiation markers, namely nitroblue tetrazolium reduction, activation of vimentin and leukocyte integrin (CD11b/CD18 and CD11c/CD18) expression, and downregulation of c-myc expression. The DNA intercalators doxorubicin and mitoxantrone, which like mAMSA induced the cells to accumulate at the G2 phase and increased the cell mass, induced the expression of differentiation markers. In contrast, the intercalators aclarubicin and caffeine and the non-intercalator novobiocin, which produced minor alterations on cell-cycle distribution and caused cell shrinkage, did not significantly elicit differentiation. These results support the conclusion that differentiation of myeloid leukemia cells by cytostatic drugs depends on the perturbations of the cell cycle, leading to disproportionate increases in cell mass.

Amsacrine↗

PubMed1996

Comparison of the cell cycle regulated synthesis and phosphorylation of stress proteins, actin isoforms and a novel actin-like protein following drug administration in cultured rat lymphocytes.

Administration of phytohemagglutinin initiated cycling of rat lymphocytes in vitro, and following treatment with this drug and other drugs in combination, lymphocytes were pulse labeled with [3H] leucine of [32P] phosphate. The nuclei were isolated from lymphocytes and collected from partitions of the cell cycle, and the proteins analyzed from fluorographs following gel electrophoresis for protein biomarkers after drug exposure. Stress proteins (sps) were dependent on a specific drug or drugs in combination (i.e., interleukin-2, bleomycin) for their synthesis that occurred only during the G1-phase of the cell cycle. An "actin-like" protein (A4) with electrophoretic mobilities similar to the actin complex, was synthesized in S and G2 phases and phosphorylated in all phases of the cell cycle only following the administration of drugs in combination. A4 exhibited a binding affinity for sp 24 that was cell cycle regulated (i.e., A4 from S phase did not bind with sp 24, but A4 from G2 phase did bind with the sp. Protein A4 appeared similar in some structural aspects to the nonmuscular actin isoform family but differed in epitope, suggesting a unique relationship and represented a stable protein, perhaps a product from the mutation of an actin gene. The dependence of certain sps and protein A4 for their induction by drugs in combination may serve as biomarkers of chemical interaction and toxicity.

Actins↗

PubMed1992

Effects of adenine arabinoside and coformycin on the kinetics of G2 chromatid aberrations in X-irradiated human lymphocytes.

The kinetics of chromatid aberrations have been studied in human lymphocytes exposed to X-rays in the G2 phase of the cell cycle and incubated with or without the nucleoside analogue 9-beta-D-arabinofuranosyladenine (ara A), known to inhibit the repair of DNA double-strand breaks. In the absence of ara A an exponential decrease in frequencies of chromatid breaks occurred which we interpret as repair. Few breaks were observed if samples were harvested immediately following irradiation. The frequency of chromatid breaks at 1 h after X-irradiation (442 per 100 cells/Gy) was similar to that previously observed in Chinese hamster ovary (CHO) K1 cells. However, the exponential decrease of chromatid breaks between X-irradiation and sampling occurred with a t1/2 of 0.87 h, a faster rate than we have previously observed in CHO K1 cells and was not inhibited by 200 microM ara A alone, in contrast with our previous findings in a human fibroblast line. However, in the presence of the ADA inhibitor coformycin, inhibition of break repair was already observed at an ara A concentration of 100 microM indicating that the apparent unresponsiveness to ara A of lymphocyte chromatid break rejoining results from the deamination of this nucleoside analogue. This deamination effect was confirmed by measurements of DNA synthesis which showed stable inhibition of synthesis by ara A only when coformycin was present. Frequencies of chromatid exchanges in irradiated cells remained constant except at the sampling time directly after irradiation, consistent with the view that chromosomal radiosensitivity remained constant throughout the G2 phase, except for the period immediately prior to mitosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatids↗

PubMed1997

Spontaneous premature chromosome condensation and mitotic catastrophe following irradiation of HeLa S3 cells.

PURPOSE: To study the mechanisms underlying the loss of G2/M checkpoint control which leads to mitotic catastrophe in human tumour cells following exposure to ionizing radiation. MATERIALS AND METHODS: Asynchronous HeLa S3 cells were irradiated with doses of 5, 10 and 20 Gy X-rays. Cell-cycle progression and cyclin B1 levels were measured using bivariate flow-cytometric techniques as a function of time after irradiation. As indicators of mitotic catastrophe, the appearance of spontaneous premature chromosome condensation (SPCC) and cells presenting nuclear fragmentation were analysed using microscopy. Cyclin B1-dependent kinase activity was determined in immunoprecipitates and analysed using gel electrophoresis. RESULTS: After X-irradiation of HeLa cells, delays in late S and G2 phases of the cell cycle were followed by SPCC and nuclear fragmentation, both indicative of mitotic catastrophe. The kinetics of appearance of cells that had apparently undergone mitotic catastrophe (i.e. the fraction of cells exhibiting nuclear fragmentation) was independent of the dose-dependent radiation-induced division delay, while the extent of fragmentation (expressed as the number of nuclear fragments per fragmented cell) did increase with dose. Also observed was a 5-fold elevation of cyclin B1 levels in late S/G2 cells, which correlated temporally with the observed delays late in the cell cycle. Following the appearance of elevated cyclin levels, cyclin B1-associated histone H1 kinase activity showed similar increases; these increases in kinase activity occurred prior to increases in the fraction of cells exhibiting nuclear fragmentation. CONCLUSIONS: In human cells, cyclin B1 gene expression occurs in late S and G2 phases, and thus the increase observed in this protein may be due to the increased time spent by cells in these phases as a result of cell-cycle delays caused by the radiation exposure. It is possible that, under these conditions, over accumulation of cyclin B1 dilutes the mitosis-inhibitory action of the weel or other inhibitory pathways. Thus, this study presents a possible mechanism for G2/M checkpoint abrogation following ionizing radiation which may depend solely on effects associated with perturbed cell-cycle progression.

Animals↗

PubMed1984

The influence of G2 progression on X-ray sensitivity of two-cell mouse embryos.

Naturally synchronous, two-cell mouse embryos were X-irradiated in vitro. In experiment 1, irradiation was either in the early or in the late G2 phase, which lasts about 14 hours. In experiment 2, irradiation of all the embryos was in late G2 but embryos with different intervals between irradiation and the first mitosis after irradiation were separated and investigated independently. After 2 Gy the time interval between irradiation in late G2 and the first mitosis post-irradiation was on the average about 9 hours; after irradiation in the early G2 phase about 13.5 hours. Development (hatching of blastocysts) and cell proliferation (cell number per embryo at the stage of the hatched blastocyst) was most impaired and the frequency of micronuclei (determined in four- or eight-cell embryos) was highest in the case of a short interval between irradiation in G2 and the first mitosis post-irradiation. It is concluded that a longer interval allows a longer period of DNA repair. The results also demonstrate a positive correlation between the extent of chromosomal damage (micronuclei) and the extent of cell death as well as the impairment of the development of the whole biological system.

Animals↗

PubMed2000

Two proteins, a goldfish 20S proteasome subunit and the protein interacting with 26S proteasome, change in the meiotic cell cycle.

To investigate the regulatory mechanism for the proteasome in the meiotic cell cycle, we purified the 26S proteasome from immature (in G2-phase) and mature (in M-phase) oocytes, and compared its subunits by immunoblotting. At least two protein bands, at 30 kDa (detected by GC3beta antibody) and 62 kDa (detected by 1-4D5 antibody), differed between 26S proteasomes. A monoclonal antibody, GC3beta cross-reacted with two bands in the 26S proteasome from immature oocytes, however, the upper band was absent in the 26S proteasome from mature oocytes. The 62-kDa protein band detected by 1-4D5 antibody was not detected in the immature oocyte 26S proteasome; however, a band was detected in mature oocyte 26S proteasome. The cDNAs encoding these proteins were isolated by an immunoscreening method using the monoclonal antibodies. The 30-kDa protein was an alpha4 subunit, which is one of the alpha-subunit group of the 20S proteasome, and the 62-kDa protein was a homologue of CCTepsilon, one of the components of eukaryotic molecular chaperones. Phosphatase treatment of the 26S proteasome revealed that a part of the alpha4 subunit of goldfish 20S proteasome, alpha4_ca, is phosphorylated in G2-phase and dephosphorylated in M-phase. A binding assay using a recombinant goldfish CCTepsilon revealed that unmodified CCTepsilon interacts with the 26S proteasome. Fertilization triggers a transition from meiotic metaphase to mitotic interphase. During fertilization, a GC3beta cross-reacting upper band reappeared. The 62-kDa band dissociated from the 26S proteasome. As a result, the 26S proteasome changed to an immature type from a mature type during fertilization. These results suggest that the 26S proteasome is changed reversibly during the meiotic cell cycle by modification of its subunits and interactions between regulators.

Amino Acid Sequence↗

PubMed1975

[Circadian rhythm of the mitotic activity and of the number of nuclei synthesizing DNA in sarcoma 37 in white mice].

Circadian variations in the frequency of mitoses and the number of nuclei labed with thymidine-H3 in sarcoma-37 of mice were investigated. It was shown that the circadian rhythm of mitotic activity was composed of diurnal variations in the frequency of labeled and unlabeled mitoses. The G2-phase of mitotic cycle of the cells with labeled mitosis was approximately one hour. The G2-phase of the cells with unlabed mitosis lasted four hours and more. It is suggested that there are two cell populations in sarcoma-37.

Animals↗

PubMed1985

[DNA synthesis and content and the accumulation of total protein and hemoglobin during the differentiation of primary erythroid cells in chickens].

Using cytophotometric and autoradiographic methods, it was shown that on days 2-3 of embryogenesis primary erythroid cells (PEC) divided actively. The distribution of erythroblasts (EB) according to their DNA content is not, however, typical of a proliferating population: it contains an unusually large number of 4c cells resulting from the cell cycle arrest at the G2 phase. It is established that reticulocytes (RC) do not divide and are arrested at G1 or G2 phases, since they do not incorporate 3H-thymidine after their formation is complete and their DNA contents are strictly confined to either 2c or 4c. All types of PEC include a large number of cells containing H2c DNA which is due either to the cell cycle arrest at the S phase, or to the formation of accessory nuclei. All PECs have much higher contents of hemoglobin and total protein than do adult hen erythrocytes (EC). Hemoglobin and total protein contents of H2c and accessory nuclei containing cells are much higher than those in 2c-cells. We have calculated that adult birds and embryos contain the same amount of hemoglobin per gram of weight, but the quantity of red blood cells in the former is ten times higher. A conclusion is drawn that proliferation and cytodifferentiation regulation mechanisms are directed, in primary erythropoiesis, to intense hemoglobinization of the cells, and, in adult erythropoiesis, to increasing their number. In both the cases homeostatic regulation of erythropoiesis works.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Alteration of gamma-ray-induced chromosome aberration by 0.5 M NaCl in Chinese hamster cells.

Hypertonic treatment (0.5 M NaCl in phosphate-buffered saline, pH 7.2) at 37 degrees C for 20 min slightly delayed the mitotic frequency for non-irradiated cells in G1 and G2 phases. The mitotic frequency for irradiated cells in G2 was delayed by hypertonic treatment, and that in G1 was slightly delayed by hypertonic treatment. Hypertonic treatment in non-irradiated cells did not induce any chromosomal or chromatid aberrations in either G1 or G2. Chromosomal aberrations caused by gamma-irradiation were slightly enhanced by hypertonic treatment, and chromatid aberrations were markedly enhanced by hypertonic treatment. The enhancement ratio of gamma-irradiation-induced chromatid breaks and exchanges was 1.4 and 3.0, respectively. This cell cycle dependency of chromosome aberrations induced by postirradiation hypertonic treatment was the same as that of cell survival. These findings suggested that hypertonic treatment modifies the rejoining of DNA strand breaks in G2, but slightly modifies that in G1.

Animals↗

PubMed1985

Induction of endoreduplication in temperature-sensitive mutants of rat 3Y1 fibroblasts.

Four temperature-sensitive mutants of rat 3Y1 fibroblasts belonging to separate complementation groups (3Y1tsD123, 3Y1tsF121, 3Y1tsG125, and 3Y1tsH203) are arrested mainly with a 2C DNA content, when cells proliferating at 33.8 degrees C are shifted up to 39.8 degrees C (Ohno et al., 1984). Zaitsu and Kimura (submitted for publication) showed that 3Y1tsF121 cells synchronized in the early S phase were arrested with a 4C DNA content at 39.8 degrees C. We studied the traverse through the S and G2 phases at 39.8 degrees C in the four ts mutants synchronized at the early S phase and found that 3Y1tsG125 and 3Y1tsH203 cells were arrested with a 4C DNA content as 3Y1tsF121, while 3Y1tsD123 cells went through S and G2 phases and underwent mitosis. When 3Y1tsF121 and 3Y1tsG125 mutants arrested at 39.8 degrees C were shifted down to 33.8 degrees C, a substantial fraction of the cells with a 4C DNA content started, with a certain lag period, DNA synthesis without intervening mitosis and underwent the first mitosis with a lag period similar to that in the cells arrested with a 2C DNA content. The tetraploid cells thus generated had a proliferating ability lower than that of diploid cells.

Animals↗

PubMed1997

Mutagenic and cytotoxic activity of an isocoumarin (Paepalantine) isolated from Paepalanthus vellozioides.

A new isocoumarin with antimicrobial activity was isolated from Paepalanthus vellozioides (a native Brazilian plant) and called paepalantine. This study was carried out to assess the mutagenic activity of this new agent in assays with Salmonella typhimurium TA100, TA98, and TA102 and in Chinese hamster ovary (CHO) cell cultures, as well as cytotoxicity to McCoy cells. paepalantine caused a significant dose-dependent increase in the frequency of revertants in the three strains used in the assay, both with and without S9 mix, in concentrations varying from 2 to 128 micrograms/plate. The mutagenicity was confirmed in assays with CHO cells treated in the G1, S, and G2 phases of the cell cycle. There was an increase in the chromosomal aberration frequency, mainly in the G2 phase. Furthermore, the mitotic index of the treated cultures (40,80, and 160 micrograms/ml) was significantly lower, indicating cytotoxicity. The midpoint cytotoxicity values of McCoy cells by the neutral red (NR) and microculture tetrazolium (MTT) techniques resulted in a NR50 and MTT50 of 30 and 38 micrograms/ml, respectively. Alterations to the paepalantine structure are suggested to reduce its mutagenic and cytotoxic activity in investigations for its antineoplastic potential.

Animals↗

PubMed1993

Mechanism of induction of chromosomal aberrations by inhibitors of DNA topoisomerases.

Evidence is provided that antitopoisomerase drugs induce chromosomal aberrations via the formation of DNA double strand breaks. Camptothecin, an inhibitor of DNA topoisomerase I, produced only chromatid-type aberrations, and in order to be effective it has to be present during the DNA replication. The fact that it induces chromosomal aberrations also in the G2 phase of the cell cycle suggests the presence of a residual DNA synthesis in this phase. A pretreatment with aphidicolin, an inhibitor of DNA polymerases, reduces the camptothecin induced aberrations in the G2 phase, confirming the need of DNA synthesis for the induction of aberrations by the inhibitor of DNA topoisomerase I.

Animals↗

PubMed1985

Human monocyte-released cytotoxic factor. Modulation of cytotoxic activity by inhibitors of cellular DNA, RNA, and protein synthesis.

Human lymphokine-activated monocytes release a cytotoxic protein factor (CF). The cytostatic activity of CF was potentiated by the DNA and RNA synthesis inhibitors actinomycin D, daunomycin, and mitomycin C. These inhibitors increased the sensitivity for detecting CF approximately 10-fold, and this is of great practical value when assaying CF. The CF-potentiating inhibitors had a similar effect on the cell cycle distribution in that they all induced an accumulation of cells in the S and G2 phases of the cell cycle. Cytolytic activity was shown to be associated with CF, and this activity was also greatly potentiated by daunomycin and actinomycin D. The two other inhibitors studied, cycloheximide and 5-fluorouracil (5-FU), had an adverse effect on the cytostatic activity of CF. These two inhibitors reduced the sensitivity of the assay for CF about fivefold. Cycloheximide had no apparent effect on the relative cell cycle distribution, whereas 5-FU induced an accumulation of cells in the G1 phase. Of the inhibitors studied, only those that induced an accumulation of cells in the S and G2 phases of the cell cycle potentiated the cytotoxic activity of CF, suggesting that CF may preferentially act in these parts of the cell cycle.

Cell Cycle↗