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At least 919 records · Page 51Linked to original sources
PubMed1992

12-O-tetradecanoylphorbol-13-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2.

The growth of Demel human metastatic melanoma cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA) and other nonphorbol tumor promoters including palytoxin and okadaic acid. Using flow cytometry, we have demonstrated that the cells arrested growth in G1 and G2 phases of the cell cycle. Detailed analysis of the kinetics of the growth arrest in unsynchronized cells showed that (a) the growth arrest was transient and peaked 16-20 h following addition of TPA; (b) effects of TPA on cell growth began within 1-2 h after the addition; and (c) cells completed S phase and arrested in G2. In addition, TPA induced a pronounced morphological change, which peaked by 1 h and gradually subsided over 24 h. In populations of cells synchronized in G1 using lovastatin, (a) addition of TPA blocked the onset of DNA synthesis up to the end of G1; (b) the lag between addition of the drug and onset of DNA synthesis was less than 30 min; and (c) addition of TPA at the end of G1 prevented the increased phosphorylation of p34cdc2, as determined by immunoprecipitation. The experiments reported here show that TPA transiently blocked the proliferation of Demel melanoma cells at the G1-S border and in G2, thus preventing cells from progressing through the cell cycle. These experiments suggest that pathways involving protein kinase C interact with and rapidly alter the molecular pathways involving p34cdc2 which regulate the onset of DNA synthesis and the G2-M transition.

Breast Neoplasms↗
PubMed1991

Physical, biophysical, and cell-biological factors that can contribute to enhanced neoplastic transformation by fission-spectrum neutrons.

In radiobiology, fission-spectrum neutrons frequently have been used as a surrogate for other high-LET radiations, particularly when thick absorbers were involved as in animal studies. However, the spectrum of proton secondaries, plus the gamma rays generated in the absorption processes, suggests that a characterization of such a beam, based upon an average LET alone, may not adequately account for the spectrum of biological properties that it may have. Conflicting results have been reported on the relative effectiveness of reduced dose rates of fission-spectrum neutrons, and other high-LET radiations, for the induction of noeplastic transformation of cells in culture. Enhanced rates of neoplastic transformation were reported for C3H 10T1/2 mouse cells, Syrian hamster embryo cells, and human hybrid cells-all with the same beam of fission-spectrum neutrons generated by the JANUS reactor at the Argonne National Laboratory. No enhancement was observed with C3H 10T1/2 cells exposed to the beam from the TRIGA reactor at the Armed Forces Radiobiological Research Institute, or to maximally effective alpha particles. The recent report that an enhancement was also observed when human hybrid cells were exposed at a low dose rate to the TRIGA beam indicated that physical factors alone were not responsible for the differences observed with C3H 10T1/2 cells exposed to these various beams. To resolve the lack of consistency in the results that had been reported, a biophysical model was developed based, in part, on the existence of a narrow age interval in the growth cycle of a cell during which it is particularly sensitive to radiation neoplastic transformation. Because of the special physical and biological properties of cells in M phase, and/or in late G2 phase or early G1 phase, these cohorts of cells were proposed as those that are hypersensitive to neoplastic transformation by radiation.

Animals↗
PubMed1989

Variation of tubulin half-life during the cell cycle in the synchronous plasmodia of Physarum polycephalum.

The half-life of tubulin has been studied during the cell cycle of the myxomycete Physarum, using a specific quantitative immunological method. In asynchronous microplasmodial and amoebal cultures the apparent half-life of tubulin was greater than 15 h. In contrast, in the naturally synchronous plasmodia, in which tubulin exhibits a cyclic synthesis, we have shown for the first time that tubulin half-life was not constant through the cell cycle. There was no tubulin degradation before mitosis, while tubulin half-life was reduced to about 1 h during the postmitotic period. Such a variation of stability through the cell cycle has not been observed in the case of thymidine kinase, another protein showing a cyclic synthesis in Physarum plasmodia. The decrease of tubulin half-life that occurred during the S-phase immediately following mitosis (no G1-phase in Physarum) was independent of the increase of growth temperature between 22 and 32 degrees C, in contrast with the half-life of thymidine kinase which decreased in the same conditions. Tubulin did not completely disappear after mitosis. A 20% residual amount of tubulin persisted from late S-phase to early G2-phase. We have shown that tubulin degradation was not modified by actinomycin D or cycloheximide but was prevented when DNA synthesis was inhibited by fluorodeoxyuridine and hydroxyurea. In contrast, inhibition of S-phase did not modify the half-life of thymidine kinase. These results indicate that: 1) during the cell cycle, the pool of tubulin is regulated not only at the transcriptional and translational levels but also by a cell cycle-dependent degradative process.(ABSTRACT TRUNCATED AT 250 WORDS)

Cycloheximide↗
PubMed1988

A fraction of labelled mitoses study on adrenal chromaffin tissue in the newborn mouse and the effect of hydrocortisone.

Hydrocortisone was administered to gravid mice from the thirteenth day of pregnancy until term. In vivo fraction of labelled mitoses experiments on intra-adrenal chromaffin tissue of newborn mice were performed to assess the effect of hydrocortisone on the cell cycle in this tissue. In untreated mouse intra-adrenal chromaffin tissue the total cell cycle time was 7 hours, being made up as follows: S phase 1 1/2 hours, G2 phase 1 hour, M phase 4 hours (by analysis of results, not by assumption) and G1 phase 1/2 hour (by subtraction). Hydrocortisone administration was without marked effect on these values. These results are discussed in the context of the influence of corticosteroids on the development biology of chromaffin tissue, both intra- and extra-adrenal.

Adrenal Medulla↗
PubMed1988

Study of different phases in growth cycle of human bone marrow cells and their growth speed, using rat-human cell hybridization, premature chromosome condensation, and sister chromatid differentiation techniques.

The cytokinetic activity of bone marrow cells is an indication of hemopoietic status. In the routine examination of bone marrow smears, only M phase can be identified, whereas the different phases of the remainder of the cell cycle are not possible to determine. However, by using premature chromosome condensation and bromodeoxyuridine differential staining techniques, cell stage and cell kinetics can be easily determined. Ninety-eight samples of human bone marrow were collected, cells were hybridized with mitotic M3 cells, and 5016 randomly selected hybrid cells were analyzed for cell stage. Our data demonstrated that 80.37% of the cells were in G1 phase, 12.66% were in S phase, 5.29% were in G2 phase, and 1.68% were in M phase. In specimens that had been cultured for 48 h in the presence of bromodeoxyuridine, 57.46% had completed at least two rounds of DNA replication. In 72-h specimens, 69.27% of the cells had completed at least two S phases. In 96-h specimens, 2S and 2S+ cells occupied 74% of the cell population. The use of cell hybridization techniques, premature chromosome condensation, and bromodeoxyuridine-dependent differential staining revealed the phases of the cell cycle distinctly, as well as the kinetics of cell growth.

Animals↗
PubMed1985

[Flow fluorimetry of the cellular DNA of the bone marrow in normal mice and after exposure to extreme factors].

The distribution of murine bone marrow cells in regard to cell cycle was examined using flow cytometry technique. In normal NIH mice the percentage of cells being into phases G1/0, S and G2 + M constitutes 78, 15 and 7%, respectively. In mice subjected to X-irradiation (2, 12 Gy), the thermal burn, and X-irradiation plus the burn the proportion of G2 + M-cells increased, which may be presumably due to their delay on stage G2 of the cell cycle. The start and duration of the delay in the G2 phase depend upon the kind of damage applied.

Animals↗
PubMed1984

[Stimulation of cell division by Ehrlich carcinoma cell surface antibodies].

Some Ehrlich ascites cancer cells of the mouse show nuclear division as a response to cell surface signals. Antibodies to plasma membrane produce a membrane molecular redistribution, but only 25 per 100 proceed to nuclear division. This division is not associated to DNA synthesis, showing that the effect is produced in G0 phase cells originated from G2 phase cells.

Animals↗
PubMed2000

Induction of M-phase arrest and apoptosis after HIV-1 Vpr expression through uncoupling of nuclear and centrosomal cycle in HeLa cells.

The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces cell cycle arrest in the G2 phase of the cell cycle followed by apoptosis. The mechanism of the arrest is unknown but the arrest is believed to facilitate viral replication. In the present study, we have established cell lines that allow conditional expression of Vpr, and have examined the mechanism of cell death following Vpr expression. We found that cells expressing Vpr enter M phase after long G2 arrest but formed aberrant multipolar spindles that were incapable of completing karyokinesis or cytokinesis. This abnormality provided the basis for apoptosis, which always followed in these cells. The multipolar spindles formed in response to abnormal centrosomal duplication that occurred during the G2 arrest but did not occur in cells arrested in G2 by irradiation. Thus, the expression of Vpr appears to be responsible for abnormal centrosome duplication, which in turn contributes in part to the rapid cell death following HIV-1 infection.

Apoptosis↗
PubMed2002

Germanium oxide inhibits the transition from G2 to M phase of CHO cells.

We report here for the first time that germanium oxide (GeO(2)) blocks cell progression. GeO(2) is not genotoxic to Chinese hamster ovary (CHO) cells and has limited cytotoxicity. However, GeO(2) arrests cells at G2/M phase. The proportion of cells stopped at G2/M phase increased dose-dependently up to 5 mM GeO(2) when treated for 12 h, but decreased at GeO(2) concentration was greater than 5 mM. Analysis of 5-bromodeoxyuridine-labeled cells indicated that GeO(2) delayed S phase progression in a dose-dependent manner, and blocked cells at G2/M phase. Microscopic examination confirmed that GeO(2) treatment arrested cells at G2 phase. Similar to several other events that cause G2 block, the GeO(2)-induced G2 block can also be ameliorated by caffeine in a dose- and time-dependent manner. To explore the mechanism of G2 arrest by GeO(2), cyclin content and cyclin-dependent kinase activity were examined. Cyclin B1 level was not affected after GeO(2) treatment in CHO cells. However, GeO(2) decreased p34(cdc2) kinase (Cdk1) activity. The kinase activity recovered within 9 h after GeO(2) removal and correlated with the transition of G2/M-G1 phase of the cells. This result suggests that GeO(2) treatment reduces Cdk1 activity and causing the G2 arrest in CHO cells.

Animals↗
PubMed1997

Conversion of DNA damage into chromosome damage in response to cell cycle regulation of chromatin condensation after irradiation.

Cell fusion, premature chromosome condensation (PCC) and conventional cytogenetics were used to test whether the biochemical process of chromatin condensation-decondensation throughout the cell cycle, which depends on cyclin-regulated histone H1 kinase activity, affects the conversion of DNA damage into chromosome damage and determines intrinsic cell cycle-stage radiosensitivity. Results from three sets of experiments are presented. Irradiated G0 human lymphocytes were fused to exponentially growing hamster cells and time allowed for repair, while following the hamster cells in their progress towards mitosis. Severe fragmentation was observed in the induced lymphocyte PCCs when hamster cells entered mitosis 13 h after irradiation, suggesting conversion of DNA damage into non-repairable chromosome damage during G1/S transition. When PCC was used to analyse chromosome damage directly in G0 and G2 phase lymphocytes, the induction of breaks per cell per chromatid per Gy was found to be similar, suggesting that G2 increased radiosensitivity is related to chromatin condensation occurring during G2/M transition and not to an inherent chromatin structure at this phase. When chromatin condensation-decondensation at the G1/S and G2/M transitions was modified after irradiation by using conditioned media or elevated temperature (40 degrees C), a dramatic change in the yield and the type of chromosomal aberrations was observed. All results obtained were consistent with the proposed hypothesis. They may be also helpful in the characterization of a DNA-chromosome damage conversion process which could give a biochemical explanation of the variability in radiosensitivity observed at the various stages of the cell cycle as well as among mutant cells and cells of different origin. The proposed conversion process is cell cycle-regulated and, therefore, subject to up-regulation or down-regulation following mutagen exposure and genetic alterations.

Animals↗
PubMed1998

Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing.

In developing organs, the regulation of cell proliferation and patterning of cell fates is coordinated. How this coordination is achieved, however, is unknown. In the developing Drosophila wing, both cell proliferation and patterning require the secreted morphogen Wingless (Wg) at the dorsoventral compartment boundary. Late in wing development, Wg also induces a zone of non-proliferating cells at the dorsoventral boundary. This zone gives rise to sensory bristles of the adult wing margin. Here we investigate how Wg coordinates the cell cycle with patterning by studying the regulation of this growth arrest. We show that Wg, in conjunction with Notch, induces arrest in both the G1 and G2 phases of the cell cycle in separate subdomains of the zone of non-proliferating cells. Wg induces G2 arrest in two subdomains by inducing the proneural genes achaete and scute, which downregulate the mitosis-inducing phosphatase String (Cdc25). Notch activity creates a third domain by preventing arrest at G2 in wg-expressing cells, resulting in their arrest in G1.

Animals↗
PubMed1997

Expression of wild-type p53 increases etoposide cytotoxicity in M1 myeloid leukemia cells by facilitated G2 to M transition: implications for gene therapy.

We have evaluated the role of p53 in the induction of cell death by the DNA topoisomerase II inhibitor etoposide in M1 myeloid leukemia cells. Three different clones of M1 cells were used: S6, which lacks p53; Phe-132, which expresses mutant p53 constitutively; and LTR-13, which expresses mutant protein at 37 degrees C and wild-type p53 at 32 degrees C. As described previously, LTR-13 cells undergo rapid apoptosis upon induction of wild-type p53 at 32 degrees C. Multiparameter flow cytometric analysis showed that etoposide treatment (0.5 microg/ml) of all three cell lines at 37 degrees C is associated with a block in the G2 phase of the cell cycle, whereas the cells preferentially die out of the next S phase. Induction of wild-type p53 in LTR-13 cells is associated with a loss of cells in late S and G2-M phase, and the cells die out of the early S phase. Interestingly, the simultaneous induction of apoptosis by both pathways (wild-type p53 and etoposide) leads to suppression of the etoposide-induced G2 block. To determine the effect of p53 on the G2 to M transition, LTR-13 cells were incubated with etoposide for 24 h at 37 degrees C and then either maintained for an additional 12 h at 37 degrees C or shifted to 32 degrees C to activate wild-type p53. The expression of wild-type p53 resulted in an increase in mitosis-specific phosphorylation, as determined by the MPM-2 antibody as well as the formation of mitotic spindles. This was associated with an important augmentation of the cytotoxic effect of etoposide. In contrast, a similar temperature shift of Phe-132 cells, which express mutant p53, had no effect on either immunostaining with MPM-2 or the cytotoxicity. Taken together, our results indicate that wild-type p53 can override the etoposide-induced G2 block in at least some cell types. These data propose a new role for p53 in the cell death induced by chemotherapeutic agents and may have important implications for gene therapy.

Animals↗
PubMed1995

Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation.

A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.

Animals↗
PubMed2005

Ethylnitrosourea induces neural progenitor cell apoptosis after S-phase accumulation in a p53-dependent manner.

Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53.

Animals↗
PubMed1993

Cell-cycle-dependent phosphorylation and activity of Chinese-hamster ovary topoisomerase II.

Cell-cycle-dependent protein levels and phosphorylation of DNA topoisomerase II in relation to its catalytic and cleavage activities were studied in Chinese-hamster ovary cells. Immunoreactive topoisomerase II protein levels were maximal in G2-phase cells, intermediate in S- and M-phase cells, and minimal in a predominantly G1-phase population. When the phosphorylation of topoisomerase II in vivo was corrected for differences in specific radioactivity of intracellular ATP, the apparent phosphorylation of S- and M-phase topoisomerase II was altered significantly. Relative phosphorylation in vivo was found to be greatest in M-phase cells and decreased in the other populations in the order: S > G2 > asynchronous. Phosphoserine was detected in every phase of the cell cycle, with a minor contribution of phosphothreonine demonstrated in M-phase cells. Topoisomerase II activity measured in vivo as 9-(4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-demethylepipodophylloto xin (VP-16)-induced DNA double-strand breaks (determined by neutral filter elution) increased in the order: asynchronous < S < G2 < M. Topoisomerase II cleavage activity, assayed in vitro as the formation of covalent enzyme-DNA complexes, was lowest in S phase, intermediate in asynchronous and G2-phase cells, and maximal in M phase. Topoisomerase II decatenation activity was 1.6-1.8-fold greater in S-, G2- and M-phase populations relative to asynchronous cells. Therefore DNA topoisomerase II activity measured both in vivo and in vitro is maximal in M phase, that phase of the cell cycle with an intermediate level of immunoreactive topoisomerase II but the highest level of enzyme phosphorylation. The discordance between immunoreactive topoisomerase II protein levels, adjusted relative phosphorylation, catalytic activity, cleavage activity and amino acid residue(s) modified, suggests that the site of phosphorylation may be cell-cycle-dependent and critical in determining catalytic and cleavage activity.

Animals↗
PubMed2000

Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells.

Important aspects of cell cycle regulation are the checkpoints, which respond to a variety of cellular stresses to inhibit cell cycle progression and act as protective mechanisms to ensure genomic integrity. An increasing number of tumor suppressors are being demonstrated to have roles in checkpoint mechanisms, implying that checkpoint dysfunction is likely to be a common feature of cancers. Here we report that histone deacetylase inhibitors, in particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle checkpoint response in normal human cells, and this checkpoint is defective in a range of tumor cell lines. Loss of this G2 checkpoint results in the tumor cells undergoing an aberrant mitosis resulting in fractured multinuclei and micronuclei and eventually cell death. This histone deacetylase inhibitor-sensitive checkpoint appears to be distinct from G2/M checkpoints activated by genotoxins and microtubule poisons and may be the human homologue of a yeast G2 checkpoint, which responds to aberrant histone acetylation states. Azelaic bishydroxamic acid may represent a new class of anticancer drugs with selective toxicity based on its ability to target a dysfunctional checkpoint mechanism in tumor cells.

Cell Cycle↗
PubMed1997

Cell division in placentas of appropriate and small-for-gestational-age infants. A flow cytometry study.

BACKGROUND: The purpose of this study was to examine if placentas of small- for-gestational-age (SGA) and non-SGA infants differ with respect to proliferative cell activity. METHOD: Cell cycle distribution was studied in placentas from 181 SGA (birthweight < 10th percentile) and 528 non-SGA births by flow cytometry measurements of relative DNA content. RESULTS: The fraction of cells in various cell cycle phases (G1-, S- and G2-phases) did not differ with gestational age from 30 to 43 weeks in either of the groups. The placentas of the SGA infants had a significantly lower mean (+/-1 SEM) growth fraction than placentas of non-SGA infants (S-phase 5.2 +/- 0.2 vs 5.5 +/- 0.1, p = 0.05, and G2-fraction 5.4 +/- 0.2 vs 6.3 +/- 0.1, p < 0.001), but the overlaps of the distributions were large. Thus sensitivity, specificity and predictive values of low fractions did not differ substantially-from a purely random prediction of SGA. CONCLUSIONS: Cell division in the placenta is maintained until and beyond term. Placentas of SGA infants have on average, lower proliferative activity than placentas of non-SGA infants, but the difference is too small to be of predictive value in identifying intrauterine growth retardation.

Adult↗