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PubMed1994

Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol.

In addition to its tumor-promoting activity in hormone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were formed during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus formation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the G0/G1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of S and G2 transit may involve a process ultimately leading to micronucleus formation.

Animals↗
PubMed1986

Effect of serum on heat response of synchronized mouse neuroblastoma cells: protection of cell cycle progression, protein synthesis and survival.

The effect of serum and temperature elevation on proliferation has been studied in synchronized mouse neuroblastoma (Neuro-2A) cells. The effects of serum were studied on the induction of (a) mitotic delay due to a non-lethal heat treatment (30 min at 42.7 degrees C) and (b) the loss of colony-forming capacity after a more extensive heat treatment (45 min at 44 degrees C or a continuous 42.7 degrees C heat treatment). The following results were obtained. Under conditions of serum depletion, cell cycle extension of heated G1 phase cells was more than that of heated G2 phase cells. Serum protected against heat-induced alterations of cell cycle progression in G1- but not in G2 phase cells. This effect of serum could be mimicked by a supplement to the medium of human transferrin, bovine pancreas insulin and selenium, and was correlated with protection of protein synthesis. Serum also affected heat-induced cell killing. Under conditions of serum depletion, G1 phase cells were more resistant to heat compared to G2 cells. The presence of serum during heat treatment further increased the thermoresistance of G1 phase cells, but did not affect sensitivity of G2 phase cells. This effect of serum could not be mimicked by a supplement of transferrin, insulin and selenium. These results indicate that serum protects G1 phase cells for heat-induced changes of cell cycle progression as well as on cell survival, but the mechanisms involved in both phenomena seem to be different.

Animals↗
PubMed1990

Isolation of temperature-sensitive cell cycle mutants from mouse FM3A cells. Characterization of mutants with special reference to DNA replication.

A large number of mutants that are temperature sensitive (ts) for growth have been isolated from mouse mammary carcinoma FM3A cells by an improved selection method consisting of cell synchronization and short exposures to restrictive temperature. The improved method increased the efficiency of isolating DNA ts mutants, which showed a rapid decrease in DNA-synthesizing ability after temperature shift-up. Sixteen mutants isolated by this and other methods were selected for this study. Flow microfluorometric analysis of these mutants cultured at a nonpermissive temperature (39 degrees C) for 16 h indicated that five clones were arrested in the G1 to S phase of the cell cycle, six clones were in the S to G2 phase, and two clones were arrested in the G2 phase. The remaining three clones exhibited 8C DNA content after incubation at 39 degrees C for 28 h, indicating defects in mitosis or cytokinesis. These mutants were classified into 11 complementation groups. All the mutants except for those arrested in the G2 phase and those exhibiting defects in mitosis or cytokinesis showed a rapid decrease in DNA synthesis after temperature shift-up without a decrease in RNA and protein synthesis. The polyomavirus DNA cell-free replication system, which consists of polyomavirus large tumor antigen and mouse cell extracts, was used for further characterization of these DNA ts mutants. Among these ts mutants, only the tsFT20 strain, which contains heat-labile DNA polymerase alpha, was unable to support the polyomavirus DNA replication. Analysis by DNA fiber autoradiography revealed that DNA chain elongation rates of these DNA ts mutants were not changed and that the initiation of DNA replication at the origin of replicons was impaired in the mutant cells.

Animals↗
PubMed2001

Continuity with ganglionic eminence modulates interkinetic nuclear migration in the neocortical pseudostratified ventricular epithelium.

Cells of the pseudostratified ventricular epithelium (PVE) undergo interkinetic nuclear migration whereby position of cell soma with nucleus is systematically dependent upon cell cycle phase. We examined if the interkinetic nuclear migration in the neopallial PVE is influenced by tissue continuity with the ganglionic eminence (GE) of the basal forebrain in explants from embryonic day 13 mice. We found that when continuity between the neopallial wall and the GE is intact, some neopallial PVE cells discontinue interkinetic nuclear migration following S-phase and upon entry into G2-phase. The somata and nuclei of those cells shift outward from the S-phase zone toward the subventricular and the intermediate zones. The outward migration of post-S-phase cells is observed only in the lateral region of the cerebral wall, which is closely adjacent to the GE, but not in the medial region, and only when tissue continuity with GE is maintained. We suggest that the outward moving PVE cells seed the secondary proliferative population (SPP) and that exit of the SPP seeding cells occurs in G2-phase. The phenomenon recapitulates similar migratory behavior of neopallial PVE cells in vivo and appears to represent a "choice" between two opposing options available to post-S-phase cells of the PVE. The choice appears to be imposed by mechanisms dependent upon continuity with the GE. We conclude that GE, and/or other adjacent basal forebrain structures, modulates interkinetic nuclear migration in the neopallial PVE.

Animals↗
PubMed1996

Phosphatidic acid mobilized by phospholipase D is involved in the phorbol 12-myristate 13-acetate-induced G2 delay of A431 cells.

This study was aimed at gaining an understanding of metabolic events responsible for the inhibition of cells in G2 phase, a known physiological restriction site in the cell cycle of multicellular organisms. In an earlier study, phosphatidic acid was proposed as an inhibitory mediator in the epidermal growth factor (EGF)-induced inhibition of A431 cells in G2 phase via the phospholipase C pathway [Kaszkin, Richards and Kinzel (1992) Cancer Res. 52, 5627-5634]. We show here that the phorbol ester phorbol 12-myristate 13-acetate (PMA) induces a reversible inhibition of the G2/M transition in A431 cells under conditions of phospholipase D-catalysed phosphatidic acid formation. Such PMA-induced inhibition in G2 phase is largely attenuated in the presence of 1-propanol (but not of 2-propanol). In this case the amount of phosphatidic acid is reduced to almost control levels, and instead phosphatidylpropanol is formed. In the case of EGF-induced activation of a phospholipase D the amount of phosphatidic acid is only slightly decreased in the presence of a primary alcohol. Under these conditions the EGF-induced G2 delay was not affected. The correlation between the formation of phosphatidic acid and the G2 delay induced by PMA, as well as by an exogenous bacterial phospholipase D (from Streptomyces chromofuscus), could be supported by using synchronized cells in order to increase the population of cells in G2 phase. This study indicates that the formation of substantial amounts of phosphatidic acid immediately before entry into mitosis seems to be important for establishing a delay in the cell cycle at the G2/M border by exogenous ligands.

1-Propanol↗
PubMed1999

Cell cycle arrest and morphological alterations following microinjection of NIH3T3 cells with Pur alpha.

Levels of Pur alpha, a protein implicated in control of both DNA replication and gene transcription, fluctuate during the cell cycle, being lowest in early S phase and highest just after mitosis. Here we have employed a new video time-lapse technique enabling us to determine the cell cycle position of each cell in an asynchronous culture at a given time and to ask whether introduction of Pur alpha protein at specific times can affect cell cycle progression. Approximately 80% of all NIH3T3 cells injected with Pur alpha were inhibited from passing through mitosis. Cells injected with Pur alpha during S or G2 phases were efficiently blocked with a 4N (G2 phase) DNA level, as determined by quantitative DNA photometry of individual cells. Of the cells injected with Pur alpha during G1 phase, 40% experienced a rapid cell death characterized by extreme cellular fragmentation. Of those G1 injected cells which remained viable, approximately equal numbers were arrested with either 2N or 4N DNA levels. Cells arrested by Pur alpha in G2 phase grew to cover a large surface area. These results link fluctuations in Pur alpha levels to aspects of cell cycle control.

3T3 Cells↗
PubMed2000

Activating the DNA damage checkpoint in a developmental context.

BACKGROUND: Studies in unicellular systems have established that DNA damage by irradiation invokes a checkpoint that acts to stall cell division. During metazoan development, the modulation of cell division by checkpoints must occur in the context of gastrulation, differential gene expression and changes in cell cycle regulation. To understand the effects of checkpoint activation in a developmental context, we examined the effect of X-rays on post-blastoderm embryos of Drosophila melanogaster. RESULTS: In Drosophila, DNA damage was previously found to delay anaphase chromosome separation during cleavage cycles that lack a G2 phase. In post-blastoderm cycles that included a G2 phase, we found that irradiation delayed the entry into mitosis. Gastrulation and the developmental program of string (Cdc25) gene expression, which normally regulates the timing of mitosis, occurred normally after irradiation. The radiation-induced delay of mitosis accompanied the exclusion of mitotic cyclins from the nucleus. Furthermore, a mutant form of the mitotic kinase Cdk1 that cannot be inhibited by phosphorylation drove a mitotic cyclin into the nucleus and overcame the delay of mitosis induced by irradiation. CONCLUSIONS: Developmental changes in the cell cycle, for example, the introduction of a G2 phase, dictate the response to checkpoint activation, for example, delaying mitosis instead of or in addition to delaying anaphase. This unprecedented finding suggests that different mechanisms are used at different points during metazoan development to stall cell division in response to checkpoint activation. The delay of mitosis in post-blastoderm embryos is due primarily to inhibitory phosphorylation of Cdk1, whereas nuclear exclusion of a cyclin-Cdk1 complex might play a secondary role. Delaying cell division has little effect on gastrulation and developmentally regulated string gene expression, supporting the view that development generally dictates cell proliferation and not vice versa.

Animals↗
PubMed1991

The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in primary gastrointestinal lymphomas and its relationship to histological grade, S+G2+M phase fraction (flow cytometric analysis) and prognosis.

PCNA is a nuclear protein that is synthesized in late G1 and S phases of the cell cycle and is, therefore, correlated with the cell proliferative state. A new monoclonal antibody (PC10) to genetically engineered PCNA has been shown to label proliferating cells in formalin-fixed paraffin-embedded normal human tissues. Previous studies in lymphomas, using various markers of cell proliferation, have shown a strong correlation between indices of cell proliferation and histological grade. These studies have shown that within each histological subtype there is often a wide range of proliferative indices and that these may be of some prognostic significance. Thirty-one gastrointestinal lymphomas were studied. Our results show that there is a good correlation between PC10 index and histological grade of tumour (0.01 P greater than P greater than 0.001) and also a significant relationship between PC10 index and S+G2+M phase fraction as measured by flow cytometric analysis (r2 = 0.62; P less than 0.01). Twenty-three cases were available for survival analysis. In these cases a high PC10 score correlated with poor survival (P = 0.04). Based on this series, it appears that there is a significant relationship between PC10 index and histological grade, and between PC10 index and S+G2+M phase as measured by flow cytometric analysis. In addition, our results suggest that a high PC10 index is an adverse prognostic factor in primary gastrointestinal lymphoma.

Cell Cycle↗
PubMed1986

[Flow cytometric analysis of the effect of THP-adriamycin on the cell cycle traverse of RPMI-8402 cells--comparison with adriamycin].

THP-adriamycin (THP) is a new derivative of adriamycin (ADM) which is reported to have a lower cardiotoxicity than ADM. In this report, the effects of THP on cell growth, cell cycle traverse and colony-forming ability of RPMI-8402 cells were investigated in comparison with ADM. The growth-inhibitory effect of THP was equal or superior to that of ADM in this system. Analysis of the DNA histogram obtained by flow cytometry showed that THP exerted its growth-inhibitory effect by blocking cells at the G2 phase. At higher concentrations, THP inhibited the traverse of cells through the S phase and further through the whole cell cycle completely. These effects were quite similar to those of ADM, which suggested a similar mechanism of action for the two drugs from the aspect of the cell cycle. A follow-up study of cells accumulated at the G2 phase and a study on colony-forming ability revealed that the G2 phase accumulation was an irreversible and fatal effect of THP, so that G2-phase accumulation could be considered as a cytocidal effect of THP, indicating the clinical usefulness of this system for evaluation of the drug effect. From these results and the low cardiotoxicity, it was suggested that THP could be a good candidate for use as an antitumor agent in clinics.

Cell Cycle↗
PubMed1995

Apoptosis by antitumor agents and other factors in relation to cell cycle checkpoints.

More than a dozen cancer patients died in 1993 after treatment with antineoplastic derivatives of 5-fluorouracil and the antiherpes drug Sorivudine. This paper gives a short review of previous reports showing that killing of cells by 5-fluorouracil and other antitumor agents, including radiation at high doses, results from activation of apoptosis in the G2 phase. On the other hand, apoptosis of lymphocytes by radiation at low doses and treatment with other agents is known to occur in the G1 phase. The cells dying in the G1 or G2 phase could share the same final self-killing steps. For these common steps, I assume a mitotic catastrophe model, in which commitment to self-killing results from premature activation of the mitosis machinery, and propose a concept of a 'G1/G2 death circuit' for cells dying in the G1/G2 phase by short circuit to the M phase. Based on this model, reported modes of cell death, spontaneously occurring or after treatment with various agents, are classified by the phase of dying cells. The associations of incomplete apoptosis with production of chromosomal aberrations and prevention of tumorigenesis by complete apoptosis of carcinogen-treated cells are discussed. A presumptive rule for differentiation of G1 apoptosis and G2 apoptosis is proposed.

Antineoplastic Agents↗
PubMed1998

Fostriecin-mediated G2-M-phase growth arrest correlates with abnormal centrosome replication, the formation of aberrant mitotic spindles, and the inhibition of serine/threonine protein phosphatase activity.

Fostriecin, a structurally unique phosphate ester, is presently under evaluation in clinical trials to determine its potential use as an antitumor drug in humans. Fostriecin has been reported as having inhibitory activity against DNA topoisomerase type II and protein phosphatases implicated in cell-cycle control. However, the relative contribution of these mechanisms to the antitumor activity of fostriecin has not yet been elucidated. In this study, after confirming that fostriecin is a potent inhibitor of serine/threonine protein phosphatase type 2A and a weak inhibitor of serine/threonine protein phosphatase type 1, we show that fostriecin inhibits approximately 50% of the divalent cation independent serine/threonine protein phosphatase (PPase) activity contained in whole cell homogenates of Chinese hamster ovary cells at concentrations associated with antitumor activity (1-20 microM). Investigations into the cellular effects produced by fostriecin treatment reveal that 1-20 microM fostriecin induces a dose-dependent arrest of cell growth during the G2-M phase of the cell cycle. Immunostaining of treated cells indicates that growth arrest occurs before the completion of mitosis and that fostriecin-induced growth arrest is associated with the aberrant amplification of centrosomes, which results in the formation of abnormal mitotic spindles. The "mitotic block" induced by fostriecin is reversible if treatment is discontinued in <24 h. However, after approximately 24-30 h of continuous treatment, growth arrest is not reversible, and treated cells die even when placed in fostriecin-free media. Correlative studies conducted with established PPase inhibitors reveal that, when applied at concentrations that inhibit PPase activity to a comparable extent, both okadaic acid and cantharidin also induce aberrant centrosome replication, the appearance of multiple aberrant mitotic spindles, and G2-M-phase growth arrest. These studies add additional support to the concept that PPase inhibition underlies the antitumor activity of fostriecin and suggest that other type-selective PPase inhibitors should be evaluated for potential antitumor activity.

Alkenes↗
PubMed1994

Simian virus 40 prevents activation of M-phase-promoting factor during lytic infection.

Simian virus 40 (SV40) infection stimulates confluent cultures of monkey kidney cells into successive rounds of cellular DNA synthesis without intervening mitosis. As an initial step in defining the mechanisms responsible for viral inhibition of mitosis, M-phase-promoting factor (MPF) was examined in SV40-infected CV-1 cells passing from G2 phase into a second S phase. MPF is a serine-threonine protein kinase that is essential for mitosis in eukaryotic cells. In SV40-infected cells exiting G2 phase, there was a reduced amount of MPF-associated H1 kinase activity relative to that of uninfected cells passing through mitosis. Both subunits of MPF, cyclin B and the p34cdc2 catalytic subunit, were present and in a complex in infected cells. In uninfected cultures, passage through mitosis was associated with the dephosphorylation of the p34cdc2 subunit, which is characteristic of MPF activation. In contrast, the p34cdc2 subunit remained in the tyrosine-phosphorylated, inactive form in SV40-infected cells passing from G2 phase into a second S phase. These results suggest that although the MPF complex is assembled and modified normally, SV40 interferes with pathways leading to MPF activation.

Animals↗
PubMed1994

Growth condition-induced precocious activation of p34cdc2 kinase inhibits the expression of developmental competence.

We examined the effect of growth conditions upon mitotic p34cdc2 kinase and developmental competence in Acanthamoeba castellanii. At G2/M of the cell cycle p34cdc2 kinase activity peaks in level, and p34cdc2 is transiently in a complex with newly synthesized cyclin B and phosphorylated on tyrosine (pre-MPF). Developmental competence peaks in level slightly preceding p34cdc2 kinase activation and pre-MPF accumulation. Under adverse growth conditions p34cdc2 kinase activation and transient pre-MPF accumulation occur at a reduced G2 phase length and smaller cell size. Developmental competence is not expressed during the shortened G2 phase. Cycloheximide inhibits the precocious p34cdc2 kinase activation and both the precocious accumulation of cyclin B and tyrosine phosphorylation on p34cdc2. No-codazole inhibits the precocious p34cdc2 kinase activation as well; however, it does not affect the precocious accumulation of pre-MPF. Developmental competence increases in level during artificially elongated G2 phases. The results indicate that, first p34cdc2 kinase activation requires cyclin B in a complex with p34cdc2 and the presence of intact microtubuli, second establishment of competence requires a certain length of G2, and third the regulation of pre-MPF accumulation, and thus of cyclin B expression, plays a role in the relationship among growth condition, cell cycle progression, and expression of the developmental program.

Acanthamoeba↗
PubMed1984

Changes in the DNA content of amoebae of Dictyostelium discoideum during growth and development.

A fluorimetric assay has been used to determine the DNA content of amoebae of Dictyostelium discoideum during growth and development. Amoebae grown in axenic culture tended to be multinucleate and had a greater DNA content than amoebae grown with a bacterial substrate, which were mononucleate. During the first 10 h of development there was little change in the DNA content of amoebae grown with a bacterial substrate, but the average DNA content per cell in amoebae grown axenically decreased as the amoebae became virtually mononucleate. Amoebae at 10 h development that had been harvested during exponential axenic growth were divided into two populations by countercurrent distribution in a polymer two-phase system. DNA content indicated that one population was largely in the G2-phase of the cell cycle, whereas the other population was largely in the G1-phase. Similar results were obtained at 10 h development with amoebae harvested during the stationary phase of axenic growth, although these amoebae start development all in the G2-phase of the cell cycle. Spores had a low DNA content, indicating that they were in G1-phase. It is proposed that all amoebae in G2-phase after early development differentiate, after mitosis, into spores and that stalk cells are formed from amoebae that remain in G1-phase after 10 h development.

Cell Nucleus↗
PubMed1975

Instability of the duration of G1 phase of Yoshida sarcoma and ascites hepatomas.

The durations and coefficients of variance of G1, S and G2 phase were obtained for 8 cell lines of ascites tumours originated from hepatomas in rats, and these were compared. Although changes in the durations of S and G2 phases were small, the duration of G1 phase increased with the cell cycle time. The coefficient of variance of G1 phase was larger than that of S and G2 phases, most remarkedly at short cycle time. It was concluded that the G1 phase is the most unstable as well as the most variable in its duration.

Animals↗
PubMed1997

Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle.

Mice homozygous for the scid (severe combined immune deficiency) mutation are defective in the repair of DNA double-strand breaks (DSBs) and are consequently very X-ray sensitive and defective in the lymphoid V(D)J recombination process. Recently, a strong candidate for the scid gene has been identified as the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex. Here, we show that the activity of the DNA-PK complex is regulated in a cell cycle-dependent manner, with peaks of activity found at the G1/early S phase and again at the G2 phase in wild-type cells. Interestingly, only the deficit of the G1/early S phase DNA-PK activity correlated with an increased hypersensitivity to X-irradiation and a DNA DSB repair deficit in synchronized scid pre-B cells. Finally, we demonstrate that the DNA-PK activity found at the G2 phase may be required for exit from a DNA damage-induced G2 checkpoint arrest. These observations suggest the presence of two pathways (DNA-PK-dependent and -independent) of illegitimate mammalian DNA DSB repair and two distinct roles (DNA DSB repair and G2 checkpoint traversal) for DNA-PK in the cellular response to ionizing radiation.

Animals↗
PubMed1988

[Composition of DNA-bound lipids in the regenerating rat liver].

Using thin-layer chromatography, the qualitative and quantitative composition of specific DNA-bound neutral lipids (NL) and phospholipids (PL) of regenerating rat liver 22 hours (S-phase) and 28 hours (G2-phase) after hepatectomy was studied. These lipids are represented by light and tightly bound components. The intact liver DNA contains minor amounts of NL and PL (15.02 micrograms and 5.82 micrograms per mg of DNA, respectively). The composition of DNA-bound lipids in rat liver differs markedly from that of nuclear membrane and chromatin total lipids. The former are strongly deficient in free cholesterol (FC), but are rich in cholesterol esters (CE), very rich in cardiolipin (CL) and deficient in phosphatidylcholine. The basic parameters of DNA-bound lipids of rat liver (NL/PL, CE/FC and cholesterol/PL) are more than unity and depend on the cell cycle. It was shown that in the S-phase the content of DNA-bound NL and PL increases 1.5-fold, in the G2-phase the NL content shows a still greater increase--2.3-fold, while that of DNA-bound PL decreases to normal values. The basic changes of the DNA-bound lipids in regenerating rat liver are due to FC, CE and CL, which determine the tissue specificity of these lipids.

Animals↗
PubMed1993

[The effect of inhibitors on induced mutagenesis].

The mutagenic effect induced by mitomycin C (MC) 20 mg/ml in early, middle and late G1-phase of Crepis capillaris seeds was modified by DNA synthesis inhibitors--caffeine 5 mM, hydroxyurea (HU) 5 x 10(-3) M, 1-beta-D-arabinofuranosylcytosine (araC) 1 x 10(-3) M and aphidicolin (APC) 0.5 mg/ml in the DNA post-synthesis phase (G2). It was shown that under the action of MC in early G1 and the inhibitors in the G2 the total number of aberrations for fixations is lower in all the cases than under the action of MC only. The action of MC in the middle phase results in the differential effect of the inhibitors. HU and APC were shown to potentiate the effect induced by MC and ara-C to reduce it. In both cases, caffeine at the dose 5 mM had small effect on DNA damages induced by MC in early and middle G1. Under the action of caffeine and HU in the G2-phase the crosslinks induced by MC in the late G1 result in aberrations of chromosomal type, illegal for the S-dependent mutagenesis. On the whole, the process of mutation formation turned out to be sensibilized. The specificity of mutagenesis under the action of MC suggests the appearance of mutations of the chromosomal type after the DNA synthesis in G2 phase.

Aphidicolin↗