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PubMed1993

Targets for radiation-induced cell death: target replication during the cell cycle evaluated in cells exposed to X-rays or 125I decays.

Chinese hamster ovary cells were labelled with 125I-iododeoxyuridine (1.15 x 10(3) Bq/ml) for 12 h, then synchronized by mitotic selection, plated for cell cycle traverse, and harvested during successive stages of the cell cycle for freezing and accumulation of 125I decays. Cell viability was evaluated by the colony-forming assay. Cells subjected to 125I decays during the G1 phase exhibited exponential survival curves with an N = 1 and a D0 = 38-41 decays/cell. A continuous increase in 125I resistance was observed as cells progressed through the S phase and cells in late-S/G2 yielded shouldered survival curves with a N = 2 and a D0 = 78-84 decays/cell. After mitosis, the radiation resistance of cells returned to G1 values. These findings suggest that the primary target for radiation-induced cell death is duplicated during S phase, with G1 cells containing one target and G2 cells two targets. Dual targets, although located within a single cell, act as independent entities as if already distributed between two separate daughter cells. Therefore, the colony-forming assay provides survival values representative of single cells/single targets only for cells irradiated during the G1 phase of the cell cycle. For cells irradiated in S or G2 phases, when intracellular target multiplicity > 1, the colony-forming assay systematically gives higher values of cell survival by up to 100% due to the target multiplicity. Experiments with external X-rays confirm these conclusions.

Animals↗

PubMed1996

Aquaporin 1 expression during the cell cycle in A5 cells.

Aquaporin 1 is an integral membrane protein which functions as a water channel. It is reportedly (Lanahan et al., 1992) encoded by a delayed early response gene. We asked if the expression of aquaporin 1 varied during the cell cycle in an epithelial cell line (A5) in which its is constitutively expressed. A5 cells were synchronized by double thymidine block and cell cycle stages defined by flow cytometric analysis. AQP1 mRNA and protein levels were highest when most cells were in G0/G1, then decreased approximately 40-60% when the cells moved into the S and G2/M phases. These results provide the first demonstration that constitutive aquaporin 1 expression can fluctuate during the cell cycle.

Animals↗

PubMed2002

CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL.

CD10 constitutes a favourable prognostic marker for childhood acute lymphoblastic leukaemia. Since correlations between CD10, cell cycle and apoptotic abilities were demonstrated in various cell types, we investigated whether differences existed in the cycling/apoptotic abilities of CD10-positive and CD10-negative B acute lymphoblastic leukaemia cells. Twenty-eight cases of childhood acute lymphoblastic leukaemia (mean age of 6.8 years) were subdivided into two groups according to high (17 cases, 93.2+/-4.5%, MRFI 211+/-82 CD10-positive cells) or low (11 cases, 11.5+/-6.2%, MRFI 10+/-7 CD10-negative cells) expression of CD10. CD10-positive acute lymphoblastic leukaemia cells were cycling cells with elevated c-myc levels and propensity to apoptosis, whereas CD10-negative acute lymphoblastic leukaemia cells had lower cycling capacities and c-myc levels, and were resistant to apoptosis in vitro. A close correlation between all these properties was demonstrated by the observations that the few CD10-positive cells found in the CD10-negative acute lymphoblastic leukaemia group displayed elevated c-myc and cycling capacities and were apoptosis prone. Moreover, exposure of CD10-positive acute lymphoblastic leukaemia B cells to a peptide nucleic acid anti-gene specific for the second exon of c-myc caused inhibition of c-myc expression and reduced cell cycling and apoptotic abilities as well as decreased CD10 expression.

Antigens, CD↗

PubMed1987

Humoral regulation of human leukemic progenitor cell cycle: the case for turning off the cell cycle.

Colony-forming cells of chronic myelocytic leukemia as well as acute nonlymphocytic leukemia in the resting state can be turned on and mobilized into cell cycle with exposure to leukocyte conditioned medium. In addition, evidence indicates that the leukemic colony-forming cells in cell cycle can be turned off and mobilized out of cell cycle by withholding the leukocyte conditioned medium. The system used in this study will be invaluable in biologic studies of leukemic cell cycling and its manipulation. With the concept of leukemic cell-cycle manipulation established, new approaches to treatment of leukemia based on growth manipulation should be explored.

Cell Cycle↗

PubMed1990

Acute effects of 3'-azido-3'-deoxythymidine on the cell cycle of HL60 cells.

The average doubling times of HL60 cells grown in the presence of 0,5,10 and 100 microM 3'-azido-3'-deoxythymidine (AZT) for 72 h were, respectively, 51.1, 65.7, 69.0 and 76.3 h. This drug-concentration-dependent prolongation of the cell-doubling time was associated with a progressive increase in modal cell volume. The technique of combined Feulgen microspectrophotometry and 3H-thymidine autoradiography revealed that the cell cycle distribution of HL60 cells cultured in the presence of 5 and 100 microM AZT for 48 h was abnormal, with an increased percentage of cells in the S phase and a decreased percentage in the G1phase. From the cell doubling times and the cell cycle distribution data, and making a number of assumptions, upper limit estimates for the duration of the S phase in cultures containing 0,5 and 100 microM AZT were calculated to be 26.2, 35.8 and 49.6 h, respectively. The data indicate that concentrations of AZT achieved in the plasma of patients receiving this drug (i.e. 5 microM) cause a substantial prolongation of both the cell cycle time and the duration of the S phase of HL60 cells. It therefore seems likely that some of the toxic effects of AZT seen in vivo, including impairment of bone marrow function, are at least partly related to AZT-induced disturbances of DNA synthesis and proliferation in human cells.

Cell Count↗

PubMedDate not supplied

[Radiosensitive mutants of yeast-Saccharomyces with disruptions in the cell division cycle. Cell inactivation by restrictive temperature, ultra-violet and ionizing radiation in relation to the passage of the generated cycle].

Three thermo- and radiosensitive mutants of yeast-Saccharomyces were used to study cell inactivation under the effect of elevated temperature, UV-light, and ionizing radiation. The forms of cell inactivation were shown to be identical with all the factors under study and to resemble lethal "terminal phenotypes" of Hartwell cds mutants. It is suggested that the cell division cycle is blocked due to the disorders in the system of gene product synthesis and not to defects in the enzymes themselves.

Cell Division↗

PubMed2001

Use of flow and laser scanning cytometry to study mechanisms regulating cell cycle and controlling cell death.

Applications of FC and more recently LSC in the fields of cell cycle progression and cell death already have revealed a wealth of knowledge about mechanisms involved in regulation of these pathways. The cytometry instrumentation and the associated methodologies complement tools of molecular biology by providing information that is unavailable from the latter alone. The use of cytometry side by side with classic molecular biology methods offers the means for deeper exploration of these mechanisms at molecular and cellular levels. Recent years brought the availability of new cytometric probes that sense the functional changes in the cell, such as chemical modifications (phosphorylation, acetylation, ubiquitinylation, and so forth) of the regulatory molecules, or their translocations between different cell compartments. Such probes will be particularly useful in mechanistic studies on cell cycle and cell death. One expects that the progress in these fields will expand at a continuously accelerating pace, propelled by development of new methodologies and probes. One of the dominating motors for this progress will be further development of cytometry instrumentation and the applicability of this instrumentation, methods, and probes.

Apoptosis↗

PubMed2004

Cell cycle arrest and cell death are controlled by p53-dependent and p53-independent mechanisms in Tsg101-deficient cells.

Our previous studies have shown that cells conditionally deficient in Tsg101 arrested at the G(1)/S cell cycle checkpoint and died. We created a series of Tsg101 conditional knock-out cell lines that lack p53, p21(Cip1), or p19(Arf) to determine the involvement of the Mdm2-p53 circuit as a regulator for G(1)/S progression and cell death. In this new report we show that the cell cycle arrest in Tsg101-deficient cells is p53-dependent, but a null mutation of the p53 gene is unable to maintain cell survival. The deletion of the Cdkn1a gene in Tsg101 conditional knock-out cells resulted in G(1)/S progression, suggesting that the p53-dependent G(1) arrest in the Tsg101 knock-out is mediated by p21(Cip1). The Cre-mediated excision of Tsg101 in immortalized fibroblasts that lack p19(Arf) seemed not to alter the ability of Mdm2 to sequester p53, and the p21-mediated G(1) arrest was not restored. Based on these findings, we propose that the p21-dependent cell cycle arrest in Tsg101-deficient cells is an indirect consequence of cellular stress and not caused by a direct effect of Tsg101 on Mdm2 function as previously suggested. Finally, the deletion of Tsg101 from primary tumor cells that express mutant p53 and that lack p21(Cip1) expression results in cell death, suggesting that additional transforming mutations during tumorigenesis do not affect the important role of Tsg101 for cell survival.

Animals↗

PubMed2001

Cell cycle control of cell morphogenesis in Caulobacter.

In Caulobacter crescentus, morphogenic events, such as cytokinesis, the establishment of asymmetry and the biogenesis of polar structures, are precisely regulated during the cell cycle by internal cues, such as cell division and the initiation of DNA replication. Recent studies have revealed that the converse is also true. That is, differentiation events impose regulatory controls on other differentiation events, as well as on progression of the cell cycle. Thus, there are pathways that sense the assembly of structures or the localization of complexes and then transduce this information to subsequent biogenesis or cell cycle events. In this review, we examine the interplay between flagellar assembly and the C. crescentus cell cycle.

Caulobacter crescentus↗

PubMedDate not supplied

Expression patterns of the cell-cycle inhibitor p27 and the cell-cycle promoter cyclin E in the human placenta throughout gestation: implications for the control of proliferation.

The rapid development of the placenta necessitates a high proliferative potential and cell-division rate. This, coupled with a high capacity for invasion, could confer on the placental tissue a tumour-like character. To exclude this, tight mechanisms of control are necessary for both proliferation and invasiveness. Despite their importance, very little is known about the molecular basis of these mechanisms. The present study was thus designed to investigate the molecular mechanisms implicated in the control of proliferation in the human placenta. We used immunohistochemistry to study the expression of two cell-cycle controlling molecules with opposing effects: the cell-cycle inhibitor, p27, which belongs to the Kip/Cip family of CDK inhibitors and can mediate G1 arrest, and cyclin E, a G1-cyclin esential for G1/S progression. Expression was studied throughout pregnancy in a total of 41 normal human placental samples. In addition, immunohistochemistry for Ki-67 was performed as a control for proliferation. The cell-cycle inhibitor p27 was expressed in the differentiated, non-dividing syncytiotrophoblast, while expression of cell-cycle promoter cyclin E was localized to the nuclei of the cytotrophoblast and correlated well with expression of Ki-67. No cyclin E expression was observed in the syncytiotrophoblast. In conclusion, strong expression of the cell-cycle inhibitor p27 and absence of expression of cyclin E in the syncytiotrophoblast might represent an important control mechanism in placental proliferation. This differentiates it from the proliferation of malignant tumours, where p27 has been shown to be frequently downregulated while cell cycle promoters are overexpressed.

Cell Cycle↗

PubMed2003

An analysis of changes in the expression of cyclins A and B1 by the cell array system during the cell cycle: comparison between cell synchronization methods.

BACKGROUND: A novel high-throughput analysis, cell array system, was developed for an extensive study of the expression of genes and/or the degradation of gene products at the cellular level. To exemplify the usefulness of this system, we showed the changes in the expression level of cyclin A and B1 during the cell cycle in a single experiment. METHODS: We used the cell array system to chase the changes in cyclin A and B1 expression during the cell cycle in HeLa cells. Cells were synchronized by mitotic selection and thymidine-hydroxyurea methods. Cells were harvested at intervals of 1 h from 0 through 23 h. These 48 cell samples were spotted on a circle of the cell array glass slide. Cyclin A and B1 were immunologically stained with Alexa Fluor 488, and nuclear DNA was stained with propidium iodide. The amount of cyclins and nuclear DNA were simultaneously measured by a laser scanning cytometer. RESULTS: Both cyclins were expressed in a cell cycle-dependent manner as previously reported. The precise time-course of the expression level of cyclins were obtained at a single experiment with this cell array system. CONCLUSIONS: This study indicates that the cell array system is valuable to analyze temporal course of protein expression in relation to the cell cycle position and, that it facilitates antigen expression studies at the cellular level in multiple samples.

Cell Cycle↗

PubMed1998

Simultaneous measurement of cell cycle and apoptotic cell death.

Understanding the dynamics of cell death in conjunction with those of cell cycle can be illuminating in the investigation of various cellular behaviors. Robust assays for measuring such parameters are invaluable. Many assays of apoptosis and/or cell cycle use flow cytometry. This chapter describes two different assays to measure apoptosis and cell cycle simultaneously using flow cytometry. The first involves the use of terminal transferase (the "TUNEL" assay) together with propidium iodide for identification of cell cycle. The second uses fluorescently labeled annexin V, together with propidium iodide as an indicator of cell membrane integrity; and additionally Hoechst 33342 for determination of cell cycle. Each assay has positive and negative attributes. The terminal transferase assay is performed using fixed cells and is therefore useful in the analysis of samples collected over time. The annexin V assay is performed using unfixed cells, and thus provides information regarding membrane integrity. Other practical aspects of both assays are discussed.

Animals↗

PubMed2004

Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1.

Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naive mature B cells, which are naturally arrested in G(0)/G(1) phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G(1) cell-cycle progression, but not S-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18(INK4c). Independent of its survival function, BLyS enhances the synthesis of cyclin D2, in part through activation of NF-kappaB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18(INK4c), B cell receptor signaling induces cell-cycle entry and G(1) progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27(Kip1) expression. Antagonistic cell-cycle regulation by BLyS and p18(INK4c) is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo, further indicating a physiologic role in homeostasis.

Animals↗

PubMed2004

Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines.

Flow cytometric analysis of fibroblasts, normal breast epithelial cells and breast or other cancer cell lines identified variation in the abilities of cell lines to undergo cell cycle arrest as a response to hypoxia. Human mammary epithelial cells (HMEC), normal fibroblasts (Hs68 and WI38), HeLa cervical carcinoma and HTB-30 breast carcinoma cells arrest in G(1)/S in response to severe hypoxia. Hep3B hepatocellular carcinoma cells did not exhibit orderly G(1)/S arrest in response to severe hypoxia. We found a general decrease in p16(INK4a) (p16) mRNA levels, with an associated decrease in p16 protein levels in both normal cells and in cancer cells, regardless of their cell cycle response to hypoxia. p27 protein levels did not correlate with the cell line's ability to enter a hypoxic G(1)/S arrest. Furthermore, cell lines that underwent G(1)/S arrest showed decreased expression of hypoxia inducible factor 1 (HIF-1alpha) and at least one member of INK4 or Sdi cell cycle kinase inhibitors families after 12-24 h of hypoxia. Conversely, Hep3B, which did not exhibit orderly hypoxia-associated G(1)/S arrest, also did not show decreased HIF-1alpha, INK4 or Sdi protein levels in hypoxia. Furthermore, Hep3B showed constitutive activating phosphorylation of Akt and inhibitory phosphorylation of GSK3beta, which was the opposite pattern to that exhibited by the cell lines showing the G(1)/S arrest phenotype. Inhibition of GSK3beta by lithium chloride treatment of HeLa cells converted the HIF-1alpha, p16 and p27 loss to levels unchanged by hypoxic exposure. Our results suggest that regulation of the cell cycle during hypoxia in either normal or cancer cells is not simply due to up-regulation of cell cycle kinase inhibitors. Furthermore, decreased protein expression of HIF-1alpha, p16 and p27 was associated with both a hypoxia-induced G(1)/S arrest phenotype and increased GSK3beta activity.

Apoptosis↗

PubMed1998

[Effects of matrine on telomerase activity and cell cycle in K562 cell].

OBJECTIVE: In order to search for new tumor differentiation inducer, the effects of matrine of Chinese herbal origin on differentiation of K562 cells and its mechanism were studied. METHODS: Telomerase activity was determined by PCR-ELISA in untreated or treated K562 cells, cell cycle phases were analyzed by fluorescence-activated cell sorter analysis. RESULTS: Telomerase activity of K562 cells was significantly inhibited when treated with matrine, and cell cycle of the treated K562 cells was changed with marked decrease in S phase. CONCLUSION: Matrine can induce differentiation of K562 cells, the mechanism of which might be related to the inhibition of telomerase activity and cell cycle arrest.

Alkaloids↗

PubMed1998

Changes in numbers of prolactin receptors during the cell cycle of Nb2 cells.

Lactogenic hormones including prolactin (PRL) have mitogenic effects on Nb2 cells, a pre-T lymphoma cell line. Previous studies have characterized the PRL stimulation of cellular processes such as RNA/DNA synthesis, signalling molecule activation, and the expression of specific genes. The data presented here explores the fluctuations in plasma membrane PRL receptor (PRLR) number that occur in the Nb2 cells during the course of a 24 h cell cycle. PRLR abundance was determined by measuring specific binding of [I125] oPRL to G1 arrested-intact Nb2 cells in which the cell cycle was initiated by addition of nonradioactive oPRL. Preliminary studies revealed that 1 ng/ml oPRL was the minimum PRL concentration that causes a maximal stimulation of mitogenesis, without interfering with [I125] oPRL binding measurements. Subsequent experiments revealed that upon cell cycle initiation of G1 arrested Nb2 cells with 1 ng/ml oPRL, PRLR number remained constant for the initial 6 h. After 8 h PRLR numbers decreased and at 12 h, the PRLR number was less than 25% of the initial value. After 12 hr, PRLR numbers increased and reach initial values by 18 hr. These studies show that the expression of cell surface PRL receptors is modulated in a sequential fashion during the cell cycle of Nb2 cells.

Cell Cycle↗

PubMed1977

Mitochondrial growth and division during the cell cycle in HeLa cells.

The growth and division of mitochondria during the cell cycle was investigated by a morphometric analysis of electron micrographs of synchronized HeLa cells. The ratio of total outer membrane contour length to cytoplasmic area did not vary significantly during the cell cycle, implying a continuous growth of the mitochondrial outer membrane. The mean fraction of cytoplasmic area occupied by mitochondrial profiles was likewise found to remain constant, indicating that the increase in total mitochondrial volume per cell occurs continuously during interphase, in such a way that the mitochondrial complement occupies a constant fraction( approximately 10-11(percent)) of the volume of the cytoplasm. The mean area, outer membrane contour length, and axis ratio of the mitochondrial profiles also did not vary appreciably during the cell cycle; furthermore, the close similarity of the frequency distributions of these parameters for the six experimental time-points suggested a stable mitochondrial shape distribution. The constancy of both the mean mitochondrial profile area and the number of mitochondrial profiles per unit of cytoplasmic area was interpreted to indicate the continuous division of mitochondria at the level of the cell population. Furthermore, no evidence was found for the occurrence of synchronous mitochondrial growth and division within individual cells. Thus, it appears that, in HeLa cells, there is no fixed temporal relationship between the growth and division of mitochondria and the events of the cell cycle. A number of statistical methods were developed for the purpose of making numerical estimates of certain three-dimensional cellular and mitochondrial parameters. Mean cellular and cytoplasmic volumes were calculated for the six time-points; both exhibited a nonlinear, approx. twofold increase. A comparison of the axis ratio distributions of the mitochondrial profiles with theoretical distributions expected from random sectioning of bodies of various three-dimensional shapes allowed the derivation of an "average" mitochondrial shape. This, in turn, permitted calculations to be made which expressed the two-dimensional results in three-dimensional terms. Thus, the estimated values for the number of mitochondria per unit of cytoplasmic volume and for the mean mitochondrial volume were found to remain constant during the cell cycle, while the estimated number of mitochondria per cell increase approx. twofold in an essentially continuous manner.

Cell Division↗

PubMed1995

Ionizing radiation damage to cells: effects of cell cycle redistribution.

If a population of cycling cells is exposed to a fixed dose of ionizing radiation delivered over time T, it is sometimes observed that increasing T increases the amount of cell killing. This is essentially because at first the radiation preferentially kills cells in a sensitive portion of the cycle and the surviving, more resistant cells then have time to reach more sensitive stages. We refer to this effect as population resensitization, caused by redistribution within the cell cycle. We investigate the effect theoretically by employing the McKendrick-von Foerster equation for age-structured proliferating cell populations, generalized by introducing a radiation damage term. Within our formalism, we show that population resensitization occurs whenever: (a) prior to irradiation the cell population has the stable age-distribution approached asymptotically by an unirradiated population, and (b) T is sufficiently small. Examples and other cases are outlined. The methods of Volterra integral equations, renewal theory, and positive semigroup theory are applied. The effect of varying T is evaluated by considering the ultimate amplitude of the stable age-distribution population at times much greater than both the irradiation duration and the average cell-cycle time. The main biological limitations of the formalism are the following: considering only radiation damage which is not subject to enzymatic repair or quadratic misrepair, using an overly naive method of ensuring loss of cell cycle synchrony, neglecting nonlinear effects such as density inhibition of growth, and neglecting radiatively induced perturbations of the cell cycle. Possible methods for removing these limitations are briefly discussed.

Animals↗