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At least 145 records · Page 8Linked to original sources
PubMed1980

SV40-infected muntjac cells: cell cycle kinetics, cell ploidy and T antigen concentration.

Muntjac cells in which the SV40 virus neither readily causes transformation nor replicates were used to study the effect of SV40 infection on cell ploidy and the influence of ploidy on the concentration of T antigen, which is required for the initiation of viral DNA synthesis. Both the DNA content, as measured by the flow microfluorometry of propidium iodide-DNA fluorescence, and the average number of chromosomes per cell indicated that infection with SV40 did not alter the ploidy of the host cell. SV40 infection had no effect on the ploidy distribution of muntjac cells. After immunofluorescence staining with anti-T serum and fluorescein-labeled anti-gamma G, infected and uninfected cultures were compared. In uninfected cells incubated with a 1:20 dilution of anti-T serum no fluorescence could be observed by fluorescence microscopy, but when examined by flow microfluorometry, fluorescence was detected after staining with as little as 1000-fold diluted antiserum. Determination of the amount of T antigen and DNA content in the same cell by simultaneous measurement of fluorescein isothiocyanate-conjugate and propidium iodide fluorescence, indicated that the cellular concentration of T antigen did not vary with the ploidy of the genome or the number of nuclei per cell. These results suggest that gene dosage is not a factor which determines the permissive environment for SV40 replication.

Animals↗
PubMed2000

Ras proteins in the control of the cell cycle and cell differentiation.

The Ras family of small GTPases includes three closely related proteins: H-, K-, and N-Ras. Ras proteins are involved in the transduction of signals elicited by activated surface receptors, acting as key components by relaying signals downstream through diverse pathways. Mutant, constitutively activated forms of Ras proteins are frequently found in cancer. While constitutive Ras activation induces oncogenic-like transformation in immortalized fibroblasts, it causes growth arrest in primary vertebrate cells. Induction of p53 and cyclin-dependent kinase inhibitors such as p15INK4b, p16INK4a, p19ARF, and p21WAF1 accounts for this response. Interestingly, while ras has usually been regarded as a transforming oncogene, the analysis of Ras function in most of the cellular systems studied so far indicates that the promotion of differentiation is the most prominent effect of Ras. While in some cell types, particularly muscle, Ras inhibits differentiation, in others such as neuronal, adipocytic, or myeloid cells, Ras induces differentiation, in some cases accompanied by growth arrest. Several possible mechanisms for the pleiotropic effects' of Ras in animal cells are discussed.

Animals↗
PubMed1986

Abnormal regulation of uracil-DNA glycosylase induction during cell cycle and cell passage in Bloom's syndrome fibroblasts.

The uracil-DNA glycosylase activity was compared in cell-free extracts of normal (NHSF6) and Bloom's syndrome (BS) skin fibroblasts (BS1KA and BS2KA from Japanese patients) at middle culture age. The enzyme activity in the extracts of exponentially growing NHSF6 and BS2KA cells increased linearly with the DNA synthetic activity, while such a relation was not obvious in BS1KA cells. The thermal stability and the inhibition by the end product uracil of the BS1KA enzyme did not differ from those of the NHSF6 enzyme. Synchronized-cell studies showed the following characteristics. (i) Uracil-DNA glycosylase activity was enhanced in a temporal sequence only during S phase and reached a peak level a few hours prior to that of DNA synthesis in NHSF6. (ii) BS2KA cells were normal in the temporal induction sequence but BS1KA cells revealed the delayed peak induction of the enzyme occurring simultaneously with peak DNA synthesis. (iii) With progress of culture passage, the uracil-DNA glycosylase activity became highly expressed at G0 and during G1 despite a little change in the S-phase activity in NHSF6 cells. (iv) Another abnormality of BS1KA cells was that such a culture-age-dependent dysregulation occurred earlier during middle passages. The above results (i) and (ii) suggest that the delayed enzyme induction in BS1KA cells may be related to the observation that BS1KA cells were more sensitive to 5-bromodeoxyuridine-induced cell killing and to sister chromatid exchange formation than BS2KA cells of the clinically milder subject.

Bloom Syndrome↗
PubMed1993

Chronic elevation of plasma corticosterone causes reductions in the number of cycling cells of the B lineage in murine bone marrow and induces apoptosis.

Steroid-containing implants were used to ascertain the effects of chronic elevation of physiological levels of plasma corticosterone (CS) (30-100 micrograms/dl) on lymphopoietic processes in the bone marrow of the mouse. Phenotypic analysis of bone marrow B-lineage lymphocytes using flow cytometry (FACS) indicated a 50% decrease in bone marrow Ig+ cells, and a 70-80% decrease in B220+ cells had occurred 3 days after exposure to steroid. By day 5, the B220+ Ig- precursor B cells in the marrow of mice exposed to CS were nearly depleted, with many of the remaining B cells being B220bright IgM+IgDbright. To determine if the depletion of B cells was due to disruption in cell cycling and/or induction of apoptosis, phenotype-gated FACS cell cycle analysis was utilized. The proportion of B220+ cells in the S phase of the cell cycle declined 75% after 24 hr exposure to CS. A few hours after CS implantation, the appearance of a small but distinct population of B220+ and IgM+ cells in the 'hypodiploid' region of the cell cycle was also noted, which was previously termed the Ao region and corresponded to cells undergoing apoptosis. Thus, the chronic presence of modestly elevated levels of plasma CS analogous to that produced during malnutrition, stress and trauma caused rapid depletion of developing B-lineage cells in the marrow by reducing the number of cycling precursor B cells and inducing apoptosis.

Animals↗
PubMed1996

A cell-cycle phase-associated cell-type choice mechanism monitors the cell cycle rather than using an independent timer.

Upon starvation, cells of the simple eukaryote Dictyostelium discoideum aggregate and differentiate into several cell types. Two main cell types are prestalk and prespore, which later usually become stalk and spore cells. The differentiation is plastic, and several factors can alter cell-type ratios. Two mechanisms have been proposed to regulate the initial cell type. We and others have proposed that cell type is initially determined by cell-cycle phase at the time of starvation: prestalk cells are derived from cells which, are the time of starvation, happen to be in a roughly 2-hr-long sector of the cell cycle which overlaps S and early G2 and that certain extracellular factors are then used to maintain the proper prestalk:prespore ratio and to control later stages of development such as the prestalk-to-stalk conversion. To examine the relationship between initial cell-type choice and the cell cycle, and how this 2-hr-long sector is generated, we increased the length of S phase by mild treatments of cells with DNA-synthesis inhibitors. When the fraction of the cell cycle occupied by S phase is increased and the cells are then starved, the prestalk:prespore ratio increases. This increase was observed using two markers for prestalk cells, CP2 and ecmA::lacZ. In addition, there is a close correlation between the fraction of the cell cycle occupied by S phase and the prestalk:prespore ratio, irrespective of total cell-cycle length. These results validate the hypothesis that the initial choice of cell type is determined by cell-cycle phase at the time of starvation, and indicate that the cell-type choice mechanism monitors the cell cycle rather than using an independent 2-hr-long timer started at the beginning of S phase.

Animals↗
PubMed1996

Interest of targeting AgNORs measurement in cycling cells: in vivo cell kinetic evaluation of non-small cell lung cancer.

This study investigated the actual growth rate of 30 low stage operable non-small cell lung carcinomas, including disease-free surviving and deceased patients. The actual growth rate was defined as the cell production rate and was calculated from the growth fraction and the cell cycle time of each tumor at the time of surgical resection. The growth fraction was assessed by the Ki67 index while the cell cycle time was assumed to be reflected by the AgNORs content in the cells positive for Ki67. AgNORs content was evaluated by means of image analysis of double-stained AgNOR-Ki67 tissue section. The actual growth rate did not discriminate between the disease-free surviving and deceased patients but the AgNORs content in Ki67 cells correlated with the survival time of those patients who died of the tumor. Patients expressing a small AgNORs content, which might indicate a long cell cycle, may die but later; patients with a high AgNORs content, which might indicate a short cell cycle, die early or will survive. A twilight curve was derived from this data and might provide new prognostic indicators.

Aged↗
PubMed1984

Subpopulations of slowly cycling cells in S and G2 phase in mouse epidermis.

Evidence has been presented supporting the existence of heterogeneity in cell-cycle progression in mouse epidermis, The present study was undertaken to characterize this heterogeneity in more detail. Hairless mice were continuously labelled with tritiated thymidine every 4 hr for 4 days. Basal cell suspensions were prepared from slices of mouse skin at intervals during the experiment and subjected to DNA flow cytometry. Cell-cycle analysis was combined with sorting of cells from windows in G1, S and G2 phase, and the proportion of labelled cells within each window was determined in autoradiographs. Reanalysis and resorting to control the purity of of sorted fractions were performed. Computer simulations of the data were made using a mathematical model assuming different S and G2 phase characteristics. A good fit to the data was only obtained when heterogeneity in mouse epidermal cell-cycle progression was assumed, indicating the existence of slowly traversing, distinct subpopulations of cells in G2 and S phase. These cells are assumed to contribute to about 40% of all cells in S phase and to about 70% of all in G2 phase. The estimated residence times in the resting states were 38 and 32 hr in S and G2 phase, respectively. Two-parameter sorting based on DNA and light scatter indicated that slowly cycling cells were larger than the average. There is no evidence of significant subpopulations of permanently non-proliferating keratinocytes in any of the cell-cycle phases.

Animals↗
PubMed1998

Analysis of the early embryonic cell cycles of Xenopus; regulation of cell cycle length by Xe-wee1 and Mos.

In Xenopus, cdc2 tyrosine phosphorylation is detected in the first 60-75 minute cell cycle but not in the next eleven cell cycles (cycles 2-12) which are only 30 minutes long. Here we report that the wee1/cdc25 ratio increases before the first mitotic interphase. We show that the Xe-wee1 protein is absent in stage VI oocytes and is expressed from meiosis II until gastrulation. A dominant negative form of Xe-wee1 (KM wee1) reduced the level cdc2 tyrosine phosphorylation and length of the first cycle. However, the ratio of wee1/cdc25 did not decrease after the first cycle and therefore did not explain the lack of cdc2 tyrosine phosphorylation in, nor the rapidity of, cycles 2-12. Furthermore, there was no evidence for a wee1/myt1 inhibitor in cycles 2-12. We examined the role of Mos in the first cycle because it is present during the first 20 minutes of this cycle. We arrested the rapid embryonic cell cycle (cycle 2 or 3) with Mos and restarted the cell cycle with calcium ionophore; the 30 minute cycle was converted into a 60 minute cycle, with cdc2 tyrosine phosphorylation. In addition, the injection of a non-degradable Mos (MBP-Mos) into the first cycle resulted in a dramatic elongation of this cycle (to 140 minutes). MBP-Mos did not delay DNA replication or the translation of cyclins A or B; it did, however, result in the marked accumulation of tyrosine phosphorylated cdc2. Thus, while the wee1/cdc25 ratio changes during development, these changes may not be responsible for the variety of cell cycles observed during early Xenopus embryogenesis. Our experiments indicate that Mos/MAPK can also contribute to cell cycle length.

Amino Acid Sequence↗
PubMed2003

[Effects of 3-substituted aryl oxindole(PH II-7) on cell cycle of tumor cells].

AIM: To study the antitumor mechanism of 3-substituted aryl oxindole (PH II-7) and determine its effects on cell cycle distribution of tumor cells. METHODS: The cell cycle distributions were determined with FACS. The cell cycle regulation-related proteins of K562 lysates were analyzed with Western Blot. The inhibition of PH II-7 on DNA synthesis of tumor cells were estimated though 3H-thymidine incorporation and the tyrosine kinase activity of EGFR of A431 lysates was measured with ELISA. RESULTS: PH II-7 effected cell cycle distribution of several tumor cells, including multidrug resistant tumor cell lines, and accumulation of cells in the G0-G1 stages was observed. The cell cycle regulation-related proteins CDK2, Rb and c-myc were inhibited by PH II-7 in a dose dependent manner, whereas the expression of CyclinE was increased after exposure to PH II-7. Furthermore, PH II-7 2.0 mg.L-1 was shown to inhibit the incorporation of 3H-thymidine into DNA, and 21.89%-41.29% of the PTK activity of EGFR in A431 lysates was inhibited by PH II-7 2-8 mg.L-1 in a dose-dependant manner. CONCLUSION: PH II-7, a new anti-tumor agent, blocks the transition of cell cycle of tumor cells from G1 to S phase by inhibition CDK2.

Antineoplastic Agents↗
PubMed2000

Intranuclear localization of proliferating cell nuclear antigen during the cell cycle in renal cell carcinoma.

OBJECTIVE: To investigate, with laser scanning cytometry (LSC), proliferating cell nuclear antigen (PCNA) expression during the cell cycle in renal cell carcinoma. STUDY DESIGN: DNA ploidy and intracellular localization of PCNA in renal cell carcinoma were determined using LSC and immunohistochemistry. The subjects were nine patients who had received surgery for renal cell carcinoma. After DNA ploidy analysis, the glass slides were restained by immunohistochemistry of PCNA. LSC allowed direct observation of PCNA localization during the cell cycle because we could obtain immunohistochemical staining of PCNA as a function of cell cycle phase for individual cells. RESULTS: PCNA was not demonstrated in the nuclei of G0/G1 cells. PCNA expression increased from the S phase of the cell cycle. PCNA rapidly degraded at the end of the G2 phase. In the late G2 and M phase, PCNA was not detected in almost any nucleus. CONCLUSION: LSC allows morphologic observation of the intracellular distribution of PCNA during the cell cycle in renal cell carcinoma.

Adult↗
PubMed1999

Cell cycle checkpoint evasion and protracted cell cycle arrest in X-irradiated small-cell lung carcinoma cells.

PURPOSE: To determine the longevity and dose-dependence of acute X-irradiation-induced cell cycle perturbations in a panel of seven small-cell lung carcinoma (SCLC) cell lines (COR-L32B, COR-L51B, COR-L88B, COR-L96C, COR-L103, COR-L266B, COR-L279), assessed for TP53 tumour suppressor gene status and showing characteristically long population doubling periods. MATERIALS AND METHODS: Cell lines were screened for abnormalities in TP53. Cell cycle arrest and nuclear fragmentation were determined by flow cytometry under culture conditions that minimized the propensity of SCLC cells to form multicellular aggregates. A faster growing SCLC cell line (NCI-H69) and two breast tumour cell lines were used as controls. RESULTS: NCI-H69 and five of the COR-SCLC cell lines showed clear evidence of TP53 abnormalities and the cycle arrest responses of the breast tumour cell lines established the effects of TP53 mutation on G1/S checkpoint loss. All SCLC lines, at 24 h after low dose irradiation, showed abrogation of the G1/S checkpoint together with a range of expression of a protracted G2/M delay. G2/M delay progressed in all panel cell lines up to 48 h post-irradiation while NCI-H69 showed significant recovery for the dose range 75-600cGy. Only NCI-H69 and one panel line showed dose-dependent progression to complete nuclear DNA fragmentation. CONCLUSIONS: The culture method permits the measurement of cell cycle effects that reflect the TP53 status of SCLC cells. G1/S checkpoint failure, long-term radiation-induced G2 arrest, highly muted apoptotic responses and delayed recovery appear to be typical responses of the recently derived COR-SCLC lines. The results imply that low levels of unrepaired DNA damage, induced at clinically relevant doses, can persist for days in SCLC cells with long cell cycle traverse times, and can remain capable of checkpoint activation with implications for S phase-targeted therapies.

Apoptosis↗