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At least 19 recordsLinked to original sources
PubMed1995

Late mitosis/early G1 phase and mid-G1 phase are not hypersensitive cell cycle phases for neoplastic transformation of HeLa x skin fibroblast human hybrid cells induced by fission-spectrum neutrons.

A two- to threefold increase in the rate of neoplastic transformation in cells irradiated at a dose rate of 0.22 cGy/min with fission-spectrum neutrons compared to that at 10.7 cGy/min has been confirmed with the use of alkaline phosphatase chromogenic substrate Western Blue staining to detect foci of neoplastically transformed cells through their expression of a tumor-associated antigen, the end point of the HeLa x skin fibroblast human hybrid cell transformation assay. To investigate whether the inverse dose-rate effect is due to the existence of a period in the cell cycle in which cells are significantly more sensitive to neoplastic transformation than in the rest of the cell cycle, as has been postulated previously (Rossi and Kellerer, Int. J. Radiat. Biol. 50, 353-361, 1986; Brenner and Hall, Int. J. Radiat. Biol. 58, 745-758, 1990; Elkind, Int. J. Radiat. Biol. 59, 1467-1475, 1991), we compared the sensitivity of late mitotic/early G1-phase and mid-G1-phase cells with that of asynchronous cells. The rationale for examining these particular cell cycle phases was based on the fact that mitosis has been hypothesized to be a candidate for the extremely sensitive period, and on a preliminary report that mid-G1-phase C3H 10T1/2 cells may exhibit enhanced sensitivity for neutron-induced transformation. A nominal dose of 45 cGy of fission-spectrum neutrons was delivered at approximately 10 cGy/min. The data indicate that neither late mitotic/early G1-phase nor mid-G1-phase cells are significantly more sensitive than asynchronous cells. Further, the dependence on the phase of the cell cycle for neoplastic transformation of CGL1 cells induced by fission-spectrum neutrons is different from that previously demonstrated for gamma radiation, where late-mitotic cells were approximately five times more sensitive than mid-G1-phase and asynchronous cells (Redpath and Sun, Radiat. Res. 121, 206-211, 1990).

Cell Cycle↗
PubMed1979

T98G: an anchorage-independent human tumor cell line that exhibits stationary phase G1 arrest in vitro.

T98 and T98G are two related cell lines that were derived from a human glioblastoma multiforma tumor. T98G has almost twice as many chromosomes as T98, suggesting that it is a polyploid variant of T98. Three aspects of control of cellular proliferation were studied in T98 and T98G cells in comparison to WI-38 normal human diploid cells. WI-38 cells have the following properties: (1) they can undergo only a limited number of population doublings in vitro; (2) they cannot proliferate without anchorage; and (3) they become arrested in G1 phase under stationary phase conditions. T98 cells differ from normal cells in all three of these properties, as do many other transformed cell lines. However, the derivative of T98, namely T98G, expresses an unique combination of normal and transformed aspects of the control of cellular proliferation. T98G cells are like normal cells in that they become arrested in G1 phase under stationary phase conditions, yet they also exhibit the transformed characteristics of anchorage independence and immortality. Thus, T98G cells demonstrate that transformation to immortality and anchorage independence can exist without concomitant loss of the normal mechanism for G1 arrest in response to stationary phase conditions. This result supports the hypothesis that each of these three aspects of control of cellular proliferation can be altered independently. Partially transformed cell lines, such as T98G, should be useful for sorting out the biochemical changes associated with transformation in each of these aspects.

Cell Cycle↗
PubMed1976

[Splitting of phase G1 of the mitotic cycle of guinea pig large intestine crypt cells].

Changes in shape of the second wave of the labeled mitoses curve previously observed by Rowinski and Sawicki (1972) for three crypt zones of three different parts of guinea-pig ascending colon are explained by the complicated branching structure of the G1-phase. This structure is assumed to be the same for different crypt zones and for different sections of the intestine. Changes in shape of the second wave of the labeled mitoses curve are explained by the changes in distribution of proliferating cell stream between the alternative directions at the points of branching of the G1-phase, depending on the crypt zone, the intestine section, the cell state, and on the state of intestine.

Animals↗
PubMed1978

Late S phase cells (Chinese hamster ovary) induce early S phase DNA labeling patterns in G1 phase nuclei.

Cells (Chinese hamster ovary) in G1 phase were fused with cells in late S phase to determine if a cell in late S phase can induce DNA synthesis in the nucleus of a G1 cell and, if so, to determine if the DNA synthesis so induced in a G1 phase nucleus has an autoradiographic pattern characteristic of early or of late S phase synthesis. The results indicate (i) that 89% of the G1 nuclei in late-S/G1 binucleates synthesized DNA, while only 2% of the control unfused G1 cells synthesized DNA, and (ii) that in all late-S/G1 binucleates the G1 nucleus was induced to synthesize early S phase DNA. These results are compatible with the idea that a cytoplasmically transmissible factor initiates DNA synthesis but that an intranuclear mechanism defines the temporal order of replication.

Cell Cycle↗
PubMed1991

Quantitation of G0 and G1 phase cells in primary carcinomas. Antibody to M1 subunit of ribonucleotide reductase shows G1 phase restriction point block.

Human cancers have an apparent low growth fraction, the bulk of cells presumed to being out of cycle in a G0 quiescent state due to the inability in the past to distinguish G0 from G1 cells. The allosteric M1 subunit of ribonucleotide reductase (M1-RR) is constitutively expressed by cycling cells (i.e., G1, S, G2-M). It is acquired during transition from G0 to G1, lost during exit to G0 and thus distinguishes G0 from G1 cells. To estimate the proportion of G0 and G1 cells in primary human breast (n = 5) and colorectal (n = 12) adenocarcinomas, we used both analytical DNA flow cytometry (ADFC) and immunoperoxidase staining of sections with the monoclonal antibody to M1-RR (MAb M1-RR). ADFC of fresh tumors revealed a low percentage of cells in the S phase (4.0 +/- 3.4%) but immunoperoxidase staining for M1-RR revealed an unexpectedly high proportion of positive cells (52.4 +/- 12.7%) in the G1, S, G2-M phases indicating a high G1 content of primary human tumors. Thus, human cancers are blocked in transition in G1 and are not predominantly in a G0 or quiescent differentiated state. This block was interpreted to mean that human cancers are responding to putative regulatory events at a restriction point in the G1 phase, such as relative growth factor deficiency, density inhibition, antiproliferative cytokines, or gene products. Using flow cytometry for both DNA and M1-RR content we found that human colon cancer cell lines arrest in the G1 but not G0 phase upon serum deprivation or density inhibition. Similarly, human breast cancer cell lines are arrested in G1 but not G0 phase by medroxyprogesterone acetate (MPA) or tamoxifen exposure. These findings match our in situ observations, and support the concept of a restriction point block in primary human tumors.

Adenocarcinoma↗
PubMed1983

[Cytophotometric evaluation of the transition of cells from the G0 phase to the G1 phase of the cell cycle].

Feulgen stained nuclei of PHA-stimulated human blood lymphocytes were used for cytophotometric chromatin pattern analysis. Similar distributions of low optical density values indicating the predominance of diffuse chromatin were obtained for G1, S and G2 cells. Condensed chromatin was predominant in G0 and M nuclei. Integral versus average optical densities scatter plots analyses permitted one to distinguish cells undergoing different phases of cell cycle including G0 and G1.

Cell Nucleus↗
PubMed1990

Butyrate blocks the accumulation of CDC2 mRNA in late G1 phase but inhibits both the early and late G1 progression in chemically transformed mouse fibroblasts BP-A31.

Sodium butyrate (6 mM) blocks the resumption of the cell division cycle in serum-deprived chemically transformed Balb/c-3T3 mouse fibroblasts (BP-A31). The inhibition of G1 progression by sodium butyrate is not restricted to a specific mitogenic signaling pathway and is equally effective when tetradecanoyl phorbol acetate (TPA), insulin, or fetal calf serum (FCS) is used as inducer. The inhibitor acts in early as well as late G1 phase as indicated by experiments in which inhibitor was added and withdrawn at different times after restimulation of quiescent cells by FCS. At the gene expression level, sodium butyrate does not affect the inducibility of early cell cycle-related genes (c-myc, c-jun) while blocking the induction of cdc 2 mRNA, a late G1 marker. We conclude that sodium butyrate does not interfere with the growth factor signaling pathways regulating the (early) cell cycle-related gene expression. However, the presence of sodium butyrate early in G1 phase inhibits the cascade of events leading eventually to the expression of late G1-characteristic genes such as cdc2. The antimitogenic activity of sodium butyrate may be related to its interference with an (unknown) process involved in the "mitogenic" cascade.

Animals↗
PubMed1991

A nuclear labile protein, p70, is expressed exclusively during G0-S transition but not in G1 phase of a cell cycle ts mutant, tsJT16.

tsJT16 is a cell cycle temperature-sensitive (ts) mutant from a Fischer rat cell line. When it is growth-stimulated from G0 phase it enters S phase at the permissive temperature (34 degrees C) but not at the nonpermissive temperature (40 degrees C). It induces a nuclear labile protein, p70, when it is stimulated from G0 phase at 34 degrees C, but not at 40 degrees C. In growing cell cycle it progresses through the S, G2 and M phases at both temperatures but fails to pass through G1 phase at 40 degrees C. Here we described that p70 was synthesized neither in the randomly growing cycle nor in the G1 phase synchronously progressing from M phase. The cells synchronized at early G1 phase by culturing in serum-free medium for 7.5 h from G1/S boundary induced c-fos and c-myc following serum addition, but under the same condition p70 was not synthesized. These results indicate that the synthesis of p70 is not required for progression of the G1 phase of the growing cycle and can be used as an exclusive marker of G0-S transition.

Animals↗
PubMed1994

Micronuclei and 3AB index in X-irradiated human lymphocytes in G0 and G1 phases.

We applied the cytokines-block micronucleus assay to observe the radiobiological response of human lymphocytes after X-ray treatment in the G0 and G1 phases. In addition, we used 3-aminobenzamide (3AB) to measure the 3AB index in the two phases. The experimental results show that at 2 Gy the MN yield and the 3AB index are dependent on the cell phase and show considerable inter-individual variability. The radiation-induced MN frequency obtained for 33 subjects is 0.470 +/- 0.063 for the G0 phase and 0.689 +/- 0.139 for the G1 phase; the 3AB index values are 0.326 +/- 0.144 and 0.067 +/- 0.058 for G0 and G1 phases, respectively. At the individual level, the 3AB index for the G1 phase correlates inversely with the cytogenetic effects observed in that phase. We discuss the possibility of applying the MN test combined with the 3AB index to lymphocytes at different phases to study the individual response to radiation (individual radiosensitivity).

Adult↗
PubMed1985

Cell-cycle-dependent recovery from heavy-ion damage in G1-phase cells.

The cell-cycle-dependent capacity of synchronized G1-phase human T-1 cells to repair damage from either 425 MeV/u Bragg peak neon ions or 225 kVp X rays has been compared. The dose-survival response to each radiation was measured at early (1.5 h), mid (3.0 h), and late (4.5 h) times after mitotic selection. In addition the age response was characterized by irradiating cell populations at seven ages between 1.5 and 6.0 h after mitosis with single doses of either radiation. Repair of potentially lethal damage (PLDR) was evaluated in both the dose-survival and age-response experiments by holding irradiated cultures at 37 degrees C for 6 h in PBS or PBS containing 60 microM of the DNA polymerase inhibitor 1-beta-D-arabinofuranosyladenine (beta-araA) before trypsinization and plating. Delayed plating showed significant PLDR at all ages irradiated with X rays, with up to 10-fold increases of survival depending on the dose and the cell age at irradiation. There was negligible PLDR after neon-ion exposures to early and mid G1-phase cells; only late G1-phase cells repaired neon damage. The beta-araA treatment after X rays reduced the shoulder of the survival curves at all G1 ages studied, and in early and mid G1 reduced survival below the immediately plated control. beta-araA similarly reduced repair of PLD where it was measurable after neon ions. Differences between low- and high-LET radiation damage and repair are discussed.

Cell Cycle↗
PubMed1992

Multiple kinase arrest points in the G1 phase of nontransformed mammalian cells are absent in transformed cells.

We have shown that nontransformed mammalian cells arrest early in the G1 phase of the cell cycle when treated with exceedingly low concentrations of the nonspecific kinase inhibitor staurosporine, whereas transformed cells continue to progress through the cell cycle. We have now treated normal or transformed human skin fibroblasts with four other kinase inhibitors. Three of these inhibitors are highly specific: KT5720 inhibits cAMP-dependent protein kinase, KT5823 inhibits cGMP-dependent protein kinase, and KT5926 inhibits myosin light-chain kinase. The fourth inhibitor K252b has a moderate specificity for protein kinase C but also inhibits the three kinases just mentioned. We have found that these inhibitors reversibly arrest normal human skin fibroblasts at different times in the G1 phase but do not affect the cell cycle progression of transformed cells. The times of arrest within the G1 phase can be divided into two categories. Two of the inhibitors, KT5926 and K252b, act at an early time that is approximately 4 h after the transition from G0 to G1. The cAMP- and cGMP-dependent protein kinase inhibitors KT5720 and KT5823 arrest cells at a later time that is approximately 6 h after the G0/G1 boundary. These data indicate that there are multiple kinase-mediated phosphorylations of different substrates that are essential for the progression of normal cells, but not transformed cells, through the G1 phase. These inhibitors provide us with a set of biochemical probes that should be invaluable in the study of the function of kinases during G1 phase progression of normal cells.

Alkaloids↗
PubMed1983

Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase.

We have studied the effects of tamoxifen on the cell cycle kinetics of the endocrine-responsive MCF-7 human breast cancer cells. Tamoxifen inhibits proliferation of MCF-7 cells. The tritiated thymidine labeling index is markedly reduced by tamoxifen, indicating a reduction in the fraction of cells in S phase. Flow cytometry of mithramycin-stained cells reveals that cells accumulate in G1 phase, with a concomitant depletion of S- and G2-M-phase cells with tamoxifen. Mapping of G1-phase cells by morphology of prematurely condensed chromosomes demonstrated that tamoxifen-treated cells accumulate in early G1. These studies indicate that tamoxifen inhibits proliferation of MCF-7 human breast cancer cells by invoking a transition delay early in the G1 phase of the cell cycle.

Breast Neoplasms↗
PubMed1975

Arrest of 3T3 cells in G1 phase in suspension culture.

3T3 cells do not grow in Methocel suspension culture, while other permanent cell lines do. The viability of 3T3 cells in suspension remains unchanged for at least three days with respect to plating efficiency, vital staining and resumption of normal growth when transferred into monolayer culture. When monolayer 3T3 cells in G1 phase are suspended they remain in G1 phase. Cells already in S phase which are suspended complete ongoing DNA synthesis and mitosis and then are arrested in the G1 phase. Progress through the cell cycle is reinitiated after suspended cells attach to a surface. When monolayer cells in late G1 phase (just before entering S phase) are put in suspension cultures they do not initiate DNA synthesis.

Cell Division↗
PubMed1984

Colony-stimulating factor (CSF) controls proliferation of CSF-dependent cells by acting during the G1 phase of the cell cycle.

Proliferation of granulocyte/macrophage (GM) progenitor cells in soft agar cultures is dependent on the continuous presence of colony-stimulating factors (CSF). To elucidate this dependency we studied the effect of deprivation and readdition of CSF on the cell cycle kinetics of a GM-CSF-dependent murine mast/basophil cell line (PT-18). Flow cytometry and [3H]thymidine incorporation have been used to analyze the complete cell cycle. Removal of CSF from the culture medium resulted in accumulation of the cells in the G1 phase. Eighteen hours after removal of CSF, 85% of the cells were arrested in G1 phase. Readdition of GM-CSF to such quiescent cells was followed by progression of the cells from G1 into S phase with a lag period of 10 hr. A similar lag period was observed when cells released from G2+M arrest progressed, in the presence of CSF, to S phase via the G1 phase. These findings indicate that deprivation of GM-CSF does not move PT-18 cells out of the cycle to a G0 phase but rather arrests them at early G1 phase. Finally, we demonstrate that, for the cells to progress through the cell cycle, the requirement for the presence of GM-CSF is limited to the first 6 hr of the 10-hr duration of the G1 phase.

Animals↗
PubMed1991

Identification of a prominent 85-kDa cAMP-dependent phosphoprotein associated with late G1 phase in mitogen-stimulated B lymphocytes.

In order to elucidate late regulatory events which may be involved in the onset of S phase in B lymphocytes, we studied the effect of anti-Ig on phosphorylation of soluble proteins at late G1 phase. Stimulation of murine splenic B lymphocytes with anti-Ig and other mitogens for 18 h was found to be associated with a major increase in phosphorylation of an 85 kDa/pI approximately 5.3 cytosolic protein, conversely, stimulation of the cells with non-mitogenic stimuli did not induce the phosphorylation of pp85. The increase in phosphorylation of pp85 could not be detected after 30 min, was barely detectable after 6 h, but was very prominent after 18 h of stimulation with anti-Ig. Thus, the increase in phosphorylation of pp85 is not an early signal but is rather correlated with the late G1 phase. pp85 could not be detected in the nuclei of either control or stimulated cells. Stimulation of B cells for 30 min with forskolin induced the phosphorylation of pp85, while phorbol ester did not have any effect. The phosphorylation of pp85 was induced by the catalytic subunit of cAMP protein kinase. Comparison of the phosphopeptide map of pp85 phosphorylated by anti-Ig in intact cells to the phosphopeptide map phosphorylated by forskolin or by the catalytic subunit of cAMP protein kinase, showed a striking similarity indicating that cAMP protein kinase may be involved in phosphorylation of pp85 in mitogen-stimulated cells. An increase in intracellular cAMP levels at late G1 phase was found in B cells stimulated by mitogens. These results implicate an important role for cAMP-dependent phosphorylation events, specifically the phosphorylation of pp85/pI 5.3, at late G1 phase during the cell cycle.

Animals↗
PubMed1982

Glucocorticoid hormone renders a rat glioma cell line sensitive to a G1 phase block by microtubule disrupting agents.

1. Hydrocortisone, a glucocorticoid hormone, renders C6 rat glioma cells (clone ST1) sensitive to a block by colchicine or nocodazole (microtubule disrupters) at the G1 phase of the cell cycle. Restimulation of DNA synthesis in hydrocortisone-treated glioma cells arrested at G0/G1 phase by serum step-down is inhibited (85%) by colchicine (0.4 microgram/ml) added during the first 6 h of restimulation by serum step-up. 2. Exponentially growing, hydrocortisone-treated glioma cell cultures when subjected to colchicine treatment accumulated mitoses for 16.5 h, resulting in two types of cell cycle blocked cells: mitotic (round, detached or poorly attached) and G1 phase cells (flat and well attached to the solid substrate). The latter reinitiated DNA synthesis 15 h after colchicine withdrawal. Plating efficiency assays showed that while the colchicine block was highly toxic for mitotic cells, the survival of G1 phase arrested cells was not affected. In conclusion, in these rat glioma cells, hydrocortisone reversibly makes G1 phase progress dependent on microtubule integrity. 3. Restimulation of DNA synthesis in "normal" 3T3 fibroblasts arrested at the G0/G1 phase by serum deprivation was not inhibited by colchicine when the drug was added at the time of serum step-up. However, 70% inhibition occurred when colchicine was added at 10 h of serum stimulation.

Animals↗
PubMed1989

Photoreactivation of lethal damage and damage leading to chromatid deletions induced in G1 phase hamster x Xenopus hybrid cells by UV.

A86 Xenopus cells, cloned from a Xenopus line that exhibited a high level of photoreactivation of UV-induced lethal damage, and V79M1 hamster cells, cloned from a hamster line that did not exhibit efficient photoreactivation of such damage, were fused to produce the V79M1 x A86 cell line--a hybrid line in which approximately 84% of the cells contained the entire V79M1 and A86 genomes. Ultraviolet and UV plus photoreactivation fluence-survival relations were then determined and compared for hybrid and parental G1 phase cells in a first attempt to elucidate interactions of the parental genetic potentials for photoreactivation in the hybrid. Specifically, it was anticipated that the combined V79M1 and A86 genomes in the hybrid would produce photoreactivating enzymes sufficient to efficiently photoreactivate UV-induced lethal damage in both A86 and V79M1 DNA and little difference would be observed in the levels of photoreactivation exhibited by V79M1 x A86 and A86 G1 phase cells. To the contrary, the level of photoreactivation observed for the hybrid did not closely approach that observed for the A86 line. To assist in the interpretation of this somewhat unexpected observation, three additional studies were performed: (1) comparison of 'optimal' schemes for photoreactivation of UV-induced lethal damage in the hybrid and parental G1 phase cells, (2) comparison of the effects of some different types of growth medium on photoreactivation of UV-induced lethal damage in hybrid and parental G1 phase cells, and (3) comparison of the levels of photoreactivation of UV-induced chromatid deletions in the V79M1 and A86 chromosomes of G1 phase hybrid cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗