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At least 19 recordsLinked to original sources
PubMed1978

Genetic analysis of the G1 period: isolation of mutants (or variants) with a G1 perior from a Chinese hamster cell line lacking G1.

Cells of the Chinese hamster line V79-8 multiply without a G1 period (i.e., they are G1(-)) and have an average generation time of 9.5 hr. After mutagenesis and selection we have derived five stable mutants (or variants) of this line that have longer generation times. In each case the increase in generation time is due solely to the introduction of a G1 period into the cell cycle, with no measurable effect on S, G2, or M. Fusions among these five G1(+) mutant lines and another presumably nonmutant G1(+) line (V79-743) produce hybrid cells lacking a G1 period in all but one case. These complementation tests define five complementation groups among these six G1(+) cell lines. The six G1(+) lines represent five different causes or bases for the presence of a G1 period. The two G1(+) mutants belonging to complementation group V are temperature sensitive for expression of the G1(+) phenotype (G1 congruent with 0, 4, and 6 hr at 33 degrees , 37 degrees , and 39 degrees , respectively). In all cases the G1(-) state is dominant over the G1(+) state, suggesting that the presence of G1 represents a "deficient" condition. Mutants of this type may be useful in the analysis of the switch from G1(-) to G1(+) that occurs normally in cleaving embryos and in elucidation of the genetic mechanism(s) responsible for the presence of a measurable G1 in most cells.

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↗
PubMed1992

Characterization of centromere arrangements and test for random distribution in G0, G1, S, G2, G1, and early S' phase in human lymphocytes.

The arrangement of centromeres, cluster formation and association with the nucleolus and the nuclear membrane were characterized in human lymphocytes during the course of interphase in a cell-phase-dependent manner. We evaluated 3,893 cell nuclei categorized by five parameters. The centromeres were visualized by means of indirect immunofluorescent labeling with anti-centromere antibodies (ACA) contained in serum of patients with CREST syndrome. The cell nuclei were classified as G0, G1, S, G2, G1' and early S' phase by comparing microscopically identified groups of cell nuclei with flow cytometric determination of cell cycle stage of synchronized and unsynchronized lymphocyte cell cultures. Based on a discrimination analysis, a program was devised that calculated the probability for any cell nucleus belonging to the G0, G1, S, G2, G1' and early S' phase using only two microscopic parameters. Various characteristics were determined in the G0, S, and G2 stages. A transition stage to S phase within G1 was detected. This stage shows centromere arrangements not repeated in later cell cycles and which develop from the dissolution of centromere clusters in the periphery of the nucleus during G0 and G1. S phase exhibits various non-random centromere arrangements and associations of centromeres with the nucleolus. G1' and early S' phase of the second cell cycle display no characteristic centromere arrangement. The duplication of centromeres in G2 is asynchronous in two phases. For all cell phases a test for random distribution of the centromeres in the cell nucleus was performed. There is a distinct tendency for centromeres to be in a peripheral position during G0 and G1; this tendency becomes weaker in S phase. Although the visual impression is a seemingly random distribution of centromeres in G2 and G1', statistical analysis still demonstrates a significant deviation from random distribution in favor of a peripheral location. Only the early S phase of the second cell cycle shows no significant deviation from a random distribution.

Cell Cycle↗
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↗
PubMed1989

A new method to discriminate G1, S, G2, M, and G1 postmitotic cells.

A new flow cytometric method combining light scattering measurements, detection of bromodeoxyuridine (BrdU) incorporation via fluorescent antibody, and quantitation of cellular DNA content by propidium iodide (PI) allows identification of additional compartments in the cell cycle. Thus, while cell staining with BrdU-antibodies and PI reveals the G1, S, and G2 + M phases of the cell cycle, differences in light scattering allow separation of G2 phase cells from M phase cells and subdivision of G1 phase into two compartments, i.e., G1A representing postmitotic cells which mature to G1B cells ready to initiate DNA synthesis. The method involves fixation of cells in 70% ethanol, extraction of histones with HC1, and thermal denaturation of DNA. This treatment appears to enhance the differences in chromatin structure of cells in the various phases of the cell cycle to the extent that cells could be separated on the basis of the 90 degrees scatter. Mitotic cells show much lower scatter than G2 phase cells, and G1 postmitotic cells (G1A) show lower scatter than G1 cells about to enter the S phase (G1B). Light scattering is correlated with chromatin condensation, as judged by microscopic evaluation of cells sorted on the basis of light scatter. The method has the advantage over the parental BrdU/DNA bivariate analysis in allowing the G2 and M phases of the cell cycle to be separated and the G1 phase to be analyzed in more detail. The method may also allow separation of unlabeled S phase cells from mitotic cells and distinguish between labeled and unlabeled mitotic cells.

Animals↗
PubMed1979

Inhibition of cellular transition from G1-resting to G1-prereplicative phase by aminonucleoside of puromycin.

Human embryonic lung fibroblasts (IMR-90 and WI-38) were arrested in the G1 phase of the cell cycle by serum deprivation and high population density. Within 1 hr after the addition of medium containing fresh serum, these cells showed an increase in rRNA synthesis. The inclusion of 100 micrograms per ml aminonucleoside of puromycin (AMS) in the fresh medium eliminated the serum stimulation of rRNA synthesis and prevented the cells from making the G1-resting phase to G1-prereplicative phase transition. AMS also prevented the synthesis of HnRNA normally found within 10 hr after serum stimulation. Serum-stimulated RNA synthesis in starved, SV-40 transformed fibroblasts (WI-38-VA-13 cells) was inhibited, but not completely prevented, by AMS indicating that transformed cells may produce specific RNA's that are not AMS-sensitive and that may be responsible for the failure of transformed cells to be arrested in G1.

Animals↗
PubMed1991

Transcriptional activation of CLN1, CLN2, and a putative new G1 cyclin (HCS26) by SWI4, a positive regulator of G1-specific transcription.

SWI4 of budding yeast codes for a component of a transcription factor (cell cycle box factor, or CCBF) necessary for G1-specific expression of HO. We show that SWI4 is essential for haploid cell viability at high temperature and in a/alpha cells at all temperatures: SWI4-deficient cells arrest as large unbudded cells. Eight high copy number plasmids were identified that allow swi4- strains to grow under nonpermissive conditions. Two carry G1 cyclin genes, CLN1 and CLN2; another carries HCS26, coding for a putative cyclin, a/alpha swi4- mutants exhibit 3- to 20-fold reductions in the levels of CLN1, CLN2, and HCS26 transcripts. The requirement of SWI4 for transcription appears to be direct: each gene contains sites similar to the CCBF-binding site; CCBF binds to the upstream region of HCS26. We propose that SWI4 participates in a positive feedback loop by which CLN1, CLN2, and possibly HCS26 promote their own transcription in G1.

Amino Acid Sequence↗
PubMed1992

The retinoblastoma protein is partially phosphorylated during early G1 in cycling cells but not in G1 cells arrested with alpha-interferon.

The retinoblastoma protein (pRB) is thought to act as a tumour suppressor which is inactivated by phosphorylation. In quiescent (G0) cells pRB exists in a hypophosphorylated form (pRB110), but proliferating cells in G1 contain a significant proportion of phosphorylated pRB (pRB112-114). Studies of synchronized or elutriated cells have suggested that the phosphorylated forms of pRB disappear as cells pass from G2/M to G0/G1 and that pRB is phosphorylated again to pRB114 at the G1/S border. In this study we used two-parameter flow cytometry and cell sorting to isolate cycling cells in early and late G1 (G1A and G1B), and we show that partially phosphorylated pRB is present in cycling human lymphoid cells even in G1A. These G1A cells contain intermediate forms of pRB which become further phosphorylated to pRB112-114 as cells pass into G1B. Therefore pRB is at least partially phosphorylated from early G1 onwards. Cell cycle arrest by alpha-interferon (alpha-IFN) results in an accumulation of cells in both G1A and G1B, and these cells contain mainly pRB110. Since pRB110 is thought to prevent cell proliferation, the cytostatic effect of alpha-IFN may therefore occur by preventing the initial phosphorylation of pRB during or prior to G1A.

Cell Cycle↗
PubMed1977

Regulation of DNA synthesis: age-dependent cooperation among G1 cells upon fusion.

The object of this study was to determine whether the inducer(s) of DNA synthesis in mammalian cells accumulates gradually throughout the G1 period or becomes available suddenly at the G1-S transition. HeLa cells, synchronized at various points in the G1 period, were fused by using UV-inactivated Sendai virus. Early G1 cells were fused with mid-G1 or late G1 cells and late G1 cells were fused with mid-G1 cells. The G1 traverse of mono-, bi-, and trinucleated cells was studied. The bi- and trinucleated cells of mid-G1 and late G1 parents traversed the G1 period significantly faster than did their mononucleated counterparts. The reduction in the duration of the G1 period was proportional to the number and age of nuclei at the time of fusion. There was no significant difference between the mono- and binucleated cells of the early G1 parent in their rates of entry into S period. In light of these findings, a model is proposed in which the inducer(s) of DNA synthesis accumulates gradually throughout the G1 period, reaching a critical level at the G1-S boundary when DNA replication is initiated; after reaching a peak during early or mid-S period, it declines to below the critical level when DNA synthesis ceases.

Cell Division↗
PubMed1979

Different Chinese hamster cell lines express a G1 period for different reasons.

Previous studies from our laboratory have shown that the absence of G1(G1-condition) in two lines of Chinese hamster cells is dominant over the presence of G1(G1+condition) in a variety of intraspecific cell hybrids. G1+ mutants or variants cna be isolated from G1- cells following mutagenesis and selection. These G1+ mutants fall into multiple complementation groups based on their abilities to form G1- cell hybrids with one another. This is evidence that different mutants have G1 intervals for different reasons, possibly as the result of deficiencies in functions necessary for G1- cell cycles. In this report we have used cell hybrid analysis to ask whether cells of different, naturally occurring G1+ lines of Chinese hamster are able to complement to produce G1- hybrids. We have found three complementation groups among the four G1+ cell lines examined. Therefore, these lines define three different reasons or bases for the existence of a G1 interval. These results lead us to suggest that multiple requirements must be met for these cells to start the S period, but that failure to fulfill only a single and different requirement is responsible for the presence of a G1 interval in any given cell line.

Animals↗
PubMed1991

The G1 interval in the mammalian cell cycle: dual control by mass accumulation and stage-specific activities.

The temporal determinants of the G1 cell cycle interval were investigated using nine mammalian cell lines. In each case, cells were allowed to proliferate for many cell cycles under conditions that slowed progress through S phase without an equivalent impairment of overall mass accumulation. This disproportionate inhibition of progress through the cell cycle caused newly produced cells to be more massive than usual. Under these growth conditions, the determinants of the length of the G1 interval became evident. For two cell lines, HeLa S3 and NIH 3T3, a protracted S phase, and the resultant increase in mass, resulted in a dramatically shortened G1 interval. Thus, for these cell lines, a major portion of G1 time exists to accommodate mass accumulation needed to initiate the subsequent S phase. Nevertheless, under conditions that protracted S phase and shortened the G1 interval, cells still exhibited a measurable G1 time, reflecting the stage-specific activities within G1. One activity that may be responsible for this obligatory G1 time is the synthesis of a labile protein. For other cells studied here, protraction of S phase also caused proliferating cells to become more massive, but in these cases there was no diminution of the G1 time. For these cells, the entire G1 interval must accommodate G1-specific activities necessary to initiate a new cell cycle. A unifying view of the G1 interval recognizes the two distinct influences that determine the time spent in G1: the need to accumulate sufficient mass to initiate a new DNA-division sequence; and the stage-specific events necessary for the subsequent S phase. The length of the G1 interval is dictated by the longer of these two time-consuming activities.

Animals↗
PubMed1985

L-Triiodothyronine (T3) stimulates growth of cultured GC cells by action early in the G1 period: evidence for mediation by the nuclear T3 receptor.

Incubation with T3 results in a dose-dependent increase in growth rate of cultured GC cells, a GH-producing rat pituitary tumor cell line. The T3-induced increase in growth rate results mainly from shortening of the G1 period from 79.4 +/- 4.3 (SD) h in cells grown in T3-depleted medium (-T3) to 10.0 +/- 0.9 h. This effect can also be demonstrated in synchronized populations. Addition of T3 (0.3 nM) to cells synchronized in early G1 in the absence of T3 shortened the G1 period, estimated from graphic data, from more than 40-50 h to 13.4 +/- 2.1 h (n = 7). To determine the mechanism of this T3 effect, GC cells were grown in Dulbecco's modified Eagle's medium containing 10% serum plus or minus T3 (0.3 nM) and synchronized at the beginning of the G1 period by mitotic selection. Mitotic cells (85-100%), obtained by controlled mechanical shaking, were isolated by centrifugation and replated. The end of G1 was determined by the onset of DNA synthesis with [3H]thymidine as assessed by autoradiography (percent labeled nuclei). L-T3-induced shortening of G1 was detectable at 0.05 nM T3, half-maximal at physiological T3 (0.17 nM), and maximal between 0.3 nM and 1.0 nM T3. Addition of cycloheximide, 0.025 microgram/ml or 1.0 microgram/ml, decreased protein synthesis by 50% and 90%, respectively, and attenuated the T3 effect on G1 by 80-90%. The attenuation of the T3 effect on G1 by cycloheximide at a dose which inhibited protein synthesis suggests that T3-induced shortening of G1 may require new protein synthesis. Since glucocorticoids decrease the effect of T3 on induction of alpha-aminoisobutyric acid transport, their effect on T3-induced shortening of G1 was determined in G1-synchronized GC cells and in asynchronous cultures. Cortisol, 100 nM, significantly decreased the growth rate of asynchronous GC cells and attenuated the effect of T3 in G1-synchronized cells. Finally, T4 also decreased the length of G1 in a dose-dependent manner with a half-maximal effect at 40.0 nM. The half-maximal effect of T4 occurred at a nuclear iodothyronine concentration that was comparable to that achieved in incubations with 0.17 nM T3 (half-maximal dose). Thus, half-maximal shortening of G1 in synchronized GC cell cultures occurred at iodothyronine concentrations required for half-maximal occupancy of nuclear T3 receptors and for half-maximal induction of GH synthesis, growth rate, alpha-aminoisobutyric acid uptake, and depletion of the nuclear T3 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1979

Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line.

Growth of a human leukemic T-cell line (CEM C7) in 10(-6) M dexamethasone results in inhibition of growth and rapid loss of cell viability after a delay of approximately 18 to 24 hours. Analysis of dexamethasone-treated cells by flow-microfluorometry showed that they were arrested in the G1 phase of the cell cycle. Loss of cell viability began at the same time as G1 accumulation was first detectable, and 20% of all cells were found to be blocked in G1 at this time suggesting that loss of viability and G1 arrest were coincident events. Half-maximal and maximal effects on both viability and G1 arrest after 48 hours in steroid were nearly identical with respect to steroid concentration and corresponded to half-maximal and full occupancy of glucocorticoid specific receptor by hormone, consistent with a glucocorticoid receptor mediated mechanism for both phenomena. Most non-viable cells were arrested in G1, and accumulation of cells in G1 was irreversible; removal of steroid in the presence of colcemid did not result in a decreased fraction of G1 cells. Furthermore, dexamethasone treatment did not protect cells against the effects of 33258 Hoechst-amplified killing of bromodeoxyuridine substituted cells exposed to light. These results show that dexamethasone arrests these leukemic cells in G1 and strongly suggest that dexamethasone-treated cells are killed upon entry into G1.

Cell Cycle↗
PubMed1991

Identification of a G1-type cyclin puc1+ in the fission yeast Schizosaccharomyces pombe.

In rapidly growing cells of the budding yeast Saccharomyces cerevisiae, the cell cycle is regulated chiefly at Start, just before the G1-S boundary, whereas in the fission yeast Schizosaccharomyces pombe, the cycle is predominantly regulated at G2-M. Both control points are present in both yeasts, and both require the p34cdc2 protein kinase. At G2-M, p34cdc2 kinase activity in S. pombe requires a B-type cyclin in a complex with p34cdc2; this complex is the same as MPF (maturation promoting factor). The p34cdc2 activity at the G1-S transition in S. cerevisiae may be regulated by a similar cyclin complex, using one of the products of a new class of cyclin genes (CLN1, CLN2 and WHI1 (DAF1/CLN3)). At least one is required for progression through the G1-S phase, and deletion of all three leads to G1 arrest. WHI1 was isolated as a dominant allele causing budding yeast cells to divide at a reduced size and was later independently identified as DAF1, a dominant allele of which rendered the cells refractory to the G1-arrest induced by the mating pheromone alpha-factor. The dominant alleles are truncations thought to yield proteins of increased stability, and the cells are accelerated through G1. Without WHI1 function, the cells are hypersensitive to alpha-factor, enlarged and delayed in G1. Heretofore, this G1-class of cyclins has not been identified in other organisms. We have isolated a G1-type cyclin gene called puc1+ from S. pombe, using a functional assay in S. cerevisiae. Expression of puc1+ in S. pombe indicates that it has a cyclin-like role in the fission yeast distinct from the role of the B-type mitotic cyclin.

Amino Acid Sequence↗