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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↗
PubMed2003

A subclass of soluble HLA-G1 modulates the release of cytokines from mononuclear cells present in the decidua additively to membrane-bound HLA-G1.

PROBLEM: Our previous studies have demonstrated that a subclass of soluble human leukocyte antigen-G1 protein (sub-sHLA-G1), that has alpha1 to alpha3 extra-cellular portion but lacks C-terminus of authentic soluble HLA-G1 secreted by trophoblasts, fine-tunes the release of cytokines from peripheral blood mononuclear cells (PBMCs) chiefly by counterbalancing membrane-bound HLA-G1 (mHLA-G1), and thereby may play a role in maintaining pregnancy. In this study, we investigated whether the presence of sHLA-G1 protein altered the release of cytokines from decidual mononuclear cells (DMCs) which are localized at the interface of feto-maternal interaction and whose cell population is completely different from PBMCs. METHOD OF STUDY: We cultured peripheral DMCs with either HLA-A and -B lacking B lymphoblast cell line (721.221 cells) or the cells transfected with mHLA-G1 (721.221-G1 cells) with or without sub-sHLA-G1. Cytokines concentrations in the culture media were determined by an enzyme-linked immunosorbent assay. RESULTS: Regardless of the presence of mHLA-G1 expressing cells, the addition of the recombinant sub-sHLA-G1 protein in the DMC culture media decreased the amounts of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, with the release of IL-4 from DMCs being unchanged. CONCLUSION: The sub-sHLA-G1 protein modulates the release of cytokines from DMCs additively to mHLA-G1 expressing cells. In view of the distinct fetomaternal interaction during implantation, it appears that sHLA-G1 might play a role in the establishment of pregnancy by regulating cytokine release in concert with mHLA-G1.

Cell Membrane↗
PubMedDate not supplied

Molecular cloning of G1 phase mRNAs from a subtractive G1 phase cDNA library.

Many G1-phase-specific mRNAs have been identified from various normal or transformed cells based on serum induction and re-entry into the cell cycle from quiescence. However, these mRNAs may not represent some important genes expressed during G1 phase in continuously cycling cells. The eukaryotic cell cycle possesses two cdk (cyclin-dependent kinase) dependent regulatory gates through which cells pass during late G1 phase and G2 phase of each cycle. Subtractive hybridization was employed to synthesize a high R0t fraction cDNA library enriched in sequences expressed during G1 phase prior to passage through the G1-phase gate. To prepare G1-phase cells from continuously cycling cell populations, G1-phase HeLa cells were collected by centrifugal elutriation and highly synchronous S phase cells were obtained by double thymidine block followed by centrifugal elutriation. A G1-phase subtractive cDNA library was prepared by subtracting G1-phase cDNA with a 10-fold excess of S-phase mRNA. Single-stranded, G1-phase cDNAs were isolated by oligo(dA) chromatography. The library was screened with a high R0t fraction subtractive probe population. Following two rounds of screening, 20 positive clones were obtained. Northern blot analysis indicated that six of these clones were enhanced in expression level during G1 phase when compared with S phase. Nucleotide sequence comparison of each clone with the GenBank data base revealed that hG1.11 was highly homologous (99%) to the apoferritin light chain gene and clones hG1.6, hG1.10, hG1.17, and hG1.18 represented new G1-phase-enriched members of four human ribosomal protein gene families (71-95% homology). The last clone, hG1.1, encoded a highly charged polypeptide not previously identified. Additional study of these G1-phase-enriched mRNAs will be required to determine their role in cell cycle progression and the G1-phase gateway through which cells transit as they proceed through the cell cycle.

Actins↗
PubMed1983

The G1 distribution of "G1-less" V79 Chinese hamster cells.

The V79-8 line of Chinese hamster cells has been reported to lack a measurable G1 phase. However, using a combination of time-lapse cinemicroscopy and [3H]thymidine autoradiography, we have found these cells to have a median G1 duration ranging from 1.4 to 2.6 h in different experiments, accounting for more than 15% of the median cycle time. The youngest cell labelled (in seven experiments) was 0.73 h old at the time of fixation suggesting a minimum G1 of between 0.40 and 0.73 h (the duration of the [3H]thymidine pulse being 0.33 h). In those experiments where steady-state proliferation could be established unequivocally, variability in G1 times accounted for all of the variability in cycle times. In addition, the distribution of G1 times (and cycle times) was well described by the two-transition version of the transition probability model. Nevertheless, changes in the average duration of G1 (and hence changes in the transition probabilities) played a comparatively minor role in determining proliferation rate. Instead, the length of S + G2 was markedly influenced by the composition of the culture medium. For purposes of comparison with the 'G1-less' V79-8 line, we have also examined a revertant derived from it (G1+5c) reported to have regained a substantial G1 phase. We are able to confirm that its G1 is indeed longer, the youngest labelled cell being 2.48 h old at the time of fixation. Unlike the parent line, there appeared to be more variability in G1 times than could be explained by two random transitions alone. The proliferation rate of the G1+5c revertant was unusually sensitive to the composition of the culture medium, suggesting the possibility of a metabolic defect.

Animals↗
PubMed1995

E2F-1 accumulation bypasses a G1 arrest resulting from the inhibition of G1 cyclin-dependent kinase activity.

Numerous experiments have defined a critical role for the G1 cyclins and associated kinases in allowing a normal progression of cells from a quiescent state, through G1, and into S phase. We now demonstrate that G1 cyclin-dependent kinase activity is critical for the accumulation of E2F activity late in G1. Moreover, E2F-1 overexpression can overcome a G1 arrest caused by the inhibition of G1 cyclin-dependent kinase activity, consistent with E2F activation being an important consequence of the action of G1 cyclins. E2F-1 also overcomes a G1 block caused by gamma irradiation and leads to an apparent complete replication of the cellular genome and entry into mitosis. This E2F-1-mediated induction of S phase and mitosis is not accompanied by the rise in either cyclin D-associated kinase activity or cdk2 activity that is normally observed during the G1 phase of the cell cycle. We conclude that one key function for G1 cyclin-dependent kinase activity is the activation of E2F-1, that the accumulation of E2F activity may be sufficient to allow initiation and completion of S phase, but that additional events, including G1 cyclin kinase activity, are likely necessary for a normal proliferative event.

Blotting, Western↗
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↗
PubMed2006

Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase.

The G1 phase of the cell cycle is characterized by a high rate of membrane phospholipid turnover. Cells regulate this turnover by coordinating the opposing actions of CTP:phosphocholine cytidylyltransferase and the group VI Ca2+-independent phospholipase A2 (iPLA2). However, little is known about how such turnover affects cell-cycle progression. Here, we show that G1-phase phospholipid turnover is essential for cell proliferation. Specific inhibition of iPLA2 arrested cells in the G1 phase of the cell cycle. This G1-phase arrest was associated with marked upregulation of the tumour suppressor p53 and the expression of cyclin-dependent kinase inhibitor p21cip1. Inactivation of iPLA2 failed to arrest p53-deficient HCT cells in the G1 phase and caused massive apoptosis of p21-deficient HCT cells, suggesting that this G1-phase arrest requires activation of p53 and expression of p21cip1. Furthermore, downregulation of p53 by siRNA in p21-deficient HCT cells reduced the cell death, indicating that inhibition of iPLA2 induced p53-dependent apoptosis in the absence of p21cip1. Thus, our study reveals hitherto unrecognized cooperation between p53 and iPLA2 to monitor membrane-phospholipid turnover in G1 phase. Disrupting the G1-phase phospholipid turnover by inhibition of iPLA2 activates the p53-p21cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.

Cell Cycle↗
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↗
PubMed1998

Yeast G1 cyclins are unstable in G1 phase.

In most eukaryotes, commitment to cell division occurs in late G1 phase at an event called Start in the yeast Saccharomyces cerevisiae, and called the restriction point in mammalian cells. Start is triggered by the cyclin-dependent kinase Cdc28 and three rate-limiting activators, the G1 cyclins Cln1, Cln2 and Cln3. Cyclin accumulation in G1 is driven in part by the cell-cycle-regulated transcription of CLN1 and CLN2, which peaks at Start. CLN transcription is modulated by physiological signals that regulate G1 progression, but it is unclear whether Cln protein stability is cell-cycle-regulated. It has been suggested that once cells pass Start, Cln proteolysis is triggered by the mitotic cyclins Clb1, 2, 3 and 4. But here we show that G1 cyclins are unstable in G1 phase, and that Clb-Cdc28 activity is not needed fgr G1 cyclin turnover. Cln instability thus provides a means to couple Cln-Cdc28 activity to transcriptional regulation and protein synthetic rate in pre-Start G1 cells.

Anaphase-Promoting Complex-Cyclosome↗
PubMed1996

Growth factor dependence of progression through G1 and S phases of adult rat hepatocytes in vitro. Evidence of a mitogen restriction point in mid-late G1.

Several hepatocyte mitogens have been identified, but the signals triggering the G0/G1 transition and cell cycle progression of hepatocytes remain unknown. Using hepatocyte primary cultures, we investigated the role of epidermal growth factor/pyruvate during the entry into and progression through the G1 phase and analyzed the expression of cell cycle markers. We show that the G0/G1 transition occurs during hepatocyte isolation as evidenced by the expression of early genes such as c-fos, c-jun, and c-myc. In culture, hepatocytes progress through G1 regardless of growth factor stimulation until a restriction point (R point) in mid-late G1 beyond which they cannot complete the cell cycle without mitogenic stimulation. Changes in cell cycle gene expression were associated with progression in G1; the cyclin E mRNA level is low early in G1 but increases at the G1/S boundary, while the protein is constantly detected during cell cycle but undergoes a change of electrophoretic mobility in mid-late G1 after the R point. In addition, a drastic induction of cyclin D1 mRNA and protein, and to a lesser extent of cyclin D2 mRNA, takes place in mitogen-stimulated cells after the R point. In contrast, cyclin D3 mRNA appears early in G1, remains constant in stimulated cells, but accumulates in unstimulated arrested cells, paralleling the cyclin-dependent kinase 4 mRNA expression. These results characterize the different steps of G1 phase in hepatocytes.

Animals↗
PubMed2006

Constraining G1-specific transcription to late G1 phase: the MBF-associated corepressor Nrm1 acts via negative feedback.

G1-specific transcription in yeast depends upon SBF and MBF. We have identified Nrm1 (negative regulator of MBF targets 1), as a stable component of MBF. NRM1 (YNR009w), an MBF-regulated gene expressed during late G1 phase, associates with G1-specific promoters via MBF. Transcriptional repression upon exit from G1 phase requires both Nrm1 and MBF. Inactivation of Nrm1 results in prolonged expression of MBF-regulated transcripts and leads to hydroxyurea (HU) resistance and enhanced bypass of rad53Delta- and mec1Delta-associated lethality. Constitutive expression of a stabilized form of Nrm1 represses MBF targets and leads to HU sensitivity. The fission yeast homolog SpNrm1, encoded by the MBF target gene nrm1(+) (SPBC16A3.07c), binds to MBF target genes and acts as a corepressor. In both yeasts, MBF represses G1-specific transcription outside of G1 phase. A negative feedback loop involving Nrm1 bound to MBF leads to transcriptional repression as cells exit G1 phase.

Amino Acid Sequence↗
PubMed1999

G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation.

7-Hydroxystaurosporine (UCN-01), which was originally identified as a protein kinase C selective inhibitor, is currently in clinical trials as an anti-cancer drug. We previously showed that UCN-01 induced preferential G1-phase accumulation in tumor cells and this effect was associated with the retinoblastoma (Rb) protein and its regulatory factors, such as cyclin-dependent kinase 2 (CDK2) and CDK inhibitors p21Cip1/WAF1 and p27Kip1. We demonstrate here that G1-phase accumulation was induced by UCN-01 in Rb-proficient cell lines (WiDr and HCT116 human colon carcinomas and WI-38 human lung fibroblast), and it was accompanied by dephosphorylation of Rb. In addition, UCN-01-induced G1-phase accumulation was also demonstrated in a Rb-defective cell line (Saos-2 human osteosarcoma), but not in a simian virus 40 (SV40)-transformed cell line (WI-38 VA13). Apoptosis was induced by UCN-01 in the two Rb-deficient cell lines, but not in the other Rb-proficient cell lines. These observations suggest that G1-checkpoint function might be important for cell survival during UCN-01 treatment. In addition, there may be a UCN-01-responsive factor in the G1-checkpoint machinery other than Rb which is targeted by SV40. Further studies revealed a correlation between UCN-01-induced G1-phase accumulation and reduction of cellular CDK2 kinase activity. This reduction was strictly dependent on down-regulation of the Thr160-phosphorylated form of CDK2 protein, and coincided in part with up-regulation of p27Kip1, but it was independent of the level of the p21Cip1/WAF1 protein. These results suggest that G1-checkpoint function, including a CDK2-regulatory pathway, may be a significant determinant of the sensitivity of tumor cells to UCN-01.

Alkaloids↗
PubMed2001

Novel findings regarding photoinduced commitments of G1-, S- and G2-phase cells to cell-cycle transitions in darkness and dark-induced G1-, S- and G2-phase arrests in Euglena.

Effects of light and darkness on cell-cycle progression were studied in the log-linear photoautotrophic growth mode of Euglena gracilis. We found that there are light-dependent restriction points in the post-G1 phases, quite in contrast to Chlamydomonas, where a light-dependent restriction is known to exist only in the G1 phase. Thus, in E. gracilis, there are photoinduced commitments of G1-, S- and G2-phase cells that allow them to progress to the G1, S and G2 phases in darkness, and there are dark-induced G1-, S- and G2-phase arrests. In darkness, only committed cells were able to progress to the committed phases (G1, S or G2), whereas uncommitted cells were unable to undergo a cell-cycle transition. Whether or not cells were induced to commit by irradiation, they were eventually arrested somewhere in the G1, S or G2 (but not M) phase within 14 h of being transferred to darkness. We also describe the dependence of photoinduced commitment on light intensity and discuss the results as they relate to cell-cycle progression in continuous light.

Animals↗
PubMed1996

G1 cyclin/CDK-independent phosphorylation and accumulation of p130 during the transition from G1 to G0 lead to its association with E2F-4.

During the transition from G1 to G0, p130 undergoes a specific phosphorylation event-leading to p130-form 2- that is mediated by a kinase/s other than the known G1, S and G2/M cyclin/CDKs. Changes in the phosphorylation status of p130 during this transition are responsible, at least in part, for the concomitant formation of p130/E2F-4 complexes, which are characteristic of G0. These complexes remain abundant during early G1 upon restimulation, but not after mitosis, and are dissociated in mid G1 when p130 is abruptly hyperphosphorylated to form 3. Subsequently, p130 forms 1 and 2 are no longer detected during the remainder of the cell cycle. Consistently, phosphorylation to form 3 and dissociation from E2F-4 complexes is reproduced by a cyclin/CDK holoenzyme in vitro. TGF-beta-induced G1 arrest abrogates cyclin/CDK phosphorylation of p130 but not phosphorylation to form 2. The cell cycle-dependent phosphorylation pattern of p130 is thus shown to comprise two distinct steps that are catalyzed by different kinases. The differential regulation of p130 and pRB phosphorylation during the transition from G1 to G0 may explain the fact that p130 and E2F-4 are the major components of E2F complexes in quiescent cells. Moreover, the newly described phosphorylation of p130 at the transition from G1 to G0 defines a novel mechanism of cell cycle exit regulation.

3T3 Cells↗
PubMed1986

Analysis of the G1 arrest position of senescent WI38 cells by quinacrine dihydrochloride nuclear fluorescence. Evidence for a late G1 arrest.

Senescence of the human diploid fibroblast-like cell line, WI38, is characterized by a loss of proliferative activity and an arrest of cells with a 2C DNA content (G1 or G0). To examine the specific region within G1 in which senescent cells arrest, senescent cells were stained with quinacrine dihydrochloride (QDH) and their nuclear fluorescence was compared with that of young cultures arrested in early and late G1 by serum deprivation and hydroxyurea exposure, respectively. Release of these G1-arrested young cultures from their blocking conditions and timing the kinetics of their entry into the S phase by autoradiographic detection of [3H]thymidine incorporation revealed that serum-deprived cells entered the S phase within 15-18 h, whereas hydroxyurea-exposed cells entered the S phase within 1.5 h, thus confirming their relative G1-arrest positions. QDH-stained, serum-deprived and hydroxyurea-exposed young cells exhibited relative nuclear fluorescence intensities of 51.7 and 23.9, respectively. Senescent cells exhibited a relative nuclear fluorescence intensity of 17.4, closely resembling the fluorescence of young cultures arrested in late G1 by hydroxyurea exposure. These data support the concept that senescent cells are arrested from further progression in the cell cycle in late G1.

Blood↗
PubMed2003

Recruitment of Cdc28 by Whi3 restricts nuclear accumulation of the G1 cyclin-Cdk complex to late G1.

The G1 cyclin Cln3 is a key activator of cell-cycle entry in budding yeast. Here we show that Whi3, a negative G1 regulator of Cln3, interacts in vivo with the cyclin-dependent kinase Cdc28 and regulates its localization in the cell. Efficient interaction with Cdc28 depends on an N-terminal domain of Whi3 that is also required for cytoplasmic localization of Cdc28, and for proper regulation of G1 length and filamentous growth. On the other hand, nuclear accumulation of Cdc28 requires the nuclear localization signal of Cln3, which is also found in Whi3 complexes. Both Cln3 and Cdc28 are mainly cytoplasmic during early G1, and become nuclear in late G1. However, Whi3-deficient cells show a distinct nuclear accumulation of Cln3 and Cdc28 already in early G1. We propose that Whi3 constitutes a cytoplasmic retention device for Cln3-Cdc28 complexes, thus defining a key G1 event in yeast cells.

Blotting, Western↗
PubMed1995

Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest.

Employing the myeloblastic leukemia M1 cell line, which does not express endogenous p53, and genetically engineered variants, it was recently shown that activation of p53, using a p53 temperature-sensitive mutant transgene (p53ts), resulted in rapid apoptosis that was delayed by high level ectopic expression of bcl-2. In this report, advantage has been taken of these M1 variants to investigate the relationship between p53-mediated G1 arrest and apoptosis. Flow cytometric cell cycle analysis has provided evidence that activation of wild-type (wt) p53 function in M1 cells resulted in the induction of G1 growth arrest; this was clearly seen in the M1p53/bcl-2 cells because of the delay in apoptosis that unmasked p53-induced G1 growth arrest. This finding was further corroborated at the molecular level by analysis of the expression and function of key cell cycle regulatory genes in M1p53 versus M1p53/bcl-2 cells after the activation of wt p53 function; events that take place at early times during the p53-induced G1 arrest occur in both the M1p53 and the M1p53/bcl-2 cells, whereas later events occur only in the M1p53/bcl-2 cells, which undergo delayed apoptosis, thereby allowing the cells to complete G1 arrest. Finally, it was observed that a spectrum of p53 target genes implicated in p53-induced growth suppression and apoptosis were similarly regulated, either induced (gadd45, waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of wt p53 function in M1p53 and M1p53/bcl-2 cells. Taken together, these findings show that wt p53 can simultaneously induce the genetic programs of both G1 growth arrest and apoptosis within the same cell type, in which the genetic program of cell death can proceed in either G1-arrested (M1p53/bcl-2) or cycling (M1p53) cells. These findings increase our understanding of the functions of p53 as a tumor suppressor and how alterations in these functions could contribute to malignancy.

Animals↗
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↗