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PubMed1997

Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest.

The human immunodeficiency virus type 1 (HIV-1) vpr gene encodes a protein which induces arrest of cells in the G2 phase of the cell cycle. Here, we demonstrate that following the arrest of cells in G2, Vpr induces apoptosis in human fibroblasts, T cells, and primary peripheral blood lymphocytes. Analysis of various mutations in the vpr gene revealed that the extent of Vpr-induced G2 arrest correlated with the levels of apoptosis. However, the alleviation of Vpr-induced G2 arrest by treatment with the drug pentoxifylline did not abrogate apoptosis. Together these studies indicate that induction of G2 arrest, but not necessarily continued arrest in G2, was required for Vpr-induced apoptosis to occur. Finally, Vpr-induced G2 arrest has previously been correlated with inactivation of the Cdc2 kinase. Some models of apoptosis have demonstrated a requirement for active Cdc2 kinase for apoptosis to occur. Here we show that accumulation of the hypophosphorylated or active form of the Cdc2 kinase is not required for Vpr-induced apoptosis. These studies indicate that Vpr is capable of inducing apoptosis, and we propose that both the initial arrest of cells and subsequent apoptosis may contribute to CD4 cell depletion in HIV-1 disease.

Animals↗

PubMedDate not supplied

Abrogation of G2 checkpoint specifically sensitize p53 defective cells to cancer chemotherapeutic agents.

BACKGROUND: Chkl is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates Cdc25C at the late G2 phase. The inactivation of Cdc25C and consequently, the inactivation of Cdc2, are required for the G2 arrest induced by DNA damage. METHODS: We treated 184B5 cell line and its E6 transformed cell lines with adriamycin in the presence of staurosporine or UCNO1 and examined G2 arrest and cell death. RESULTS: We found that adriamycin induced a p53 and p21 response as well as a G1 arrest in 184B5 cells, but not in its E6 transformed cells. Staurosporine or UCNO1 abrogated the G2 arrest induced by adriamycin in both cell lines. In addition, staurosporine or UCNO1 specifically sensitized p53 incompetent cells to adriamycin. CONCLUSION: G2/M checkpoint abrogators can potentially enhance the cytotoxic effect of conventional chemotherapeutic reagents specifically to tumor cells.

Alkaloids↗

PubMed1991

Association of protein phosphorylation and cell cycle progression after X-irradiation of two-cell mouse embryos.

Studies of protein phosphorylation in the second cell cycle of mouse embryos were assessed by [32P]-incorporation and one- and two-dimensional electrophoresis. Unirradiated and X-irradiated embryos were compared. X-irradiation in the G2 phase led to a block in this cell cycle phase. The phosphorylation of proteins with molecular weights of 30 and 46 kDa specifically correlated with the G2 phase-mitosis transition in normally dividing and in irradiated embryos. The time lag in the phosphorylation of these proteins between the unirradiated and X-irradiated embryos was identical to the duration of the radiation-induced G2 block. X-irradiation immediately decreased the phosphorylation of a 29 kDa protein to below detectable levels. Re-phosphorylation of this protein preceded the following mitosis. It is suggested that the 29 kDa protein may be involved in the regulation of events that led to the radiation induced G2 block and the initiation of mitosis after release.

Animals↗

PubMed1996

Further characterization of the c-mos transcript and its cell cycle specific expression in NIH3T3 cells.

The mouse c-mos proto-oncogene is primarily expressed in germ cells. Our previous studies demonstrated c-mos RNA expression in mouse somatic cells, with the highest level present in the G2 phase of the cell cycle (Tsui et al., 1993). We have identified the transcription start site of this G2 specific c-mos transcript to be located about 1580 bp upstream from the open reading frame based on RT-PCR and RNase protection experiments. Upstream sequences containing this transcription start site directed highest expression of the luciferase reporter gene in M phase of the cell cycle. These results suggest that c-mos transcripts are produced in G2 phase and that c-Mos protein albeit at extremely low levels would accumulate in M phase.

3T3 Cells↗

PubMed2006

The fate of irradiated tumor cells.

Radiotherapy remains a key component of modern multimodal anticancer treatment approaches. Although most clinically relevant improvements in radiation oncology are based on optimized radiation technology, it now becomes obvious that biology-based approaches will further boost the efficacy of modern radiation oncology. Of relevance to this is the question of the ultimate fate of an irradiated cell and the mechanistic basis of the induced cell death or inactivation observed. Research bearing on this question is reported in this issue of Oncogene by Wendt et al. (2005), who show that the levels of p21CIP/WAF1 play a key role in determining whether an irradiated tumour cell is arrested in the G2 phase of the cell cycle, rather than apoptosing. The demonstration that caffeine treatment can abrogate this G2 arrest, and that the cells go on to die, has implications for overcoming treatment resistance imposed by radiation-induced upregulation of p21CIP/WAF1.

Caffeine↗

PubMed1997

Amount of the two major Ag-NOR proteins, nucleolin, and protein B23 is cell-cycle dependent.

To know the biological basis allowing the use of Ag-NOR protein expression as proliferation marker in human malignancies, the relationship between cell cycle and amount of Ag-NOR protein was analyzed. The quantification of the two major Ag-NOR proteins, nucleolin and protein B23, was performed in exponentially growing, serum-deprived, and cell-cycle stimulated cells. Expression of nucleolin was low in serum-deprived cells and increased mostly in S phase during cell-cycle stimulation. Conversely, expression of protein B23 was slightly repressed in serum-deprived cells, and increased progressively until G2 phase during cell-cycle stimulation. The accumulation of nucleolin and protein B23 in G2 compared to G1 was demonstrated using sorted phase-specific cells. In G0, cells sorted according to their very low RNA content, and the amount of Ag-NOR proteins was half of that found in G1 cells, nucleolin being only weakly detectable. Therefore, the expression of nucleolin increased between G0-G1 and G1-S phases. These data support the hypothesis that quantification of Ag-NOR proteins is an estimation of the percentage of cells in each cell cycle phase because their amount is high in S-G2 and low in G1 phases.

Animals↗

PubMed2004

A PSTAIRE CDK-like protein localizes in nuclei and cytoplasm of Physarum polycephalum and functions in the mitosis.

CDKs play key roles in controlling cell cycle progression in all eukaryotes. In plants, multiple CDKs are present, among which the best characterized CDKs are PSTAIRE CDKs. In this study, we carried out Western blot, immunoelectron microscopy and antibody treatment with an anti-PSTAIRE monoclonal antibody to explore the subcellular localization and functions of PSTAIRE CDKs in Physarum polycephalum. The results of western blot and immunoelectron microscopy showed that in P. polycephalum, a PSTAIRE CDK-like protein was 34 kD in molecular weight and located in both nuclei and cytoplasm. In nuclei, the protein was mainly associated with chromosomes and nucleoli. The expression of the PSTAIRE CDK-like protein in both the plasmodia and nuclei showed little fluctuation through the whole cell cycle. When treated with an anti-PSTAIRE monoclonal antibody at early S phase, the cells were arrested in S phase, and the mitotic onset of P. polycephalum was blocked for about 1 h when treated at early G2 phase. Our data indicated that the PSTAIRE CDK- like protein has a direct bearing on the mitosis.

Animals↗

PubMed2003

Beta-catenin regulation during the cell cycle: implications in G2/M and apoptosis.

Beta-catenin is a multifunctional protein involved in cell-cell adhesion and Wnt signal transduction. Beta-catenin signaling has been proposed to act as inducer of cell proliferation in different tumors. However, in some developmental contexts and cell systems beta-catenin also acts as a positive modulator of apoptosis. To get additional insights into the role of beta-catenin in the regulation of the cell cycle and apoptosis, we have analyzed the levels and subcellular localization of endogenous beta-catenin and its relation with adenomatous polyposis coli (APC) during the cell cycle in S-phase-synchronized epithelial cells. Beta-catenin levels increase in S phase, reaching maximum accumulation at late G2/M and then abruptly decreasing as the cells enter into a new G1 phase. In parallel, an increased cytoplasmic and nuclear localization of beta-catenin and APC is observed during S and G2 phases. In addition, strong colocalization of APC with centrosomes, but not beta-catenin, is detected in M phase. Interestingly, overexpression of a stable form of beta-catenin, or inhibition of endogenous beta-catenin degradation, in epidermal keratinocyte cells induces a G2 cell cycle arrest and leads to apoptosis. These results support a role for beta-catenin in the control of cell cycle and apoptosis at G2/M in normal and transformed epidermal keratinocytes.

Adenomatous Polyposis Coli Protein↗

PubMed1985

Cell proliferation in human colorectal mucosa in organ culture: the early adaptive changes.

In organ culture tissues undergo adaptive changes which complicate the assessment of proliferative indices. In the present study, a technique devised to preserve collagen metabolism and mesenchymal stroma in tissues of mixed origin was employed to investigate the kinetic behaviour of human colorectal mucosa over the first 24 hours in culture. During this period the structural preservation of tissue is good. The mitotic index in mucosa is profoundly depressed throughout the explants during the first 2-6 hours in culture. During this same period, however, heavy uptake of tritiated thymidine, indicating DNA synthesis, is observed within 150 micron of the cut edge of the samples but not centrally. This phenomenon has been described previously and assumed to be the result of inadequate diffusion of oxygen into the tissue. The 'edge labelling' phenomenon is followed by a wave of mitosis in the tissue edge at 8-18 hours in culture. This delay between tritiated thymidine uptake and the appearance of mitoses in the tissue edge may simply represent the duration of the S + G2 phase of the cell cycle, but is more likely to be due to cells in G1 moving into the S phase followed by cells hitherto blocked in G2 being stimulated into the M phase. After 18 hours the mitotic and labelling indices become more uniform throughout the samples suggesting that 'edge labelling' is partly due to local stimulation of cell proliferation by trauma rather than central inhibition due to diffusion problems. These results suggest that in this organ culture system, assessment of proliferative indices should be carried out after these adaptive changes have settled.

Adaptation, Physiological↗

PubMed2001

Cytoplasmic occurrence of the Chk1/Cdc25 pathway and regulation of Chk1 in Xenopus oocytes.

Chk1, a nuclear DNA damage/replication G2 checkpoint kinase, phosphorylates Cdc25 and causes its nuclear exclusion in yeast and mammalian cells, thereby arresting the cell at the G2 phase until DNA repair/replication is completed. Chk1 is also involved, at least in part, in the natural G2 arrest of immature Xenopus oocytes, but it is unknown how Chk1 inhibits Cdc25 function and undergoes regulation during oocyte maturation. By using enucleated oocytes, we show here that Chk1 inhibits Cdc25 function in the cytoplasm of G2-arrested oocytes and that Cdc25 is activated exclusively in the cytoplasm of maturing oocytes. Moreover, we show that Chk1 activity is not appreciably altered during maturation, being maintained at basal levels, and that C-terminal truncation mutants of Chk1 have very high kinase activities, strong abilities to inhibit maturation, and altered subcellular localization in oocytes. These results, together with other results, suggest that the Chk1/Cdc25 pathway is involved cytoplasmically in G2 arrest of Xenopus oocytes, but moderately and independent of the G2 checkpoint, and that the C-terminal region of Chk1 negatively regulates its kinase activity and also determines its subcellular localization. Based on these results, we discuss the possibility that Chk1 (with the basal activity) may function as an ordinary regulator of Cdc25 in oocytes (and in other cell types) and that Chk1 might be hyperactivated in response to the G2 checkpoint via its dramatic conformational change.

14-3-3 Proteins↗

PubMed2002

Cell cycle: stressed out of mitosis.

Cells in early stages of chromosome condensation are very vulnerable, and many stresses that do not damage DNA induce a transient return to late G2 phase. Such stresses include the drug-induced disassembly of microtubules, which triggers an ATM-independent G2 checkpoint pathway involving a novel ubiquitin ligase.

Cell Cycle↗

PubMed1999

Differentiation-related mechanisms which suppress DNA replication.

Differentiation of mammalian cells implies cessation of DNA replication and cell proliferation; the potential controls of this coupling are examined here. It is clear that the known or proposed mechanisms of down-regulation of replicative cellular activities vary in different lineages of cell differentiation, and occur in all phases of the cell cycle. In G1 these regulators include p21/Cip1 or p27/Kip1, pRb, and p53; the novel, recently reported mechanisms of their action are summarized. In S phase the availability of nucleotide precursors, the origin recognition complex (ORC), and other replication proteins may be important in differentiation, and in G2 phase the cdc2/cyclin B complex and replication licensing factors determine normal G2 traverse versus an arrest or polyploidisation. Other replication-related mechanisms include transcription factors, e.g., Sp1, telomerase, and nuclear matrix changes. Thus, differentiation alters the activity not only of the various checkpoint proteins, but also of the components of the replicative machinery itself.

Animals↗

PubMed1995

Cell cycle phase-dependent changes of localization and oligomerization states of nucleophosmin / B23.

Nucleophosmin / B23, an abundant nucleolar phosphoprotein, accumulates in the nucleoplasm of cells during the stationary phase of growth or after exposure to selected cytotoxic drugs [Chan, P.K. (1992) Exp. Cell Res. 203, 174-181]. Monomeric and hexameric forms of nucleophosmin / B23 are present in cells [Yung, B.Y.M. and Chan, P.K. (1987) Biochim. Biophys. Acta. 925, 74-82]. Using indirect immunofluorescence, here we show that there are changes in nucleophosmin / B23's cellular localizations throughout the cell cycle. The alternation of the nuclear and nucleolar localizations of nucleophosmin / B23 is most frequently observed in cells of G1 and G1/S phases. The incidence of the changes of localizations of nucleophosmin / B23 decreases as cells enter into S and G2 phases. In parallel, using Western blotting, the reversible change of oligomerization states between the hexameric and monomeric forms of nucleophosmin / B23 is also found to occur most frequently in cells of G1 and G1/S phases. As cells progressed into S, G2 and M phases, the frequency of the reversible change of hexameric and monomeric forms of nucleophosmin / B23 decreases. These findings suggest that nucleophosmin / B23 being possibly involved in rRNA processing and transport, is highly active at G1 and G1/S phases as demonstrated by the dynamic, reversible changes of localization and oligomerization states of nucleophosmin / B23.

Biological Transport, Active↗

PubMed1999

Mitotic control in the absence of cdc25 mitotic inducer in fission yeast.

Fission yeast cells tolerate the total absence of the cdc25 mitotic inducer in two cases, either in cdc2-3w or in wee1 genetic backgrounds. In the cdc2-3w cdc25Delta double mutant, the rate-limiting step leading to mitosis is reaching a critical size. However, the size control of this mutant operates in late G2, which is different from wild-type (WT) cells. This fact suggests that in WT the rate-limiting molecular process during the G2 timer is the Tyr15 dephosphorylation of cdc2, for which the cdc25 phosphatase (together with its back-up, pyp3) is dependent. In the wee1-50 cdc25Delta mutant, the population splits into different clusters, all lacking mitotic size control. This strain maintains size homeostasis by a novel method, which is random movement of the cells from one cluster to another in the successive generations. These cells should normally have a 'minimal cycle', a 'timer' with short G1 and G2 phases. However, very often the cells abort mitosis, possibly at an early event and return back to early G2, thus lengthening their cycles. The inability of these cells to start anaphase might be caused by the absence of the main mitotic regulators (wee1 and cdc25) and the improper regulation of their back-up copies (mik1 and pyp3, respectively).

Cell Cycle Proteins↗

PubMed2005

Cell death mechanisms associated with G2 radiosensitivity in patients with prostate cancer and benign prostatic hyperplasia.

Cells respond to genotoxic insults such as ionizing radiation by halting in the G2 phase of the cell cycle. Delayed cell death (mitotic death) can occur when the cell is released from G2, and specific spindle defects form endopolyploid cells (endoreduplication/tetraploidy). Enhanced G2 chromosomal radiosensitivity has been observed in many cancers and genomic instability syndromes, and it is manifested by radiation-induced chromatid aberrations observed in lymphocytes of patients. Here we compare the G2 chromosomal radiosensitivity in prostate patients with benign prostatic hyperplasia (BPH) or prostate cancer with disease-free controls. We also investigated whether there is a correlation between G2 chromosomal radiosensitivity and aneuploidy (tetraploidy and endoreduplication), which are indicative of mitotic cell death. The G2 assay was carried out on all human blood samples. Metaphase analysis was conducted on the harvested chromosomes by counting the number of aberrations and the mitotic errors (endoreduplication/tetraploidy) separately per 100 metaphases. A total of 1/14 of the controls were radiosensitive in G2 compared to 6/15 of the BPH patients and 15/17 of the prostate cancer patients. Radiation-induced mitotic inhibition was assessed to determine the efficacy of G2 checkpoint control in the prostate patients. There was no significant correlation of G2 radiosensitivity scores and mitotic inhibition in BPH patients (P = 0.057), in contrast to prostate cancer patients, who showed a small but significant positive correlation (P = 0.029). Furthermore, there was no significant correlation between G2 radiosensitivity scores of BPH patients and endoreduplication/ tetraploidy (P = 0.136), which contrasted with an extremely significant correlation observed in prostate cancer patients (P < 0.0001). In conclusion, cells from prostate cancer patients show increased sensitivity to the induction of G2 aberrations from ionizing radiation exposure but paradoxically show reduced mitotic indices and aneuploidy as a function of aberration frequency.

Aged↗

PubMed1997

Lack of uncoupling of S phase and mitosis after irradiation in p53- human lymphoblast cell lines.

It has been shown that p53- human colorectal cancer cells arrest after DNA damage in a G2-like state and may then undergo DNA synthesis without intervening mitosis (Waldman et al., Nature 381, 713-716, 1996). To further clarify the role of p53 in the regulation of the G2/M-phase checkpoint, we have studied cells of three closely related human lymphoblastoid cell lines (TK6, WTK1 and TK6E6, an HPV16 E6-transfected TK6 line) with differing p53 status. The cells were irradiated with 1.5-12 Gy gamma rays with or without 2 mM caffeine. There was no evidence of uncoupling of DNA synthesis and mitosis after irradiation in the p53- cell lines, WTK1 and TK6E6, suggesting that this uncoupling may not be a universal phenomenon. The apparent formation of tetraploid cells after irradiation of cells of the p53- WTK1 line was due to the occurrence of a G2-phase block in a pre-existing tetraploid population. These results support the conclusion that control of the G2/M-phase checkpoint after irradiation may differ among different cell types.

Caffeine↗

PubMed1991

[Application of anti-p-105 monoclonal antibody to analysis of mode of action of antitumor agents].

For the elucidation of the mode of action of anti-tumor agents, the cell cycle analysis of etoposide and podophyllotoxin was examined by means of the multiparameter flow cytometry using an anti-p-105 monoclonal antibody. The p-105 is one of the proliferation associated nuclear antigens and its expression increases with a cell cycle progression, especially in mitotic phase. Thus, we have applied its anti-monoclonal antibody to the discrimination between M and G2 phases of the gastric cancer cells. The results revealed that etoposide caused a G2 block and retarded an S phase transition, and podophyllotoxin caused both G2 and M phase blocks in the gastric cancer cells. This cell cycle analysis using an anti-p-105 monoclonal antibody would be a useful analysis of the antitumor agents, especially for M phase analysis of human cancer cells because of its rapidity and convenience.

Antibodies, Monoclonal↗

PubMed1996

Effect of melphalan and hyperthermia on p34cdc2 kinase activity in human melanoma cells.

We previously reported that combined treatment with melphalan and mild hyperthermia (1 h at 42 degrees C) caused a synergistic cytotoxic effect in JR8 melanoma cells, paralleled by a stabilisation of a melphalan-induced G2-phase cell block. In this study, we investigated the effect of melphalan and hyperthermia on proteins that regulate G2-M transition. Neither hyperthermia nor melphalan at a concentration of 2.5 micrograms ml-1, which had no antiproliferative effect at 37 degrees C, interfered with cyclin B1 expression or p34cdc2 kinase activity. At a concentration of 8.5 micrograms ml-1, which reduced cell growth by 50% at 37 degrees C, melphalan inhibited p34cdc2 kinase activity as a consequence of an increased tyrosine phosphorylation of the protein. A similar inhibitory effect on p34cdc2 kinase was obtained when the lowest melphalan concentration (2.5 micrograms ml-1) was used under hyperthermic conditions. Our results indicate that thermal enhancement of melphalan cytotoxicity could be mediated at least in part by an inhibition of p34cdc2 kinase activity, which prevents cell progression into mitosis.

Antineoplastic Agents, Alkylating↗