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Results for “Resting Phase, Cell Cycle”

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PubMed1999

Effects of ultraviolet C radiation on cellular proliferation in p53-/- keratinocytes.

Skin cancer is the most common tumor type in Caucasians, with an incidence that approaches the lifetime risk for all other cancer subtypes combined. The most common predisposing factor is exposure to ultraviolet (UV) radiation present in sunlight. The purpose of this investigation was to evaluate the effects of UVC on the proliferation of a p53-/- human keratinocyte cell line, HaCaT, and how UVC alters the response of these cells to transforming growth factors (TGF)-alpha and TGF-beta1. UVC treatment during G0/G1 phase resulted in decreased incorporation of [3H]thymidine, an effect that was enhanced by pretreatment with TGF-beta1. However, irradiation of HaCaT cells in S or G2/M phase had no effect on the incorporation of [3H]thymidine, suggesting that these cells failed to undergo G2/M arrest in response to UV-mediated DNA damage. UVC had no effect on TGF-beta1-mediated growth inhibition, but decreased the mitogenic response of HaCaT cells to TGF-alpha. Seven days after irradiation, there were no differences between the number of cells that were exposed to UVC and those that were not, suggesting that the effects of UVC on proliferation of HaCaT cells was transient. These results suggested that UVC did not stimulate proliferation of p53-/- HaCaT cells, or cause cell cycle arrest in G2/M, which would allow transmission of chromosomal damage to daughter cells during M phase. Failure of the G2/M cell cycle checkpoint may be one of the mechanisms by which p53 results in genomic instability.

Cell Division↗

PubMed1996

C/EBP-beta/LAP controls down-regulation of albumin gene transcription during liver regeneration.

Expression of the albumin gene in the liver is controlled by several liver-enriched transcription factors. However, the mechanisms which contribute to its regulation during pathophysiological states, such as liver regeneration, are still little understood. In the present study we found that during liver regeneration down-regulation of albumin mRNA expression is transcriptionally controlled through a minimal element (nucleotide -170 to +22) of the albumin promoter and is observed mainly during the G1 phase of the cell cycle, while high levels of albumin expression are preserved at later time points. Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/EBP-beta/LAP, a protein known to bind to the D site of the albumin promoter and also to be involved in cell cycle control. In contrast, nuclear expression of other factors such as HNF-1 or C/EBP-alpha, which also have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-translational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to its increased binding toward the D site of the albumin promoter. Finally, in vitro transcription assays with liver nuclear extracts and recombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly down-regulate transcription mediated by the minimal element of the albumin promoter. Additionally the inhibitory role of C/EBP-beta/LAP on the albumin minimal promoter could be confirmed by transfection experiments in hepatoma cells. These results indicate that C/EBP-beta/LAP, while enhancing transcription of cell cycle-related genes and controlling G1/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell cycle.

Albumins↗

PubMed1994

Daidzein inhibits insulin- or insulin-like growth factor-1-mediated signaling in cell cycle progression of Swiss 3T3 cells.

An isoflavone compound, daidzein, inhibits the cell proliferation of Swiss 3T3 cells. Analysis of entry in S phase of Swiss 3T3 cells reveals that daidzein blocked cell cycle G1 phase progression 4.6 h after stimulation by bombesin plus insulin. After removal of daidzein, insulin or insulin-like growth factors (IGFs) reinitiate cell cycle progression of daidzein-blocked cells without further addition of bombesin. The order in the mitogenic action of insulin or IGFs is as follows: IGF-1 (5 ng/ml) >> IGF-2 (0.5 microgram/ml) congruent to insulin (1 microgram/ml). Studies in vivo of protein kinase activation by mitogenic stimulation reveal that the treatment with daidzein decreased the activation of a MAP2 phosphorylating protein kinase (MAP2 kinase). In vitro kinase assays showed that daidzein inhibits casein kinase II activity, but does not inhibit MAP2 kinase activity. Activation of casein kinase II by polylysine augments the activity of MAP2 kinase in digitonin-permeabilized 3T3 cells. These results suggest that daidzein blocked G1 phase cell cycle progression of Swiss 3T3 by inhibiting the activity of casein kinase II which is required for the commitment of mitogenic signal by insulin or IGF-1 in G1 phase.

3T3 Cells↗

PubMed2006

Regulation of mammalian ribonucleotide reduction and dNTP pools after DNA damage and in resting cells.

Ribonucleotide reductase (RNR) provides the cell with a balanced supply of deoxyribonucleoside triphosphates (dNTP) for DNA synthesis. In budding yeast DNA damage leads to an up-regulation of RNR activity and an increase in dNTP pools, which are essential for survival. Mammalian cells contain three non-identical subunits of RNR; that is, one homodimeric large subunit, R1, carrying the catalytic site and two variants of the homodimeric small subunit, R2 and the p53-inducible p53R2, each containing a tyrosyl free radical essential for catalysis. S-phase-specific DNA replication is supported by an RNR consisting of the R1 and R2 subunits. In contrast, DNA damage induces expression of the R1 and the p53R2 subunits. We now show that neither logarithmically growing nor G(o)/G1-synchronized mammalian cells show any major increase in their dNTP pools after DNA damage. However, non-dividing fibroblasts expressing the p53R2 protein, but not the R2 protein, have reduced dNTP levels if exposed to the RNR-specific inhibitor hydroxyurea, strongly indicating that there is ribonucleotide reduction in resting cells. The slow, 4-fold increase in p53R2 protein expression after DNA damage results in a less than 2-fold increase in the dNTP pools in G(o)/G1 cells, where the pools are about 5% that of the size of the pools in S-phase cells. Our results emphasize the importance of the low constitutive levels of p53R2 in mammalian cells, which together with low levels of R1 protein may be essential for the supply of dNTPs for basal levels of DNA repair and mitochondrial DNA synthesis in G(o)/G1 cells.

Animals↗

PubMed1995

Comparison of gamma-ray-induced chromosome ring and inversion frequencies.

A method was used to detect chromosome inversions as apparent or false sister chromatid exchanges (SCEs) in the first mitosis after gamma irradiation of human G0 cells. Dose-response relationships for small inversions have not been measured and reported previously, but it has been assumed that these are induced with a frequency equal to that of their easily measured asymmetrical counterpart, the interstitial deletion. Our experiments confirm this expectation. The results also demonstrate, as others have suggested, that in protocols where SCEs have been reported in the first postirradiation mitosis after incorporation of BrdU in the previous cell cycle, the X- or gamma-ray treatment of G0- or G1-phase cells produces virtually no true SCEs.

Cell Line↗

PubMed2005

Cutting edge: p27Kip1 deficiency reduces the requirement for CD28-mediated costimulation in naive CD8+ but not CD4+ T lymphocytes.

Cell cycle re-entry of quiescent T cells is dependent upon cyclin-dependent kinase 2. Inhibition of cyclin-dependent kinase 2 by p27(Kip1) is believed to be the principal constraint on S-phase entry in T cells. We report that deficiency for p27(Kip1) has a more pronounced effect on the expansion of murine naive CD8(+) T cells and that this disparity is due to a reduced requirement for CD28-mediated costimulation in CD8(+) but not CD4(+) T cells lacking p27(Kip1). These data highlight a previously unappreciated difference in the way CD28 signaling is coupled to the core cell cycle machinery in these two T cell subsets.

Animals↗

PubMed2007

Kinase-independent function of cyclin E.

E-type cyclins are thought to drive cell-cycle progression by activating cyclin-dependent kinases, primarily CDK2. We previously found that cyclin E-null cells failed to incorporate MCM helicase into DNA prereplication complex during G(0) --> S phase progression. We now report that a kinase-deficient cyclin E mutant can partially restore MCM loading and S phase entry in cyclin E-null cells. We found that cyclin E is loaded onto chromatin during G(0) --> S progression. In the absence of cyclin E, CDT1 is normally loaded onto chromatin, whereas MCM is not, indicating that cyclin E acts between CDT1 and MCM loading. We observed a physical association of cyclin E with CDT1 and with MCMs. We propose that cyclin E facilitates MCM loading in a kinase-independent fashion, through physical interaction with CDT1 and MCM. Our work indicates that-in addition to their function as CDK activators-E cyclins play kinase-independent functions in cell-cycle progression.

Animals↗

PubMed1998

G0/G1 cell cycle arrest in the brain of Sarcophaga crassipalpis during pupal diapause and the expression pattern of the cell cycle regulator, proliferating cell nuclear antigen.

During pupal diapause in the flesh fly, Sarcophaga crassipalpis, the cells of the brain are arrested in the G0/G1 phase of the cell cycle. When diapause is terminated with a topical application of hexane, cell cycling is evident within 12 hours. Four G1 and S phase regulatory genes were examined by Northern blot analysis to evaluate their expression patterns in relation to this cell cycle arrest. A distinction between diapausing and nondiapausing individuals was noted only for Proliferating Cell Nuclear Antigen (PCNA). PCNA was highly expressed after diapause was terminated but not during diapause. In contrast, cyclin E, p21, and p53 were expressed equally at all times. In situ hybridization using PCNA probes further indicated a correlation between PCNA transcription (expression) in the brain and cell cycling. Our evidence thus suggests a potential role for PCNA as an important regulator of cell cycle arrest during diapause.

Animals↗

PubMed2004

AC133+ G0 cells from cord blood show a high incidence of long-term culture-initiating cells and a capacity for more than 100 million-fold amplification of colony-forming cells in vitro.

AC133+ cells may provide an alternative to CD34+ cells as a target for cell expansion and gene therapy protocols. We examined the differences in proliferative potential between cord blood selected for AC133 or CD34 in serum-free, stroma cell-free culture for up to 30 weeks. Because most hemopoietic stem cells reside within the G0/G1 phase of the cell cycle, we combined enrichment according to AC133 or CD34 expression with G0 position in the cell cycle to identify populations enriched for putative stem cells. Our results show that AC133+ G0 cells demonstrated a long-term culture-initiating cell incidence of 1 in 4.2 cells, had a colony-forming cell incidence of 1 in 2.8 cells, were capable of producing 660 million-fold expansion of nucleated cells and 120 million-fold expansion of colony-forming units-granulocyte-macrophage over a period of 30 weeks, and were consistently superior to CD34+ G0 cells according to these parameters. Furthermore, we have shown that AC133+CD34- cells have the ability to generate CD34+ cells in culture, which suggests that at least some AC133+ cells are ancestral to CD34+ cells. We conclude that AC133 isolation provides a better means of selection for primitive hemopoietic cells than CD34 and that, in combination with isolation according to G0 phase of the cell cycle, AC133 isolation identifies a highly enriched population of putative stem cells.

AC133 Antigen↗

PubMed1994

Transforming growth factor-beta 1 (TGF-beta 1) inhibits DNA synthesis of PWM-stimulated PBMC via suppression of IL-2 and IL-6 production.

The multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1) is known to inhibit the proliferation of lymphocytes. However, the role of TGF-beta 1 in the production and secretion of various interleukins is not yet clear. In this study we have analysed in parallel the effects of TGF-beta 1 on both DNA synthesis and production of the cytokines IL-1, IL-2, IL-6, and TNF-alpha by pokeweed mitogen-stimulated peripheral blood mononuclear cells. With this stimulation system we show that TGF-beta 1 at a concentration of 15 ng/ml significantly suppresses IL-2 and IL-6 production. The release of IL-1 and TNF-alpha, however, was not influenced under these conditions. Under similar conditions DNA synthesis of PWM-stimulated PBMC was found to be inhibited by 50 +/- 10%. Using flow cytometric methods we could demonstrate that TGF-beta 1 arrested the cells in the G0/G1 phase of the cell cycle. Taken together, these results suggest that TGF-beta 1 may suppress immune responses by inhibiting the endogenous production of IL-2 and IL-6.

DNA↗

PubMed2000

Phosphorylation of the retinoblastoma-related protein p130 in growth-arrested cells.

The retinoblastoma family of proteins including pRB, p107 and p130 undergoes cell cycle dependent phosphorylation during the mid-G1 to S phase transition. This phosphorylation is dependent upon the activity of cyclin D/cdk4. In contrast to pRB and p107, p130 is phosphorylated during G0 and the early G1 phase of the cell cycle. We observed that p130 is specifically phosphorylated on serine and threonine residues in T98G cells arrested in G0 by serum deprivation or density arrest. Identification of the phospho-serine and phospho-threonine residues revealed that most were clustered within a short co-linear region unique to p130, defined as the Loop. Deletion of the Loop region resulted in a change in the phosphorylation status of p130 under growth arrest conditions. Notably, deletion of the Loop did not affect the ability of p130 to bind to E2F-4 or SV40 Large T antigen, to induce growth arrest in Saos-2 cells, and to become hyperphosphorylated during the proliferative phase of the cell cycle. p130 undergoes specific G0 phosphorylation in a manner that distinguishes it from pRB and p107.

Amino Acid Sequence↗

PubMed2006

MDDD, a 4,9-diazapyrenium derivative, is selectively toxic to glioma cells by inducing growth arrest at G0/G1 independently of p53.

4-Methyl-2,7-diamino-5,10-diphenyl-4,9-diaz-apyrenium chloride (MDDD), a stable and water soluble nucleic acid-intercalating agent, was shown to be toxic to cancer cells with IC50 around 10 microM. IC(50) We tested MDDD for its potential antitumor activities and found it inhibited cancer cell growth with IC(50) in the micromolar range for the majority of cancer cells tested, with the exception of glioma cells, for which the IC(50) is in the submicromolar range. This unique selectivity of MDDD to glioma cells can potentially be exploited for anti-glioma therapeutics. Although the underlying mechanisms for the apparent glioma specificity remain to be elucidated, our analysis indicates that MDDD significantly reduces cell clonogenicity and blockes cell proliferation at the G1 phase. MDDD treatment also triggers induction of p53 and p21 at the protein levels, suggesting the activation of DNA damage response. However, MDDD mediated growth inhibition does not require the p53 pathway since p53+/- isogenic cell pairs display the same sensitivity. These properties of MDDD favor its candidacy for evaluation as a new anti-tumor agent, particularly for glioma.

Animals↗

PubMed1994

Cell cycle regulation of V(D)J recombination-activating protein RAG-2.

The antigen receptors of B and T lymphocytes are encoded in multiple germ-line DNA segments that are joined during lymphocyte development. The recombination-activating proteins RAG-1 and RAG-2 are both essential for this process, termed V(D)J rearrangement. Phosphorylation of the RAG-2 protein at Thr-490 by one or more cyclin-dependent kinases is associated with its rapid degradation. In an immature B-cell line and in normal thymocytes, RAG-2 protein accumulates preferentially in the G0/G1 phases of the cell cycle and declines by at least 20-fold before cells enter S phase. The amount of RAG-2 protein remains low throughout the S, G2, and M phases. The amount of RAG-1 protein shows considerably less fluctuation. The variation in RAG-2 protein is likely to be established, at least in part, by a posttranscriptional mechanism. These observations suggest that V(D)J rearrangement occurs entirely or preferentially within G0/G1.

Animals↗

PubMed2001

Direct exposure of chromosomes to nonactivated ovum cytoplasm is effective for bovine somatic cell nucleus reprogramming.

We examined the in vitro developmental potential of nonactivated and activated enucleated ova receiving cumulus cells at various stages of the cell cycle. Eleven to 29% of activated ova receiving donor cells stopped developing at the 8-cell stage but 21% to 50% of nonactivated ova receiving donor cells at either the G(0), G(1), G(2), or M phase, or cycling cells developed into blastocysts. One normal calf was born after transferring five blastocysts that had developed from ova receiving donor cells at the M phase. The present study demonstrated that direct exposure of donor chromosomes to nonactivated ovum cytoplasm is effective for somatic cell nucleus reprogramming, and activated ovum cytoplasm does not reprogram the nucleus.

Animals↗

PubMed2004

Synergistic interactions between tamoxifen and trastuzumab (Herceptin).

PURPOSE: HER-2/neu and estrogen receptor (ER) are critical in the biology of breast carcinoma, and both are validated therapeutic targets. Extensive interactions between the signaling pathways of these receptors have been demonstrated. This suggests that targeting both receptors simultaneously may have a dramatic effect on the biology of breast cancer. This hypothesis was tested in cell culture experiments. EXPERIMENTAL DESIGN: ER-positive, HER-2/neu-overexpressing BT-474 human breast carcinoma cells were cultured in the presence of the anti-HER-2/neu therapeutic antibody trastuzumab (Herceptin), the antiestrogen tamoxifen, or both. The effects on cell growth, cell cycle distribution, clonogenicity, survival, and the level and activity of HER-2/neu were examined. RESULTS: The combination of tamoxifen and Herceptin resulted in synergistic growth inhibition and enhancement of cell accumulation in the G(0)-G(1) phase of the cell cycle, with a decrease in cells in S phase. Clonogenicity was inhibited in the presence of each drug and more so by the combination, although prior exposure to drugs did not affect subsequent clonogenicity in drug-free media, and neither drug nor the combination induced apoptosis. Herceptin, but not tamoxifen, inhibited signaling by HER-2/neu. CONCLUSIONS: The combination of tamoxifen and Herceptin is formally demonstrated to result in synergistic growth inhibition and enhancement of G(0)-G(1) cell cycle accumulation. In vitro, the individual drugs or combination produces a cytostatic effect. These results suggest that combined inhibition of ER and HER-2/neu signaling may represent a powerful approach to the treatment of breast cancer.

Antibodies, Monoclonal↗

PubMed2004

Antileukemic activity of rapamycin in acute myeloid leukemia.

The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Heme oxygenase overexpression attenuates glucose-mediated oxidative stress in quiescent cell phase: linking heme to hyperglycemia complications.

Heme oxygenase (HO-1) is a stress protein, which has been suggested to participate in defense mechanisms against glucose induced oxidative injury. The purpose of this study was to examine the role of human HO-1 in attenuating glucose-mediated oxidative stress. We investigated the effect of high ambient glucose (15, 33 and 66 mM) on HO-1 gene expression in endothelial cells grown in a serum deprived media compared to the effect of glucose on exponentially grown cells (10% FBS). High glucose at 15 and 33 mM caused significant inhibition of HO-1 protein and activity in G0/G1 and in cells exponentially grown. Glucose concentration at 66 mM caused a significant increase in HO-1. Addition of heme (10 microM) increased HO-1 protein and bilirubin formation in G0/G1, in a time dependent manner peaking at 16 h. Glucose attenuated heme mediated increase in HO-1 proteins. RT-PCR demonstrated that glucose decreased the levels of HO-1 mRNA in both G0/G1 or cells grown in 10% FBS. The rate of HO-1 induction in response to heme was several fold higher in serum-starved cells compared to cells cultured in 10% FBS. Cells exposed to high glucose for up to 24 h had a significant increase in cellular heme and potentiated heme-mediated increase in generation of superoxide anion and 8-epi-isoprostane PGF(2alpha). HO-1 gene transduction prevented glucose-mediated elevation of 8-epi-isoprostane PGF(2alpha). These results imply that expression of HO-1 in G0/G1 cells may be a key player in decreasing cellular heme, associated with increased generation of bilirubin, and in attenuating glucose mediated oxidative stress.

Cell Cycle↗

PubMedDate not supplied

Phenolic compounds, sodium salicylate and related compounds, as inhibitors of tumor cell growth and inducers of apoptosis in mouse leukemia L1210 cells.

The effects of a series of phenolic compounds were compared to the effects of sodium salicylate (2-hydroxybenzoate) on the growth, cell cycle and apoptotic effects in wild-type (WT) and deoxyadenosine-resistant (Y8) L1210 leukemia cells. These compounds included: salicylaldehyde, salicylaldoxime, salicylhydroxamic acid, salicylamide, 5-aminosalicylate and 5-sulfosalicylate. The IC50 values for inhibition of tumor cell growth ranged from 40 microM for salicylaldhyde to greater than 4 mM for 5-sulfosalicylate. There appeared to be an excellent correlation between the IC50 value for a compound and the ratio of octanol/aqueous distribution. Salicylamide caused a G2/M block in both the WT and Y8 L1210 cells, while salicylalehyde caused a G0/G1 block in both the WT and Y8 cells. Salicylamide and salicylaldoxime caused a much greater apoptotic effect in the Y8 cells than in the parental WT L210 cells. These data suggest that salicylaldehyde and salicylaldoxime, the most active compounds in this series, may provide the lead chemicals from which other more active drugs can be synthesized.

Aldehydes↗