[A brief developmental history of studies on cell cycle and cell cycle control].
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Cell Cycle↗
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[Regulatory role of HTm4 gene in hematopoietic cell cycle].
Cell cycle progression is tightly regulated in hematopoietic stem cells. The cycle state decides cells' fates, which includes self-renewal, proliferation and differentiation. Proper cell cycle regulation is a pivotal element for the maintenance of hematopoiesis homeostasis. HTm4 is a newly identified specific cell cycle regulator of the hematopoietic cell. Through interacting with KAP-CDK2 complex, it arrests cells in G(0)/G(1) phase. K562 is a human chronic myelogenous leukemia cell; it could be induced to megakaryoblast by phorbol 12-myristate 13-acetate (PMA). Such differentiation must be associated with cell cycle change. To further clarify HTm4's function in hematopoietic cell cycle regulation, K562 cells were treated with PMA. Cell cycle change was analysed using flow cytometric system. And during the induction process gene expression of HTm4 as well as CycleE and CDK2, which are responsible for G(1) to S transition, were analysed using semi-quantitative RT-PCR. The C-terminal domain of HTm4 protein has been shown to be important for HTm4's binding with KAP-CDK2 complex. To determine its impact on HTm4's function, HTm4 and C-terminal truncated HTm4 (HTm4-ct) were transfected into K562 cells using Tet-Off regulation expression system. Their influence on cell cycle was observed. The results showed that PMA induced both expansion and differentiation of K562 cells as measured by cell number count and NBT staining respectively. During PMA treatment, G(0)/G(1) cell proportion and HTm4 expression displayed coordinated change, which suggested that HTm4 might drive K562 cells out of cell cycle but was not involved in the quiescence maintenance. Additionally, transfection of HTm4 caused G(0)/G(1) arrest in K562 cells, while transfection of HTm4-ct did not. It is therefore suggested that the C-terminal domain is important for the function of HTm4 in cell cycle regulation.
Cell Cycle↗
Linking cell division to cell growth in a spatiotemporal model of the cell cycle.
Cell division must be tightly coupled to cell growth in order to maintain cell size, yet the mechanisms linking these two processes are unclear. It is known that almost all proteins involved in cell division shuttle between cytoplasm and nucleus during the cell cycle; however, the implications of this process for cell cycle dynamics and its coupling to cell growth remains to be elucidated. We developed mathematical models of the cell cycle which incorporate protein translocation between cytoplasm and nucleus. We show that protein translocation between cytoplasm and nucleus not only modulates temporal cell cycle dynamics, but also provides a natural mechanism coupling cell division to cell growth. This coupling is mediated by the effect of cytoplasmic-to-nuclear size ratio on the activation threshold of critical cell cycle proteins, leading to the size-sensing checkpoint (sizer) and the size-independent clock (timer) observed in many cell cycle experiments.
Animals↗
Cell cycle length, cell size, and proliferation rate in hydra stem cells.
We have analyzed the cell cycle parameters of interstitial cells in Hydra oligactis. Three subpopulations of cells with short, medium, and long cell cycles were identified. Short-cycle cells are stem cells; medium-cycle cells are precursors to nematocyte differentiation; long-cycle cells are precursors to gamete differentiation. We have also determined the effect of different cell densities on the population doubling time, cell cycle length, and cell size of interstitial cells. Our results indicate that decreasing the interstitial cell density from 0.35 to 0.1 interstitial cells/epithelial cell (1) shortens the population doubling time from 4 to 1.8 days, (2) increases the [3H]thymidine labeling index from 0.5 to 0.75 and shifts the nuclear DNA distribution from G2 to S phase cells, and (3) decreases the length of G2 in stem cells from 6 to 3 hr. The shortened cell cycle is correlated with a significant decrease in the size of interstitial stem cells. Coincident with the shortened cell cycle and increased growth rate there is an increase in stem cell self-renewal and a decrease in stem cell differentiation.
Animals↗
Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle.
Cells deprived of serum mitogens will either undergo immediate cell cycle arrest or complete mitosis and arrest in the next cell cycle. The transition from mitogen dependence to mitogen independence occurs in the mid-to late G1 phase of the cell cycle and is called the restriction point. Murine Balb/c-3T3 fibroblasts deprived of serum mitogens accumulated the cyclin-dependent kinase (CDK) inhibitor p27Kip1. This was correlated with inactivation of essential G1 cyclin-CDK complexes and with cell cycle arrest in G1. The ability of specific mitogens to allow transit through the restriction point paralleled their ability to down-regulate p27, and antisense inhibition of p27 expression prevented cell cycle arrest in response to mitogen depletion. Therefore, p27 is an essential component of the pathway that connects mitogenic signals to the cell cycle at the restriction point.
3T3 Cells↗
Control of the cell cycle.
Cell biology has made major progress in identifying the molecules that drive the cell cycle. The evidence accumulating from these studies indicates that derangements in the cell cycle machinery contribute to the uncontrolled cell growth of tumours. The cell cycle machinery has been found to be substantially altered in tumour cells and also may be crucial for carcinogenesis. In this context, various aspects of tumour cell growth have been studied in an effort to understand 1) why tumour cells display uncontrolled growth, 2) why radiation selectively affects growing cells, and 3) whether aspects of the cell cycle and tumour cell growth may be used in tumour diagnosis and prognosis.
Animals↗
New end take off: regulating cell polarity during the fission yeast cell cycle.
Cell polarization is a major event of the cell cycle and underlies the function of most cells. Cell polarity is often achieved through the coordinated organization of the microtubule and act in cytoskeletons. Dramatic changes in cell polarization occur during the cell cycle and are subject to regulation by cell cycle controls. Cells of the fission yeast Schizosaccharomyces pombe grow by tip extension in a cell cycle-controlled manner. During G2 phase, these cells exhibit a transition in cell polarization known as New End Take Off (NETO), in which monopolar cells initiate bipolar growth. Dynamic microtubules contribute to this process by depositing at cell ends the microtubule plus end proteins tea1p and tea4p, which are necessary for NETO. We discuss here how these proteins may recruit for 3p, a formin responsible for actin nucleation, as well as two other actin binding proteins, bud6p and sla2p, to initiate cell polarization at the new end of the cell. Thus, the study of NETO is revealing a mechanism by which the plus ends of microtubules regulate the spatial organization of actin.
Actins↗
[Cyclin and cell cycle].
Cell cycle progresses through the formation of cyclin produced and degraded in its specific phase and cyclin dependent kinase (Cdk) existing in all phases of the cell cycle and consequential phosphorylation of Cdk. The Cdk is activated by Cdk-activating kinase as well as cyclin, and its function is suppressed by its inhibitory subunits (CKIs). The cell cycle induced by extracellular stimuli in normal cells progresses toward cell differentiation and apoptosis or cell proliferation according to a certain law. The failure to complete cell-cycle progression can be detected and repaired at many checkpoints. Cancer cells have abnormal cell-cycle relating constituents, such as overexpression of cyclin, mutation or deletion of CKI and failures in feedback controls at checkpoints. These abnormal constituents may contribute to the evaluation of patients' prognosis and cellular sensitivity for chemotherapy and ionizing irradiation and may lead to a development of new promising anti tumor agents.
Apoptosis↗
The Arabidopsis cyclin-dependent kinase gene cdc2bAt is preferentially expressed during S and G2 phases of the cell cycle.
Cell cycle progression is regulated by cyclin-dependent kinases (CDKs). Arabidopsis thaliana contains two cdk genes, cdc2aAt and cdc2bAt. This paper compares the developmental and cell cycle phase-dependent transcription of both cdk genes. In situ hybridizations revealed that cdc2bAt steady-state mRNAs, much like cdc2aAt, are found both in meristematic cells and cells with a high proliferative competence. Cdc2aAt is expressed in every meristematic cell whereas cdc2bAt is found to be expressed in a patchy pattern. An even smaller number of meristematic cells express the mitotic cyc1At. These data indicate that cdc2bAt and cyc1At mRNAs accumulate in a particular cell cycle phase in agreement with evidence provided by hybridization experiments of flow cytometrysorted nuclei and the use of cell cycle blockers on roots. The data indicate that cdc2bAt is preferentially expressed in S and G2 phases whereas cdc2aAt expression is constitutive throughout the cell cycle, as shown previously. The existence of two distinct CDK classes in plants is proposed: (i) constitutively expressed CDKs containing a PSTAIRE motif (e.g. cdc2aAt) and (ii) CDKs with divergent motifs which are expressed during a limited interval of the cell cycle (e.g. cdc2bAt).
Arabidopsis↗
Progression through the G1-phase of the on-going cell cycle.
Cell cycle progression is dependent upon the action of cyclins and their partners the cyclin dependent kinases (CDKs). Each cell cycle phase has its own characteristic cyclin-CDK combination, cyclin D-CDK4,6 and cyclin E-CDK2 being responsible for progression through G(1)-phase into S-phase. Progression through G(1)-phase is regulated by signal transduction cascades activated by polypeptide growth factors and by extracellular matrix (ECM) components. Studies aiming to unravel the molecular mechanism by which these extracellular components activate the cyclin-CDK complexes in the G(1)-phase, are usually performed using serum-starved cells (G(0) cells). These cells are activated by addition of growth factors, or the cells are detached from the substratum by trypsinization and subsequently allowed to re-attach. An alternative approach, however, is to study the effects of growth factors and attachment in the ongoing cell cycle by synchronization of the cells by the mitotic shake-off method. These cells are not serum starved and not actively detached from the substratum. In this contribution it is shown that both methods yield significant different results. These observations demonstrate that data obtained with model systems should be interpreted with care, especially if the findings are used to explain cell cycle progression in cells in an intact organism.
Animals↗
Human glioma PKC-iota and PKC-betaII phosphorylate cyclin-dependent kinase activating kinase during the cell cycle.
Cell cycle phase transition is regulated in part by the trimeric enzyme, cyclin-dependent kinase activating kinase (CAK) which phosphorylates and activates cyclin-dependent kinases (cdks). Protein kinase C (PKC) inhibitors prevent cell cycle phase transition, suggesting a fundamental role for PKCs in cell cycle regulation. We report that in glioma cells, CAK (cdk7) is constitutively associated with PKC-iota. In vitro phosphorylation, co-immunoprecipitation, and analysis of phosphorylated proteins by autoradiography indicate that CAK (cdk7) is a substrate for PKC-iota and PKC-betaII hyperphosphorylation. These results establish a role for PKC-iota and PKC-betaII in the activation of CAK during the glioma cell cycle.
Cell Cycle↗
Translational control of p27Kip1 accumulation during the cell cycle.
Cell cycle phase transitions in eukaryotic cells are driven by regulation of the activity of protein kinases known as cyclin-dependent kinases (Cdks). A broad spectrum of Cdk-inhibitory activity associated with a 28-kilodalton protein (p28lck1) was induced in cells treated with the drug lovastatin or upon density-mediated growth arrest and was periodic in the cell cycle, with peak activity in G1. The p28lck1 protein was shown to be identical to p27Kip1, and the periodic or induced inhibitory activity resulted from a periodic accumulation of the protein. Variations in the amount of p27 protein occurred, whereas the abundance of the p27 messenger RNA remained unchanged. In every instance investigated, the posttranscriptional alteration of p27 protein levels was achieved in part by a mechanism of translational control, although in density-arrested fibroblasts and thymidine-arrested HeLa cells the half-life of the protein was also changed.
Amino Acid Sequence↗
Fundamentals of cell proliferation: control of the cell cycle.
Cell proliferation in higher eukaryotes is controlled by the extracellular environment and the state of differentiation. Many cells exist in a nondividing growth state termed quiescence. Some quiescent cells cannot proliferate and are said to be terminally differentiated. Others can be stimulated to divide in response to environmental signals or when cell replacement is needed. Finally, some cells undergo continual proliferation and differentiation. Growth regulatory factors generally act at specific stages of the cell cycle, most commonly during the first gap phase of the cell cycle. Once cells initiate DNA synthesis, they are generally committed to complete DNA replication. After DNA synthesis, additional signals determine whether cells in the last gap phase proceed through mitosis. In recent years, genes that appear to be critical for progression through the first two gap phases have been identified. Many are proto-oncogenes and therefore can neoplastically transform certain cells when mutated or inappropriately expressed. Growth factors that stimulate proliferation induce the expression of several proto-oncogenes; growth inhibitory factors often suppress proto-oncogene expression. As cells differentiate, the response to extracellular factors changes. In many cases, this may be due to intracellular controls that alter the response of certain proto-oncogenes to external signals.
Animals↗
[Effects of methyl tertiary butyl ether on cell cycle and cell apoptosis].
OBJECTIVE: To explore the effects of the new gasoline additive, methyl tertiary butyl ether (MTBE) on cell cycle and cell apoptosis. METHODS: Flow cytometry was used to evaluate the effect of MTBE (1, 2, 4 microl/ml, 24 h) on NIH/3T3 cell cycles; and the effect of MTBE on Hela cell apoptosis was evaluated by detecting cell survival using crystal violet staining. RESULTS: Flow cytometry showed that MTBE could change NIH/3T3 cell cycles, decrease the number of cells in S stage, and arrest cells at G(2) + M stage. The results suggested that MTBE could affect NIH/3T3 cell cycles and induce cell proliferation. This situation existed 48 hours after the treatment, and cell cycles came back normal 96 hours after the treatment. By detecting cell survival using crystal violet staining, we found that MTBE could inhibit the apoptosis of Hela cells which was induced by tumor necrosis factor (TNF)alpha and cycloheximide. CONCLUSION: MTBE's carcinogenicity to animals may relate to induction of cell proliferation and inhibition of cell apoptosis.
3T3 Cells↗
Variations in ADP-ribosylation of nuclear scaffold proteins during the HeLa cell cycle.
Cell cycle variations in ADP-ribosylation of nuclear scaffold proteins were determined. Nuclei of synchronized cells were isolated and labeled with [32P]NAD before nuclear scaffolds were obtained by digestion of DNA with DNase I and extraction of proteins with 2M NaCl. Autoradiograms revealed the three groups of "lamins" and a species identified as poly (ADP-ribose) polymerase to be the primary ADP-ribosylated proteins. The patterns of modification of nuclear scaffold proteins displayed similar features through the cell cycle. Radioactivity in the lamins increased from 20% in early-S phase to 40% in G1 phase of the next cell cycle.
Adenine Nucleotides↗
DNA damage-associated cell cycle and cell death control is differentially modulated by caffeine in clones with p53 mutations.
Caffeine is known to potentiate the cytotoxic effects of DNA damaging agents and increases the sensitivity of p53-deficient cells to X-irradiation (X-IR). We have analyzed the cell cycle and cell death control after X-IR in the absence or presence of caffeine in hematological cell lines with various configurations of the p53 gene; EBV-immortalized lymphoblastoid cells with heterozygous p53 mutation (wt/mt), human leukemia cell lines HL60 and KOPM28 with no and mutant p53 expression, respectively. These cell lines display an impaired G0/G1 checkpoint and G2 delay following X-IR, and resistance to apoptosis, which are in accordance with findings previously reported. When irradiated in combination with caffeine, all these cell lines overrode the G2 delay and accumulated at G0/G1. The cell cycle modifications in these cell lines correlated with the increase in radiation-induced p34Cdc2 kinase activity by caffeine. These cell cycle control modifications by caffeine, however, were not associated with enhancement of radiation-induced apoptosis or reduction of clonogenic growth activity in these cell lines. These results suggest that the cytocidal effect of caffeine may need to be verified independently of its cell cycle regulatory activities at least in some cases with p53 mutation.
Amino Acid Substitution↗
[A comparative level of expression of some proteins in XL2 cell synchronized on different phases of cell cycle].
Cells of cultured line XL2 (Xenopus laevis) were synchronized by a combine effect of serum deprivation, aphidicolin, nocodazole and ALLN treatments. Four fractions were prepared, with maximum percentage of cells being in G1, S and G2 phases of cell cycle, and in mitosis, respectively. Comparative levels of six different proteins (beta-tubulin, DNA topoisomerase IIa, Xenopus Aurora A kinase pEg2, kinesin-like motor protein X1Eg5, and two members of condensis family proteins pEg7 (XCAP D2) and XCAP E were detected by quantitative Western blot analysis of these fractions. We used a new method of mathematic processing of data that commonly provides a possibility to calculate a comparative quantity of proteins in hypothetically "clean" fraction composed of cells being in the same phase of the cell cycle. This method makes it possible to use even partly synchronized cell cultures for analysis of changes in protein quantity, provided a precede determination of cell population composition is made.
Animals↗
The plant cell cycle.
Cell division in plants is controlled by the activity of cyclin-dependent kinase (CDK) complexes. Although this basic mechanism is conserved with all other eukaryotes, plants show novel features of cell-cycle control in the molecules involved and their regulation, including novel CDKs showing strong transcriptional regulation in mitosis. Plant development is characterized by indeterminate growth and reiteration of organogenesis and is therefore intimately associated with cell division. This may explain why plants have a large number of cell-cycle regulators that appear to have overlapping and distinct functions. Here we review the recent considerable progress in understanding how core cell-cycle regulators are involved in integrating and coordinating cell division at the molecular level.
Cell Cycle↗