Development and maintenance of diverse organ systems require context‐specific regulation of stem cell behaviour. We hypothesize that this is achieved via reciprocal regulation between the cell cycle machinery and differentiation factors. This idea is supported by the parallel evolutionary emergence of differentiation pathways, cell cycle components and complex multicellularity. In addition, the activities of different cell cycle phases have been found to bias cells towards stem cell maintenance or differentiation. Finally, several direct (...) mechanistic links between these two processes have been established. Here, we focus on interactions between cyclin‐CDK complexes and differentiation regulators of the Notch pathway and Sox family of transcription factors within the context of pluripotent and neural stem cells. Thus, this hypothesis formalizes the links between these two processes as an integrated network. Since such factors are common to all stem cells, better understanding their interconnections will help to explain their behaviour in health and disease. (shrink)

It is a long-standing view that global translation varies during the cell cycle and is much lower in mitosis than in other cell-cycle phases. However, the central papers in the literature are not in agreement about the extent of downregulation in mitosis, ranging from a dramatic decrease to only a marginal reduction. Herein, it is argued that the discrepancy derives from technical challenges. Cell-cycle-dependent variations are most conveniently studied in synchronized cells, but the synchronization (...) methods by themselves often evoke stress responses that, in turn, affect translation rates. Further, it is argued that previously reported cell-cycle-dependent changes in the global translation rate to a large extent reflect responses to the synchronization methods. Recent findings strongly suggest that the global translation rate is not regulated in a cell-cycle-dependent manner. Novel techniques allowing a genome-wide analysis of translational profiles suggest that the extent and importance of selective translational regulation associated with cell-cycle transitions have been underestimated. Therefore, the main question is which messenger RNAs (mRNAs) are translated, rather than whether the global translation rate is decreased. (shrink)

Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal (...) adhesions, such as talin, paxillin, and zyxin. Re‐examining cell‐matrix adhesion reveals reticular adhesions, a new class of adhesion. These αVβ5 integrin‐mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re‐spreading after cell division. (shrink)

This study shows that double thymidine block treatment efficiently arrests the EO771 cells in the S‐phase without altering cell growth or survival. A long‐term analysis of cell behavior, using 5(6)‐carboxyfluorescein diacetate N‐succinimidyl ester (CFSE) staining, show synchronization to be stable and consistent over time. The EO771 cell line is a medullary breast‐adenocarcinoma cell line isolated from a spontaneous murine mammary tumor, and can be used to generate murine tumor implantation models. Different biological (serum or amino acid (...) deprivation), physical (elutriation, mitotic shake‐off), or chemical (colchicine, nocodazole, thymidine) treatments are widely used for cell synchronization. Of the different methods tested, the double thymidine block is the most efficient for synchronization of murine EO771 cells if a large quantity of highly synchronized cells is recommended to study functional and biochemical events occurring in specific points of cell cycle progression. (shrink)

Cell cycle arrest in M phase can be induced by the failure of a single chromosome to attach properly to the mitotic spindle. The same cell cycle checkpoint mediates M phase arrest when cells are treated with drugs that either disrupt or hyperstabilize spindle microtubules. Study of yeast mutants that fail to arrest in the presence of microtubule disruptors identified a set of genes important in this checkpoint pathway. Two recent papers report the cloning of human (...) and Xenopus homologues of one of these yeast genes, called MAD2 (for mitotic arrest deficient‐2)(1,2). Introduction of antibodies to the MAD2 protein into living mammalian cells or Xenopus egg extracts abrogates the M phase arrest induced by microtubule inhibitors. This and other recent developments suggest a model for the M phase checkpoint in which unattached kinetochores inhibit the ubiquitination of proteins whose proteolysis is necessary for chromatid separation and exit from mitosis. (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult (...) to study at a mechanistic level. We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Cyclin‐dependent kinases are Ser/Thr protein kinases best known for their cell cycle roles, where CDK1 triggers mitotic onset in all eukaryotes. CDKs are also involved in various other cellular processes, some of which, such as transcription and centrosome duplication, are coupled to cell cycle progression. A new study suggests that the mitotic CDK network is active at low levels in non‐dividing, differentiating precursors of multiciliated cells, and that it drives ciliogenesis. Manipulating the activity of CDK1 or (...) PLK1 altered transitions between the amplification, growth, and disengagement phases, in a manner analogous to the control of passage through different phases of mitosis. How the dynamics of the mitotic kinase network are controlled in these post‐mitotic cells, and whether other cell cycle regulators are also involved, remains unknown. In the present mini‐review we suggest that the redeployment of cell cycle regulators to control steps of differentiation in non‐dividing cells might be a more general, hitherto under‐recognized, feature of cell regulation. (shrink)

Significant strides have been made in recent years towards understanding the molecular basis of cell cycle progression in the model bacterium Caulobacter crescentus. At the heart of cell cycle regulation is a multicomponent transcriptional feedback loop, governing the production of successive regulatory waves or pulses of at least three master regulatory proteins. These oscillating master regulators direct the execution of phase‐specific events and, importantly, through intrinsic genetic switches not only determine the length of a given phase, (...) but also provide the driving force that catapults the cell into the next stage of the cell cycle. The genetic switches act as fail safe mechanisms that prevent the cell cycle from relapsing and thus govern the ordered production and the periodicity of these regulatory waves. Here, we detail how the master regulators CtrA, GcrA and DnaA coordinate cell cycle progression and polar development in Caulobacter. BioEssays 28: 355–361, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In nature, cells face a variety of stresses that cause physical damage to the plasma membrane and cell wall. It is well established that evolutionarily conserved cell cycle checkpoints monitor various cellular perturbations, including DNA damage and spindle misalignment. However, the ability of these cell cycle checkpoints to sense a damaged plasma membrane/cell wall is poorly understood. To the best of our knowledge, our recent paper described the first example of such a checkpoint, using (...) budding yeast as a model. In this review, we will discuss this important question as well as provide hypothetical explanations to be tested in the future. (shrink)

Kv10.1 is a voltage‐gated potassium channel relevant for tumor biology, but the underlying mechanism is still unclear. We propose that Kv10.1 plays a role coordinating primary cilium disassembly with cell cycle progression through localized changes of membrane potential at the ciliary base. Most non‐dividing cells display a primary cilium, an antenna‐like structure important for cell physiology. The cilium is disassembled when the cell divides, which requires an increase of Ca2+ concentration and a redistribution of phospholipids in (...) its basal region, both of which would be facilitated by local hyperpolarization. Cells lacking Kv10.1 show impaired ciliary disassembly and delayed entrance into mitosis. Kv10.1 is predominantly expressed during G2/M, a critical period for ciliary resorption, and localizes to the ciliary base and vesicles associated with the centrosome. This could explain the influence of Kv10.1 in cell proliferation, as well as phenotypic features of patients carrying gain of function mutations in the gene. (shrink)

Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also its mass. Numerous studies in cells ranging from yeast to mammals have shown that cellular growth, stimulated by nutrients and/or growth factor signaling, is a prerequisite for cell cycle progression in most types of cells. The textbook view of growth‐regulated cell cycles is that growth signaling activates the transcription of G1 Cyclin genes to induce cell proliferation, and also (...) stimulates anabolic metabolism and cell growth in parallel. However, genetic knockout tests in model organisms indicate that this is not the whole story, and new studies show that additional, “smarter” mechanisms help to coordinate the cell cycle with growth itself. Here we summarize recent advances in this field, and discuss current models in which growth signaling regulates cell proliferation by targeting core cell cycle regulators via non‐transcriptional mechanisms. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell (...) division are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Major events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological (...) properties of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Receptor tyrosine kinases and integrins are activated by growth factors and extracellular matrix, respectively. Their activation leads to signal transduction cascades that control many aspects of cell phenotype, including progression through the G1 phase of the cell cycle. However, the signalling cassettes driven by growth factors and matrix do not work independently of each other. Integrin triggering is essential to facilitate kinase‐ and GTPase‐mediated signals and thereby drive efficient transfer of information through the growth factor–cyclin axis. A (...) recent study indicates that an additional type of player has a key role in adhesion‐regulated control of cell cycle, namely ubiquitin ligase.(1) BioEssays 24:17–21, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The relationships between oncogenes, cell‐cycle control genes, and growth‐related genes are described. An important generalization from the data is that all the oncogenes and cell‐cycle control genes so far characterized appear to be genes for growth factors or for receptors to growth factors, or to be involved in the general metabolism and structure of the cell. It is suggested that the transition in cell growth from quiescence to the proliferative state, in early G1, may (...) be less specific than previously thought and involve a general priming of the cells for more specific later stimuli. (shrink)

An elementary semistochastic model for cell cycle analysis is presented. Various independently generated experimental data sets are compared with the theory in which for the first time, a consistent consideration of non-proliferating cells has also been taken into account.

An elementary semistochastic model for cell cycle analysis is presented. Various independently generated experimental data sets are compared with the theory in which for the first time, a consistent consideration of non-proliferating cells has also been taken into account.

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the N‐terminal domain suppresses (...) this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation. (shrink)

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational (...) repair processes. S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNR expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression genes, SSN6 and TUP1. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility of RNR1, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage. (shrink)

The transcriptional profile of the entire Caulobacter crescentus genome over a synchronous cell cycle was recently described.(1) The analysis reveals a stunning 553 cell-cycle-regulated genes or orfs, nearly 19% of the genome, including putative functions in virtually all biological activities. Over a quarter of these genes/orfs respond to the Caulobacter master regulator, CtrA, most of them apparently indirectly. The analysis confirms and extends earlier observations showing that many proteins involved in cell cycle functions are (...) expressed at the cell age when they are needed. Conversely, the data suggest that proteins specifically expressed at a particular age may be involved in a process taking place then. BioEssays 23:563–565, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In early embryonic development, the cell cycle is paced by a biochemical oscillator involving cyclins and cyclin-dependent kinases (cdks). Essentially the same machinery operates in all eukaryotic cells, although after the first few divisions various braking mechanisms (the so-called checkpoints) become significant. Haase and Reed have recently shown that yeast cells have a second, independent oscillator which coordinates some of the events of the G1 phase of the cell cycle.(1) Although the biochemical nature of this oscillator (...) is not known,it seems unlikely to be a redundant cyclin/cdk system. BioEssays 22:3–5, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Graphical AbstractRecent evidence indicates that branched actin might control cell progression through G1 in addition to lamellipodium protrusion.

We describe a recent approach for distinguishing between stochastic and deterministic sources of variability, focusing on the mammalian cell cycle. Variability between cells is often attributed to stochastic noise, although it may be generated by deterministic components. Interestingly, lineage information can be used to distinguish between variability and determinism. Analysis of correlations within a lineage of the mammalian cell cycle duration revealed its deterministic nature. Here, we discuss the sources of such variability and the possibility that (...) the underlying deterministic process is due to the circadian clock. Finally, we discuss the “kicked cell cycle” model and its implication on the study of the cell cycle in healthy and cancerous tissues. (shrink)

The Cell Cycle Ontology (CCO) has the aim to provide a 'one stop shop' for scientists interested in the biology of the cell cycle that would like to ask questions from a molecular and/or systems perspective: what are the genes, proteins, and so on involved in the regulation of cell division? How do they interact to produce the effects observed in the regulation of the cell cycle? To answer these questions, the CCO must (...) integrate a large amount of knowledge from diverse sources; the irregularity and incompleteness of this information suggests an ontology can act as the means of this integration. The volatility and continued expansion of biological knowledge means the content and modelling of the CCO will have to be frequently changed and updated. The CCO is generated from the input data automatically once every two months. This makes it easy to change the representation to enable certain queries; incorporate new knowledge; and consistently apply design patterns across the CCO. The automatic process also allows the CCO to be delivered in a variety of representations that suit the needs of various CCO customers and the abilities of existing toolsets. In this paper we present the CCO and its characteristics of utility and flexibility, that, from our perspective, make it a beautiful ontology. (shrink)

Passage through the cell cycle requires the successive activation of different cyclin‐dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the (...) profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation‐related diseases. (shrink)

Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK‐mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to (...) have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton. (shrink)

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; (i) acetylations of lysines; (ii) phosphorylations of serines and threonines and (iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well‐defined very basic N‐ and (...) C‐ terminal domains of histones. Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C‐terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle. (shrink)

Under certain conditions, the cell cycle can be arrested for a long period of time. Vertebrate oocytes are arrested at G2 phase, while somatic cells arrest at G0 phase. In both cells, nuclei have lost the ability to initiate DNA synthesis. In a pair of recently published papers,1,2 Méchali and colleagues and Coué and colleagues have clarified how frog oocytes prevent untimely DNA synthesis during the long G2 arrest. Intriguingly, they found only Cdc6 is responsible for the inability (...) of immature oocytes to replicate DNA. Cdc6 is a key component for replication licensing, and for G0 cells to re‐enter the proliferative stage. Strikingly similar strategies for preventing the untimely replication in both cells suggest that the suppression of replication licensing is a universal mechanism for securing the prolonged arrest of the cell cycle. BioEssays 25:313–316, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The three cycles of cell division immediately following theformation of the cellular blastoderm during Drosophila embryogenesis display an invariant pattern(1,2). Bursts of transcription of a gene called string are required and sufficient to trigger mitosis at this time during development(3). The activator of mitosis encoded by the string gene is a positive regulator of cdc2 kinase and a Drosophila homologue of the Saccharomyces pombe cdc25 tyrosine phosphatase(4,5). Evidence presented in a recent paper(6) demonstrates that transcription of string, and hence (...) the timing and pattern of mitosis in the postblastoderm embryo, is under complex developmental control. Several lines of evidence support this interpretation, including the analysis of string transcription in pattern formation mutants, cell cycle arrest mutants, and the preliminary characterization of an extensive cis‐acting regulatory region. (shrink)

Estimation of the repartition of asynchronous cells in the cell cycle can be explained by two hypotheses:– - the cells are supposed to be distributed into three groups: cells with a 2c DNA content (G0/1 phase), cells with a 4c DNA content (G2+M phase) and cells with a DNA content ranging from 2c to 4c (S phase); – - there is a linear relationship between the amount of fluorescence emitted by the fluorescent probe which reveals the DNA and (...) the DNA content. According to these hypotheses, the cell cycle can be represented by the following equation. (shrink)

Tetrahymena has been used as a model cell system in many studies of morphogenesis, conjugation, gene mapping, cell division and growth kinetics. In this article, we consider some advances which have resulted from the successful development of a chemically defined medium (CDM), and how subsequent work has extended the contribution that this organism has made to our understanding of different aspects of growth, nutrition, cell cycle control, cytokinesis and intercellular signalling. Finally, we discuss the considerable potential (...) that has arisen for the biotechnological exploitation of this big and rapidly growing eukaryotic cell. (shrink)

Numerous clinical, epidemiological and molecular findings link some types of Human Papillomaviruses (HPV) with cancer of the genital tract. They share a common pathway of transformation with a number of DNA tumour viruses, such as Adenovirus and SV40. Although all these viruses are termed ‘DNA tumour viruses’ and have similar in vitro transforming activities, Human Papillomavirus is the only one so far clearly involved in human cancer. Extensive studies on HPV E6 and E7 proteins have demonstrated their involvement in malignant (...) transformation. E6 and E7 bind the products of tumour suppressor genes, p53 and Rb1, respectively, modifying or inactivating their normal functions. The Rb1 and p53 genes are deleted or mutated in several cancers and both proteins regulate the transcription of genes involved in cell cycle progression control. The E6/p53 and E7/Rb1 interactions result in a deregulation of the cell cycle with loss of control of crucial cellular events, such as DNA replication, DNA repair and apoptosis. (shrink)

The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild‐type p53, as it is not observed in cells lacking functionally wild‐type protein, and at least some component of S phase and G2/M arrests is also thought to be p53‐dependent. p53 functions as a transcription (...) factor which binds specific DNA sequences, and recently major downstream targets have been identified, including p21Cip1 an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase δ auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle. (shrink)

Growth factors and the extracellular matrix provide the environmental cues that control the proliferation of most cell types. The binding of growth factors and matrix proteins to receptor tyrosine kinases and integrins, respectively, regulates several cytoplasmic signal transduction cascades, among which activation of the mitogen-activated protein kinase cascade, ras → Raf → MEK → ERK, is perhaps the best characterized. Curiously, ERK activation has been associated with both stimulation and inhibition of cell proliferation. In this review, we summarize (...) recent studies that connect ERK signaling to G1 phase cell cycle control and suggest that the cellular response to an ERK signal depends on both ERK signal intensity and duration. We also discuss studies showing that receptor tyrosine kinases and integrins differentially regulate the ERK signal in G1 phase. BioEssays 22:818–826, 2000. © 2000 John Wiley & Sons, Inc. (shrink)