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)

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)

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)

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)

Although the great majority of genes are not subject to cell‐cycle controls, those that are could play a very important role in regulation of the cell cycle itself. The tubulin and histone genes of the naturally synchronous myxomycete, Physarum polycephalum, provide an excellent paradigm for such regulation. The transcription of both is highly periodic within the Physarum cycle, and curiously, both sets of genes appear to be activated at the same time. This activation (...) appears to function as part of a developmental program, since it serves to meet future needs for each gene's product. The significance of this activation event for cell‐cycle regulation is discussed with particular regard to the nature of the mitotic oscillator. (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)

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)

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)

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)

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)

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)

Mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the tumor suppressor p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response. One posttranslational modification of p53, phosphorylation at Serine 46, selectively occurs after severe DNA damage and is envisioned as a marker of the cell (...) death response. However, the molecular mechanism of action of the p53 Ser46 phospho‐isomer, the molecular timing of this phosphorylation event, and its activating effects on apoptosis and ferroptosis still await exploration. In this essay, the current body of evidence on the molecular function of this deadly p53 mark, its evolutionary conservation, and the regulation of the key players of this response, the p53 Serine 46 kinases, are reviewed and dissected. (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)

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)

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 harmonious growth and cell‐to‐cell uniformity of steady‐state bacterial populations indicate the existence of a well‐regulated cell cycle, responding to a set of internal signals. In Escherichia coli, the key events of this cycle are the initiation of DNA replication, nucleoid segregation and the initiation of cell division. The replication initiator is the DnaA protein. In nucleoid segregation, the MukB protein, required for proper partitioning, may be a member of the myosin‐kinesin superfamily of mechanoenzymes. (...) In cell division, the FtsZ protein has a tubulin motif, is a GTPase and polymerizes in a ring around midcell during septation; the FtsA protein has an actin‐like structure. The nature of the internal signals triggering these events is not known but candidates include cell mass, the superhelical density of the chromosome and the concentration of two regulatory nucleotides, cyclic AMP and ppGpp. The involvement of cytoskeletal‐like proteins in key cycle events encourages the notion of a fundamental biological unity in cell cycle regulation in all organisms. (shrink)

Cells can change their function by rapidly modulating the levels of certain proteins at the plasma membrane. This rapid modulation is achieved by using a specialised trafficking process called constitutive cycling. The constitutive cycling of a variety of transmembrane proteins such as receptors, channels and transporters has recently been directly demonstrated in a wide range of cell types. This regulation is thought to underlie important biological phenomena such as learning and memory, gastric acid secretion and water and blood (...) glucose homeostasis. This review discusses the molecular mechanisms of constitutive cycling, its regulation by extracellular agents such as hormones and its misregulation in disease states. BioEssays 25:39–46, 2003. © 2002 Wiley Periodicals, Inc. (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 regulatory mechanism which ensures that eukaryotic chromosomes replicate precisely once per cell cycle is a basic and essential cellular property of eukaryotes. This fundamental aspect of DNA replication is still poorly understood, but recent advances encourage the view that we may soon have a clearer picture of how this regulation is achieved. This review will discuss in particular the role of proteins in the minichromosome maintenance (MCM) family, which may hold the key to understanding how DNA (...) is replicated once, and only once, per cell cycle. (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)

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)

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, (...) and epigenetic modifiers and shape their protein output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of (...) an epigenetic memory suppressing replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that (...) occur with neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (shrink)

Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission‐fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of (...) mitochondrial shape may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. (shrink)

Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin‐dependent kinase 1 (Cdk1)‐cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo‐cytoplasmic transport of critical cell cycle (...) regulators such as Cdk1‐cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo‐cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. (shrink)

This review explores the hypothesis that regulation of nucleocytoplasmic shuttling is a means of driving differentiation, using spermatogenesis as a model. The transition from undifferentiated spermatogonial stem cell to terminally differentiated spermatozoon is, at its most basic, a change in the repertoire of expressed genes. To effect this, the complement of nuclear proteins, such as transcription factors and chromatin remodelling components must change. Current knowledge of the nuclear proteins and nucleocytoplasmic transport machinery relevant to spermatogenesis is consolidated in (...) this review, and their functional linkages are highlighted not only as a means of regulating nuclear protein composition, but also as a key mechanism regulating gene transcription and hence cell fate. Through this, we hypothesize that male germ cell differentiation is mediated through regulation of nuclear transport machinery components, and thereby of the access of critical factors to the nucleus. The importance of nucleocytoplasmic trafficking to male germ cell differentiation is discussed, using the sex-determining factors Sry and SOX9, cell cycle regulators, CREM and cofactors and the Smads as specific examples, together with the roles in gametogenesis for particular nuclear transport factors in Caenorhabditis elegans and Drosophila. BioEssays 27:1011–1025, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The chromosomes undergo a condensation‐decondensation cycle within the life cycle of mammalian cells. Chromosome condensation is a complex and critical event that is necessary for the equal distribution of genetic material between the two daughter cells. Although chromosome condensation‐decondensation and segregation is mechanistically complex, it proceeds with high fidelity during the eukaryotic cell division cycle. Cell fusion studies have indicated the presence of chromosome condensation factors in mammalian cells during mitosis. If extracts from mitotic cells (...) are injected into immature oocytes of Xenopus laevis, they induce meiotic maturation (i.e. germinal vesicle breakdown and chromosome condensation) within 2–3 hours. Recently, we showed that the maturation‐promoting activity of the mitotic cell extracts is inactivated by certain protein factors present in cells during the G1 period. The activity of the G1 factors coincides with the process of chromosome decondensation that begins at telophase and continues throughout the G1 period. These studies have revealed that the mitotic factors and the G1 factors play a pivotal role in the regulation of condensation and decondensation of chromosomes. Furthermore, our studies strongly suggest that nonhistone protein phosphorylation and dephosphorylation may mediate chromosome condensation and decondensation, respectively. (shrink)

Skeletal myoblasts have their origin early in embryogenesis within specific somites. Determined myoblasts are committed to a myogenic fate; however, they only differentiate and express a muscle‐specific phenotype after they have received the appropriate environmental signals. Once proliferating myoblasts enter the differentiation programme they withdraw from the cell cycle and form post‐mitotic multinucleated myofibres (myogenesis); this transformation is accompanied by muscle‐specific gene expression. Muscle development is associated with complex and diverse protein isoform transitions, generated by differential gene expression (...) and mRNA splicing. The myofibres are in a state of dynamic adaptation in response to hormones, mechanical activity and motor innervation, which modulate differential gene expression and splicing during this functional acclimatisation. This review will focus on the profound effects of thyroid hormone on skeletal muscle, which produce alterations in gene and isoform expression, biochemical properties and morphological features that precipitate in modified contractile/mechanical characteristics. Insight into the molecular events that control these events was provided by the recent characterisation of the MyoD gene family, which encodes helix‐loop‐helix proteins; these activate muscle‐specific transcription and serve as targets for a variety of physiological stimuli. The current hypothesis on hormonal regulation of myogenesis is that thyroid hormones (1) directly regulate the myoD and contractile protein gene families, and (2) induce thyroid hormone receptor‐transcription factor interactions critical to gene expression. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research (...) on apoptosis and differentiation revealed that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

A gene's “expression profile” denotes the number of transcripts present relative to all other transcripts. The overall rate of transcript production is determined by transcription and RNA processing rates. While the speed of elongating RNA polymerase II has been characterized for many different genes and organisms, gene‐architectural features – primarily the number and length of exons and introns – have recently emerged as important regulatory players. Several new studies indicate that rapidly cycling cells constrain gene‐architecture toward short genes with a (...) few introns, allowing efficient expression during short cell cycles. In contrast, longer genes with long introns exhibit delayed expression, which can serve as timing mechanisms for patterning processes. These findings indicate that cell cycle constraints drive the evolution of gene‐architecture and shape the transcriptome of a given cell type. Furthermore, a tendency for short genes to be evolutionarily young hints at links between cellular constraints and the evolution of animal ontogeny. (shrink)

The subcellular location and function of many proteins are regulated by nuclear–cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ‐line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair (...) protein function and nuclear accumulation. BRCA1 and BARD1 shuttle between the nucleus and cytoplasm; however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1–BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications. BioEssays 27:884–893, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

As cells approach S phase, many changes occur to create an environment conducive for DNA synthesis and commitment to cell division. The transcription rate of many genes encoding enzymes involved in DNA synthesis, including the dihydrofolate reductase (dhfr) gene, increases at the G1/S boundary of the cell cycle. Although a number of transcription factors interact to finely tune the levels of dhfr RNA produced, two families of transcription factors, Sp1 and E2F, play central roles in modulating dhfr (...) levels. A region containing several Sp1‐binding sites is required for both regulated and basal transcription levels. In contrast, the E2F‐binding sites near the transcription start site are required only for regulated transcription. A model is presented for the regulation of the dhfr gene which may also pertain to other cell cycle‐associated genes. (shrink)

The finely tuned mechanisms that control cell cycle progression go awry in cancer, pointing to proto‐oncogene products as important players in cell‐cycle regulation. One such proto‐oncoprotein, c‐Src, has previously been directly implicated, based on its requirement for growth factor‐stimulated DNA synthesis. Roche et al.(1) have now shown that c‐Src or its close relatives are also required for cell division to occur. The demonstration of essential functions for the Src family at multiple points in the (...) cell cycle raises important questions about the normal and transforming activities of these and other proto‐oncoproteins. (shrink)

Zygotic gene activation (ZGA) is the critical event that governs the transition from maternal to embryonic control of development. In the mouse, ZGA occurs during the 2‐cell stage and appears to be regulated by the time following fertilization, i.e. a zygotic clock, rather than by progression through the first cell cycle. The onset of ZGA must depend on maternally inherited proteins, and post‐translational modification of these maternally derived proteins is likely to play a role in ZGA. Consistent (...) with this prediction is that protein phosphorylation catalyzed by the cAMP‐dependent protein kinase is involved in ZGA and that protein synthesis is not required for ZGA. Recent results suggest that ZGA may occur earlier than previously thought, i.e. not during the 2‐cell stage, but rather in G2 of the 1‐cell embryo. Thus ZGA may comprise a period of minor gene activation in the 1‐cell embryo that is followed by a period of major gene activation in the 2‐cell embryo. Following ZGA, the expression of constitutively activated genes may require an enhancer. (shrink)

Rho, a member of the Ras superfamily of small GTPases, has multiple biological roles: it regulates signal trasduction pathways linking extracellular growth factors to the assembly of actin stress fibres and focal adhesion complexes; it is required for G1 progression and activates the SRF transcription factor when quiescent fibroblasts are stimulated to grow; and it plays a role later in the cell cycle during cytokinesis. Two groups have recently succeeded in identifying downstream effectors of Rho that may mediate (...) some of these biological effects. One protein identified by both groups is protein kinase N (PKN), a serine/threonine kinase whose catalytic domain is closely related to that of protein kinase C(1,2). (shrink)

A large body of evidence on the activity of regulatory T (Treg) cells was gathered during the last decade, and a similar number of reviews and opinion papers attempted to integrate the experimental findings. The abundant literature clearly delineates an exciting area of research but also underlines some major controversies. A linear cause–result interpretation of experimental maneuvers often ignores the fact that the activity of Treg cells is orchestrated with the effector T (Teff) cells within an intricate network of physiological (...) immune homeostasis. Every modulation of the activity of the effector (cytotoxic) immune system revolves to affect the activity of regulatory (suppressive) cells through elaborate feedback loops of negative and positive regulation. The lack of IL‐2 production by innate Treg cells makes this cytokine a prime coupler of the effector and suppressive mechanisms. Here we attempt to integrate evidence that delineates the involvement of IL‐2 in primary and secondary feedback loops that regulate the activity of suppressive cells within the elaborate network of physiological immune homeostasis.©2007 Wiley Periodicals, Inc BioEssays 30:875–888, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Mammalian oocytes exhibit a series of cell cycle transitions that coordinate the penultimate events of meiosis with the onset of embryogenesis at fertilization. The execution of these cell cycle transitions, at G2/M of meiosis‐I and metaphase/anaphase of meiosis I and II, involve both biosynthetic and post‐translational modifications that directly modulate centrosome and microtubule behavior. Specifically, somatic cells alter the signal transduction pathways in the oocyte and influence the expression of maturation promoting factor (MPF) and cytostatic factor (...) (CSF) activity through a microtubule‐dependent mechanism. The regulation of the oocytes' cell cycle machinery by hormone‐mediated somatic cell signals, involving both positive and negative stimuli, ensures that meiotic cell cycle progression is synchronized with the earliest pivotal events of mammalian reproduction. (shrink)

Wnt signalling through β‐catenin plays a pivotal role during embryonic pattern formation, cell fate determination and tissue homeostasis in the adult organism. In the skin, as in many other tissues, Wnt/β‐catenin signalling can control lineage determination and differentiation. However, it was not known whether Wnt/β‐catenin signalling is an immediate regulator of the stem cell niche in skin tissue. A recent publication now provides evidence that Wnt/β‐catenin signalling exerts a direct effect on the stem cell compartment by inducing (...) quiescent stem cells to enter the cell cycle during early stages of hair follicle regeneration. In addition, the authors demonstrate that β‐catenin is required for maintenance of the stem cell pool in the tissue.1 The data suggest that a gradient in Wnt/β‐catenin activity levels can induce different responses within distinct cell populations reflected by activation of distinct transcriptional profiles. BioEssays 28:1–5, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Over 80% of the genes in the E. coli chromosome express fewer than a hundred copies each of their protein products per cell. It is argued here that transcription of these genes is neither constitutive nor regulated by protein factors, but rather, induced by the act of replication. The utility of such replication‐induced (RI) transcription to the temporal regulation of synthesis of determinate quantities of low copy number (LCN) proteins is described. It is suggested that RI transcription may (...) be necessitated, as well as facilitated, by the folding of the bacterial chromosome into a compact nucleoid. Mechanistic aspects of the induction of transcription by replication are discussed with respect to the modulation of transcriptional initiation by negative supercoiling effects, promoter methylation status and derepression. It is shown that RI transcription offers plausible explanations for the constancy of the C period of the E. coli cell cycle and the remarkable conservation of gene order in the chromosomes of enteric bacteria. Some experimental tests of the hypothesis are proposed. (shrink)

Three major aspects of G1 regulation acting at START in fission yeast are discussed in this review. Firstly, progression towards S phase in the mitotic cycle. This is controlled by the activation of transcription complexes at START which cause cell cycle‐dependent activation of genes required for DNA synthesis. The second aspect is the regulation of developmental fate occurring during G1. Passage through START appears to inhibit sexual differentiation because the meiotic and mitotic pathways are mutually (...) exclusive. This is brought about because the meiotic pathway is inhibited by the same gene functions that are required for S phase onset. Thirdly, distinct checkpoint, or dependency, controls operate both pre‐ and post‐START in the mitotic cycle to inhibit mitosis in the absence of replicated DNA, and also to limit rounds of DNA replication to one per cell cycle. (shrink)

Urokinase and its receptor are essential components of the cell migration machinery, providing an inducible, transient and localized cell surface proteolytic activity. This activity has been shown to be required in normal and pathological forms of cellular invasiveness (i.e. in several embryonic developmental processes, during inflammatory responses and cancer metastasis and spreading). It represents one of the best known of the protcolytic systems which are currently under investigation in this field. The urokinase receptor allows a continuous regulation (...) of the proteolytic activity at cell contacts, utilizing the different localization of urokinase and its inhibitors. The receptor, in fact, in addition to focusing the enzymatic activity at focal and cell‐cell contacts, also regulates it by internalizing and degrading only the inhibited form of urokinase. Internalized receptor releases the ligands to the lysosomes and recycles back to surface. In this way, the proteolytically active areas of the cell surface can be continuously monitored for their activity and their location modified. The cell can thus coordinate its migration efforts with a step‐wise modification of the proteolytic activity‐map of the cell surface. The urokinase cycle can be supported by one individual cell (autocrine) or by two or more cells. In the latter case, complementation and synergism of urokinase and its receptor are found. (shrink)

Understanding the impact of the p53 tumor suppressor pathway on the regulation of genome integrity, cancer development, and cancer treatment has intrigued scientists and clinicians for decades. It appears that the p53 pathway is a central node for nearly all cell stress responses, including: gene expression, DNA repair, cell cycle arrest, metabolic adjustments, apoptosis, and senescence. In the past decade, it has become increasingly clear that p53 function is directly regulated by poly(ADP‐ribose) polymerase‐1 (PARP‐1), a nuclear (...) enzyme involved in DNA repair signaling. Here, we will discuss the impact of PARP‐1 on p53 function, along with a recently described novel role for the reciprocal regulation of p53 regulated, PARP‐1 dependent necrosis following DNA damage. (shrink)

Base pair mismatches in DNA arise from errors in DNA replication, recombination, and biochemical modification of bases. Mismatches are inherently transient. They are resolved passively by DNA replication, or actively by enzymatic removal and resynthesis of one of the bases. The first step in removal is recognition of strand discontinuity by one of the MutS proteins. Mismatches arising from errors in DNA replication are repaired in favor of the base on the template strand, but other mismatches trigger base excision or (...) nucleotide excision repair (NER), or non‐repair pathways such as hypermutation, cell cycle arrest, or apoptosis. We argue that MutL homologues play a key role in determining biologic outcome by recruiting and/or activating effector proteins in response to lesion recognition by MutS. We suggest that the process is regulated by conformational changes in MutL caused by cycles of ATP binding and hydrolysis, and by physiologic changes which influence effector availability. (shrink)

Error‐free genome duplication and accurate cell division are critical for cell survival. In all three domains of life, bacteria, archaea, and eukaryotes, initiator proteins bind replication origins in an ATP‐dependent manner, play critical roles in replisome assembly, and coordinate cell‐cycle regulation. We discuss how the eukaryotic initiator, Origin recognition complex (ORC), coordinates different events during the cell cycle. We propose that ORC is the maestro driving the orchestra to coordinately perform the musical pieces (...) of replication, chromatin organization, and repair. (shrink)