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Trends in Biochemical Sciences Jun 2006Proteolysis mediated by the ubiquitin-proteasome system is a crucial regulatory mechanism in signal transduction cascades of temporal cellular processes such as cell... (Review)
Review
Proteolysis mediated by the ubiquitin-proteasome system is a crucial regulatory mechanism in signal transduction cascades of temporal cellular processes such as cell division. Two principal subtypes of modular ubiquitin ligase, the anaphase-promoting complex or cyclosome (APC/C) and the Skp1/Cullin-1/F-box protein complex, have emerged as essential regulators of key events in the cell cycle. The importance of these ligases is best illustrated by their roles in the checkpoint and repair pathways or in response to multiple stresses, where they affect activation of the M-phase-promoting factor or proper formation and/or maintenance of the mitotic spindle. Recent studies have considerably improved our understanding of the function of the concerted action of the phosphorylation and ubiquitin or SUMO systems in the regulation of the stability and activity of key components of the mitotic checkpoint.
Topics: Anaphase; Animals; Cell Division; Humans; Phosphorylation; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; SUMO-1 Protein; Signal Transduction; Ubiquitin
PubMed: 16647857
DOI: 10.1016/j.tibs.2006.04.001 -
Nature Communications 2012Current approaches to monitor and quantify cell division in live cells, and reliably distinguish between acytokinesis and endoreduplication, are limited and complicate...
Current approaches to monitor and quantify cell division in live cells, and reliably distinguish between acytokinesis and endoreduplication, are limited and complicate determination of stem cell pool identities. Here we overcome these limitations by generating an in vivo reporter system using the scaffolding protein anillin fused to enhanced green fluorescent protein, to provide high spatiotemporal resolution of mitotic phase. This approach visualizes cytokinesis and midbody formation as hallmarks of expansion of stem and somatic cells, and enables distinction from cell cycle variations. High-resolution microscopy in embryonic heart and brain tissues of enhanced green fluorescent protein-anillin transgenic mice allows live monitoring of cell division and quantitation of cell cycle kinetics. Analysis of cell division in hearts post injury shows that border zone cardiomyocytes in the infarct respond with increasing ploidy, but not cell division. Thus, the enhanced green fluorescent protein-anillin system enables monitoring and measurement of cell division in vivo and markedly simplifies in vitro analysis in fixed cells.
Topics: Animals; Brain; Cell Cycle; Cell Division; Contractile Proteins; Embryonic Stem Cells; Flow Cytometry; Green Fluorescent Proteins; Heart; Humans; In Vitro Techniques; Induced Pluripotent Stem Cells; Mice; Mitosis; Myocardial Infarction
PubMed: 23011130
DOI: 10.1038/ncomms2089 -
Molecular and Cellular Endocrinology Jan 2008Cell cycle regulation in Eukaryotes is based on common molecular actors and mechanisms. However, the canonical cell cycle is modified in certain cells. Such... (Review)
Review
Cell cycle regulation in Eukaryotes is based on common molecular actors and mechanisms. However, the canonical cell cycle is modified in certain cells. Such modifications play a key role in oocyte maturation and embryonic development. They can be achieved either by introduction of new components, pathways, substrates, changed interactions between them, or by elimination of some factors inherited by the cells from previous developmental stages. Here we discuss a particular temporal regulation of the first embryonic M-phase of Xenopus and mouse embryos. These two examples help to understand better the general regulation of M-phase of the cell cycle.
Topics: Animals; Cell Cycle; Cell Division; Cyclin B; Embryo, Mammalian; Embryonic Development; Extracellular Signal-Regulated MAP Kinases; Mice; Mitosis; Xenopus
PubMed: 18178304
DOI: 10.1016/j.mce.2007.11.023 -
Cell Stem Cell Oct 2012Asymmetric cell division (ACD) produces two daughter cells with distinct fates or characteristics. Many adult stem cells use ACD as a means of maintaining stem cell... (Review)
Review
Asymmetric cell division (ACD) produces two daughter cells with distinct fates or characteristics. Many adult stem cells use ACD as a means of maintaining stem cell number and thus tissue homeostasis. Here, we review recent progress on ACD, discussing conservation between stem and non-stem cell systems, molecular mechanisms, and the biological meaning of ACD.
Topics: Adult Stem Cells; Animals; Asymmetric Cell Division; Cell Communication; Cell Polarity; Homeostasis; Humans; M Phase Cell Cycle Checkpoints
PubMed: 23040475
DOI: 10.1016/j.stem.2012.09.003 -
Trends in Cell Biology Aug 2020The kinetochore is at the heart of chromosome segregation in mitosis and meiosis. Rather than a static linker complex for chromatin and spindle microtubules, it is... (Review)
Review
The kinetochore is at the heart of chromosome segregation in mitosis and meiosis. Rather than a static linker complex for chromatin and spindle microtubules, it is highly dynamic in composition, size, and shape. While known for decades that it can expand and grow a fibrous meshwork known as the corona, it was until recently unclear what constitutes this 'crown' and what its relevance is for kinetochore function. Here, we highlight recent discoveries in fibrous corona biology, and place them in the context of the processes that orchestrate high-fidelity chromosome segregation.
Topics: Animals; Chromosome Segregation; Humans; Kinetochores; M Phase Cell Cycle Checkpoints; Microtubules; Models, Biological; Signal Transduction
PubMed: 32386879
DOI: 10.1016/j.tcb.2020.04.006 -
Nature Sep 2007Fertilization induces a transient increase in cytoplasmic Ca2+ concentration in animal eggs that releases them from cell cycle arrest in the second meiotic metaphase. In...
Fertilization induces a transient increase in cytoplasmic Ca2+ concentration in animal eggs that releases them from cell cycle arrest in the second meiotic metaphase. In frog eggs, Ca2+ activates Ca2+/calmodulin-activated kinase, which inactivates cytostatic factor, allowing the anaphase-promoting factor to turn on and ubiquitinate cyclins and securin, which returns the cell cycle to interphase. Here we show that the calcium-activated protein phosphatase calcineurin is also important in this process. Calcineurin is transiently activated after adding Ca2+ to egg extracts, and inhibitors of calcineurin such as cyclosporin A (ref. 8) delay the destruction of cyclins, the global dephosphorylation of M-phase-specific phosphoproteins and the re-formation of a fully functional nuclear envelope. We found that a second wave of phosphatase activity directed at mitotic phosphoproteins appears after the spike of calcineurin activity. This activity disappeared the next time the extract entered M phase and reappeared at the end of mitosis. We surmise that inhibition of this second phosphatase activity is important in allowing cells to enter mitosis, and, conversely, that its activation is required for a timely return to interphase. Calcineurin is required to break the deep cell cycle arrest imposed by the Mos-MAP (mitogen-activated protein) kinase pathway, and we show that Fizzy/Cdc20, a key regulator of the anaphase-promoting factor, is an excellent substrate for this phosphatase.
Topics: Animals; Calcineurin; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cdc20 Proteins; Cell Cycle Proteins; Cell Division; Cell Extracts; Female; Fertilization; Meiosis; Mitosis; Nuclear Envelope; Oocytes; Phosphoric Monoester Hydrolases; Phosphorylation; Xenopus; Xenopus Proteins
PubMed: 17882219
DOI: 10.1038/nature06121 -
Oncogene Jan 2006The Rho activator ECT2 functions as a key regulator in cytokinesis. ECT2 is phosphorylated during G2/M phase, but the physiological significance of this event is not...
The Rho activator ECT2 functions as a key regulator in cytokinesis. ECT2 is phosphorylated during G2/M phase, but the physiological significance of this event is not well known. In this study, we show that phosphorylation of ECT2 at threonine-341 (T341) affects the autoregulatory mechanism of ECT2. In G2/M phase, ECT2 was phosphorylated at T341 most likely by Cyclin B/Cyclin-dependent kinase 1 (Cdk1), and then dephosphorylated before cytokinesis. Depletion of ECT2 by RNA interference (RNAi) efficiently induced multinucleate cells. Expression of the phospho-deficient mutant of ECT2 at T341 suppressed the multinucleation induced by RNAi to ECT2, indicating that ECT2 is biologically active even when it is not phosphorylated at T341. However, the phospho-mimic mutation at T341 weakly stimulates the catalytic activity of ECT2 as detected by serum response element reporter gene assays. As T341 is located at the hinge region of the N-terminal regulatory domain and C-terminal catalytic domain, phosphorylation of T341 may help accessing downstream signaling molecules to further activate ECT2. We found that the phospho-mimic mutation T341D increases binding with itself or the N-terminal half of ECT2. These results suggest a conformational change of ECT2 upon phosphorylation at T341. Therefore, ECT2 activity might be regulated by the phosphorylation status of T341. We propose that T341 phosphorylation by Cyclin B/Cdk1 could be a trigger for further activation of ECT2.
Topics: Amino Acid Sequence; Cell Division; Cells, Cultured; Cyclin B; Cytokinesis; G2 Phase; Humans; Mitosis; Molecular Sequence Data; Phosphorylation; Protein Conformation; Proto-Oncogene Proteins; RNA, Small Interfering; Threonine
PubMed: 16170345
DOI: 10.1038/sj.onc.1209078 -
Journal of Asian Natural Products... Aug 2005Six flavonoids, persicogenin (1), artemetin (2), luteolin (3), penduletin (4), vitexicarpin (5) and chrysosplenol-D (6), have been isolated for the first time as new...
Six flavonoids, persicogenin (1), artemetin (2), luteolin (3), penduletin (4), vitexicarpin (5) and chrysosplenol-D (6), have been isolated for the first time as new cell cycle inhibitors from Vitex trifolia L., a Chinese folk medicine used to treat cancers, through a bioassay-guided separation procedure. They were identified by spectroscopic methods. The inhibitory effects of 1-6 on the proliferation of mammalian cancer cells have been evaluated by the SRB (sulforhodamine B) method and their effects on cell cycle and apoptosis investigated by flow cytometry with the morphological observation under light microscope and by agarose-gel electrophoresis to detect internucleosomal DNA fragmentation. Compounds 1-6 inhibited the proliferation of mouse tsFT210 cancer cells with the IC50s (microg ml(-1)) > 100 (inhibition rate at 100 microg ml(-1), 47.9%) for 1, >100 (inhibition rate at 100 microg ml(-1), 49.6 %) for 2, 10.7 for 3, 19.8 for 4, 0.3 for 5, and 3.5 for 6. Flow cytometric investigations for 1-6 demonstrated that 1-5 mainly inhibited cell cycle at the G2/M phase in a dose-dependent manner with a weak induction of apoptosis on the tsFT210 cells, while 6 induced mainly apoptosis of the same tsFT210 cells also in a dose-dependent manner together with a weak inhibition of the cell cycle at the G0/G1 and G2/M phases, demonstrating that 1-6 exert their anti-proliferative effect on tsFT210 cells through inhibiting cell cycle and inducing apoptosis. In contrast to the cell cycle G2/M phase inhibitory main effect on tsFT210 cells, 5 induced mainly apoptosis on human myeloid leukemia K562 cells with a weak inhibition of the cell cycle at the G2/M phase. The present result provides flavonoids 1-6 as new cell cycle inhibitors and 1 and 4 as new anticancer flavonoids, which not only provide the first example of cell cycle G2/M phase inhibitory and apoptosis-inducing constituents of V. trifolia L. but also explain the use of Vitex trifolia L. by Chinese people to treat cancers.
Topics: Animals; Apoptosis; Biological Assay; Cell Culture Techniques; Cell Cycle; Cell Division; DNA Damage; Dose-Response Relationship, Drug; Flavonoids; Flow Cytometry; Mammary Neoplasms, Animal; Mice; Neoplasms; Vitex
PubMed: 16087636
DOI: 10.1080/10286020310001625085 -
PLoS Computational Biology Mar 2008Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal...
Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.
Topics: Animals; Biological Clocks; Cell Cycle Proteins; Cell Division; Circadian Rhythm; Computer Simulation; Feedback; Gene Expression Regulation; Humans; Models, Biological; Transcription Factors; Transcriptional Activation
PubMed: 18369419
DOI: 10.1371/journal.pcbi.1000019 -
Lancet (London, England) Oct 1967
Topics: Antineoplastic Agents; Cell Division; Humans; Neoplasms
PubMed: 4167862
DOI: No ID Found