Mitotic regulation of the anaphase-promoting complex

Orderly progression through mitosis is regulated by the anaphase-promoting complex/cyclosome (APC/C), a large multiprotein E3 ubiquitin ligase that targets key mitotic regulators for destruction by the proteasome. APC/C has two activating subunits, Cdc20 and Cdh1. The well-established view is that Cdc20 activates APC/C from the onset of mitosis through the metaphase-anaphase transition, and that Cdh1 does so from anaphase through G1. Recent work, however, indicates that Cdh1 also activates APC/C in early mitosis and that this APC/C pool targets the anaphase inhibitor securin. To prevent premature degradation of securin, the nuclear transport factors Nup98 and Rae1 associate with APC/C^Cdh1-securin complexes. In late metaphase, when all kinetochores are attached to spindle microtubules and the spindle assembly checkpoint is satisfied, Nup98 and Rae1 are released from these complexes, thereby allowing for prompt ubiquitination of securin by APC/C^Cdh1. This, and other mechanisms by which the catalytic activity of APC/C is tightly regulated to ensure proper timing of degradation of each of its mitotic substrates, are highlighted. Received 8 October 2006; received after revision 24 November 2006; accepted 8 January 2007     

Timing of mitosis in Physarum polycephalum: effects of agents affecting cyclic AMP concentrations.

Cultures of Physarum polycephalum incubated with caffeine or theophylline for over 100 min prior to mitosis exhibited mitotic delay proportional to the time of treatment before 100 min. Starved cultures exhibited mitotic delay at times of starvation longer than 180 min and slight stimulation from 100-180 min. Dibutyryl cAMP appeared to accelerate reconstruction of the nucleus following mitosis.     

Mitotic inhibition of clathrin-mediated endocytosis

Endocytosis and mitosis are fundamental processes in a cell’s life. Nearly 50 years of research suggest that these processes are linked and that endocytosis is shut down as cells undergo the early stages of mitosis. Precisely how this occurs at the molecular level is an open question. In this review, we summarize the early work characterizing the inhibition of clathrin-mediated endocytosis and discuss recent challenges to this established concept. We also set out four proposed mechanisms for the inhibition: mitotic phosphorylation of endocytic proteins, altered membrane tension, moonlighting of endocytic proteins, and a mitotic spindle-dependent mechanism. Finally, we speculate on the functional consequences of endocytic shutdown during mitosis and where an understanding of the mechanism of inhibition will lead us in the future.     

Timing of mitosis in Physarum polycephalum: Effects of agents affecting cyclic AMP concentrations

Summary Cultures ofPhysarum polycephalum incubated with caffeine or theophylline for over 100 min prior to mitosis exhibited mitotic delay proportional to the time of treatment before 100 min. Starved cultures exhibited mitotic delay at times of starvation longer than 180 min and slight stimulation from 100–180 min. Dibutyryl cAMP appeared to accelerate reconstruction of the nucleus following mitosis.Acknowledgments. The authors wish to express their appreciation to Dr. Volker Vogt and Dr. Richard Threlfall for helpful discussions, to Kathryn Behrens for able technical assistance and to the European Molecular Biology Organization for a short-term fellowship to J. R. T. during the course of this work. Supported by grant 3.501.75 of the Swiss National Science Foundation.     

Melatonin antagonizes colchicine-induced mitotic arrest.

Melatonin, in concentrations up to 10(-3) M, showed no effect on mitosis in cultures of HeLa or KB cells. However, when melatonin at 10(-4) M was preincubated with HeLa cells prior to addition of 10(-7) M colchicine, a reduction in the mitotic index, in comparison to colchicine alone, was observed.     

The antimitotic activities of some benzodiazepines

Summary Among 9 benzodiazepines, tested on the proliferation of synchronously dividing flagellate cells, only diazepam and medazepam can induce an accumulation of abnormal mitotic figures after 24 h of treatment. It seems that there is not a direct relation between the activity of benzodiazepines on the central nervous system and their ability to inhibit mitosis.     

The antimitotic activities of some benzodiazepines

Among 9 benzodiazepines, tested on the proliferation of synchronously dividing flagellate cells, only diazepam and medazepam can induce an accumulation of abnormal mitotic figures after 24 h of treatment. It seems that there is not a direct relation between the activity of benzodiazepines on the central nervous system and their ability to inhibit mitosis.     

Heparin effects on cultured mammalian cells.

Plasmacytoma cells exposed to heparin exhibited zeiotic blebs in the G1 phase, S phase, and early G2 phase. Zeiosis was not seen in mitotic cells. This heparin effect was reversible. Also fibroblasts were sensitive to heparin. After trypsinization of fibroblasts, heparin produced large non-reversible zeiotic blebs in the cells, except in those in mitosis. The primary target for heparin is apparently to be sought among components of the cellular periphery.     

Spatial control of mitosis by the GTPase Ran

Mitosis is the most potentially dangerous event in the life of a cell, during which the cell genetic identity is transmitted to daughters; errors at this stage may yield aneuploid cells that can initiate a genetically unstable clone. The small GTPase Ran is the central element of a conserved signaling network that has a prominent role in mitotic regulation. Pioneering studies with amphibian oocytes indicated that Ran, in the GTP-bound form, activates factors that regulate spindle assembly and dynamics. An increasing body of data indicate higher specificity and complexity in mitotic control operated by Ran in somatic cells. Newly identified target factors of Ran operate with different specificity, and it is emerging that mitotic progression requires the precise positioning of Ran network components and effectors at specific sites of the mitotic apparatus according to a highly regulated schedule in space and time. In this review we summarize our current understanding of Ran control of mitosis and highlight the specificity of mechanisms operating in mammalian somatic cells. M. Ciciarello, R. Mangiacasale: These authors contributed equally to this work. Received 29 December 2006; received after revision 13 March 2007; accepted 29 March 2007     

Cellular events in denervated limb stumps ofAmbystoma larvae during re-innervation and subsequent regeneration

Summary Amputated, denervatedAmbystoma forelimbs undergo cellular dedifferentiation and slight resorption through 12 days post-amputation. Subsequently, as limb stumps become re-innervated, there occur mitosis, blastema formation, and regeneration. The initial increase in the mitotic index in once-denervated limb stumps is closely correlated with the presence of ingrowing nerve fibres.This work was supported by grant PCM 76-11807 from the National Science Foundation.     

Die Mitosehäufigkeit in der normalen Epidermis der Maus nach einmaliger DMSO-Einwirkung

Summary 12 h after local application of DMSO on the epidermis of the mouse, increased mitotic activity has been observed, the maximum occurring 24 h after the onset of the experiment. Subsequently a distinct reduction of the frequency of mitosis can be seen with a minimum occurring about 53 h after the beginning of experiment. The initial mean value is reached 12 h after.     

Effects of weak electromagnetic fields onPhysarum polycephalum: Mitotic delay in heterokaryons and decreased respiration

Summary Continuous exposure ofPhysarum polycephalum to a 75 Hz, 2.0 G, and 0.7 V/m electromagnetic field results in a depressed respiration rate and a lengthening of the mitotic cell cycle. If unexposedPhysarum are mixed with exposedPhysarum the onset of synchronous mitosis in the mixed culture is delayed, occurring at a time between those of the 2 parent cultures.Acknowledgment. This work was supported by the Naval Electronics Systems Command through an Office of Naval Research Contract and a grant from Parkside's Center for the Application of Computers.     

Melatonin antagonizes colchicine-induced mitotic arrest

Summary Melatonin, in concentrations up to 10^–3 M, showed no effect on mitosis in cultures of HeLa or KB cells. However, when melatonin at 10^–4 M was preincubated with HeLa cells prior to addition of 10^–7 M colchicine, a reduction in the mitotic index, in comparison to colchicine alone, was observed.This work was supported by PHS Grant No. CA 16425.     

Aurora A kinase (AURKA) in normal and pathological cell division

Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer.     

Survival and endogenous spleen colonies of irradiated mice after skin wounding and hydroxyurea treatment

Summary Wound trauma-induced survival from radiation may be related to increased mitosis in hematopoietic cells. This is supported by the cell cycle-dependent drug hydroxyurea, which 1. blocked survival of wounded mice injected 2 or 3 days after 900 rad and 2. reduced the number of endogenous CFU-s in wounded mice injected shortly before 700 rad.Supported by the Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under Research Work Unit MJ00018. Views presented in this paper are those of the authors; no endorsement by the Defense Nuclear Agency has been given or should be inferred.Research was conducted according to the principles enunciated in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Research, National Research Council.     

Cell kinetics and experimental rearrangement of daughter chromosomes at the end of mitotic division]

The action of hexamethylene-tetramine (HMT), which causes a late disorientation of the two sets of chromosomes during telophase in Allium sativum L. meristematic root cells, has not been found again, in the same material after synchronization by hydroxyurea. The explanation put forward takes into account the special feature of cells synchronized by chemical methods. Besides, the toxicity of HMT is not the same according to the stage of the cell cycle during the treatment.     

Influence de laβ-mercaptoéthylamine sur la réponse de l'intestin grêle du rat à une irradiation rœntgénienne localisée

Summary Intra-peritoneal injections of 15 mg of B-mercaptoethylamine in rats, with an average weight of 200 g, protect the small intestine against a local irradiation of 500 r on the antero-upper portion of the abdomen.This protection is proved mainly, as compared with the control, by a smaller decrease of cells still in mitosis after 12 and 24 hours and of the migrant cells in resting stage, by a greater precocity and higher quantitative value of the post-radiation normal and subnormal mitotic processes, and by variations in the mitotic formula (namely, in protected animals, a relatively high increase in the amount of metaphases).These experiments seem to prove a certain local and immediate action of the radio-protector, whose effects are not solely limited to the preparation of the generating system of the intestine for the later complete repair of the digestive epithelium.

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(Travail du Centre anticancéreux de l'Université de Liège et du Centre national belge pour l'étude de la croissance normale et pathologique).     

热压烧结ZrB2／B4C陶瓷材料的组织与性能

以B4C、C、ZrO2为主要原料,采用反应热压法制备ZrB2／B4C陶瓷材料。通过对ZrB2／B4C陶瓷材料的显微组织及力学性能的综合分析,发现第二相ZrB2含量为20wt％时,材料具有较好的综合力学性能,相对密度为99．3％,维氏硬度为36．1GPa,抗弯强度为533．3MPa,断裂韧性为6．95MPa·m^1/2,比纯B4C陶瓷材料的性能均有所提高。材料为穿晶和沿晶断裂的混合断裂模式。     

Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells

Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.