Regulation of cell division and malignant transformation

The problem of regulation of cell division is essentially a problem of understanding regulation of transition from the resting state of a cell to the dividing state and vice versa. In malignancy the ability to revert back to a normal resting state is impaired. A model is presented which attempts to explain the control of the above transitions through control of uptake of essential nutrients by a transport-inhibitory protein. Experimental evidence in favour of the model is given.     

Progression of spontaneous malignant transformation of epithelial rat liver cell lines

Cultured epithelial cell lines from normal rat livers were shown to undergo gradual transformation and malignancy which increased with time. Morphological changes appeared both before and after cells had attained a malignant state, as detected by agar tests. The progression of the degree of malignancy was determined by the morphological appearance of the cells, the increase in the number and size of cell colonies in soft agar, the expression of gamma glutamyl transferase (GT) and the shortening of the latency period necessary for tumor formation after transplantation to syngeneic rats of cells from sequential passages.     

A mutation of the CRUMPLED LEAF gene that encodes a protein localized in the outer envelope membrane of plastids affects the pattern of cell division, cell differentiation, and plastid division in Arabidopsis

We identified a novel mutation of a nuclear-encoded gene, designated as CRUMPLED LEAF (CRL), of Arabidopsis thaliana that affects the morphogenesis of all plant organs and division of plastids. Histological analysis revealed that planes of cell division were distorted in shoot apical meristems (SAMs), root tips, and embryos in plants that possess the crl mutation. Furthermore, we observed that differentiation patterns of cortex and endodermis cells in inflorescence stems and root endodermis cells were disturbed in the crl mutant. These results suggest that morphological abnormalities observed in the crl mutant were because of aberrant cell division and differentiation. In addition, cells of the crl mutant contained a reduced number of enlarged plastids, indicating that the division of plastids was inhibited in the crl. The CRL gene encodes a novel protein with a molecular mass of 30 kDa that is localized in the plastid envelope. The CRL protein is conserved in various plant species, including a fern, and in cyanobacteria, but not in other organisms. These data suggest that the CRL protein is required for plastid division, and it also plays an important role in cell differentiation and the regulation of the cell division plane in plants. A possible function of the CRL protein is discussed.     

The surface membrane as a regulator of animal cell division

Summary The surface membrane of an animal cell is proposed to be the target for regulation of cell division. It undergoes regular periodic changes during the cell division cycle. Interference with these changes by cell-cell surface contacts is proposed to prevent the normal progression of events, and thereby can change the metabolic pattern so as to put the cells into a resting state. Through external influences, cells can escape from this resting state; when this occurs surface changes are the earliest ones observed. Cells that have become malignant, particularly after virus infection, show marked changes in their surface properties. Infection is proposed to prevent the surface changes that lead to the resting state. Recent evidence from in vitro experiments is summarized, and some speculations are made on the connection between the surface and processes of division such as nuclear replication. Presented in the Symposium on Regulation in Tumor Cells at the 22nd Annual Meeting of the Tissue Culture Association. Lake Placid, New York. This work was supported by Public Health Service Grant CA-A1-1195 and Grant E-555 from the American Cancer Society.     

Mechanokinetic model of cell membrane: theoretical analysis of plasmalemma homeostasis, growth and division

A theoretical model dealing with endocytosis, exocytosis and caveolae invagination, describing plasmalemma homeostasis during cell growth and division, is proposed. It considers transmembrane pressure, membrane tension and mechanosensitivity of membrane processes. Membrane hydraulic conductivity and the flux of transmembrane nonvesicular transport are taken into account. The developed mathematical analysis operates with a formulated set of constitutive equations describing the mechanical state and kinetics of changes in an open dynamic membrane system. The standard version of a model with adjusted parameters was implemented, and predictions including a discussion on the effect of possible parameter modifications were presented. Computer simulations indicate big changes in the magnitude of membrane tension and elasticity, and in the number of membrane buddings in young cells and during mitosis. They also show the extent of cell growth inhibition resulting from a decrease in transmembrane transport or an increase in the exerted difference in osmotic pressure. Moreover, the simulations reveal that exocytosis regulated during mitosis may not be as important for cell growth, as sometimes presumed. Finally, practical application and possible extension of the model are discussed.     

The impact of cell division and cell enlargement on the evolution of fruit size in Pyrus pyrifolia

BACKGROUND AND AIMS: Dramatic increases in fruit size have accompanied the domestication of Pyrus pyrifolia. To evaluate the contribution of cell division and cell enlargement in the evolution of fruit size, the following study was conducted. METHODS: Three wild Pyrus and 46 cultivated Pyrus pyrifolia cultivars were selected to examine cell number/size at time of pollination and at time of fruit harvest. The period of cell division was estimated by logarithmic curve of the increasing pattern of cell number, and its correlations with maturation period and final fruit size were analysed. KEY RESULTS: Final fruit size is directly related to the number of cells produced in the period immediately following pollination. Late-maturing cultivars are larger than earlier-maturing cultivars and this is due to an extended period of cell division. CONCLUSIONS: The evolution of fruit size in P. pyrifolia has mainly resulted from shifts in the ability of cells to divide rather than to enlarge.     

Changes in the pattern of phospholipid synthesis during the induction by cytokinin of cell division in soybean suspension cultures

A method is described for preparing fully viable, cytokinin-starved soybean (Glycine max (L.) Merr. cv. Acme) cells from a suspension-culture of callus tissue. The cells respond to kinetin treatment by re-initiating cell division. We present evidence, from the pattern of incorporation of ³²P-labelled inorganic phosphate into individual phospholipids during the first hour of this response, that the synthesis of phosphatidylinositol (PI) and of phosphatidic-acid head-groups is affected within 15 min. The polyphosphoinositide phosphatidylinositol 4-phosphate, but not phosphatidylinositol 4,5-bisphosphate, was detected in the tissue. The characteristics of cytokinin-induced PI synthesis in cytokinin-starved soybean cells appear to resemble the PI response of animal cells.Abbreviations DPG diphosphatidylglycerol - PA phosphatidic acid - PC phosphatidylcholine - PE phosphatidylethanolamine - PG phosphatidylglycerol - PI phosphatidylinositol - PIP phosphatidylinositol 4-phosphate - PIP₂ phosphatidylinositol 4,5-bisphosphate - PS phosphatidylserine - Pi inorganic phosphate - TLC thin-layer chromatography     

恶性转化试验及其相关试验体系在致癌机理研究中的应用

肿瘤的发生以细胞的恶性转化为基础,本就以细胞恶性转化为基础的恶性转化试验及其相关试验体系用于致癌机理的研究近况作一综述,并分别介绍了各研究体系所揭示的结果。     

Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate

Oriented cell division is a key regulator of tissue architecture and crucial for morphogenesis and homeostasis. Balanced regulation of proliferation and differentiation is an essential property of tissues not only to drive morphogenesis but also to maintain and restore homeostasis. In many tissues orientation of cell division is coupled to the regulation of differentiation producing daughters with similar (symmetric cell division, SCD) or differential fate (asymmetric cell division, ACD). This allows the organism to generate cell lineage diversity from a small pool of stem and progenitor cells. Division orientation and/or the ratio of ACD/SCD need to be tightly controlled. Loss of orientation or an altered ratio can promote overgrowth, alter tissue architecture and induce aberrant differentiation, and have been linked to morphogenetic diseases, cancer and aging. A key requirement for oriented division is the presence of a polarity axis, which can be established through cell intrinsic and/or extrinsic signals. Polarity proteins translate such internal and external cues to drive polarization. In this review we will focus on the role of the polarity complex aPKC/Par3/Par6 in the regulation of division orientation and cell fate in different mammalian epithelia. We will compare the conserved function of this complex in mitotic spindle orientation and distribution of cell fate determinants and highlight common and differential mechanisms in which this complex is used by tissues to adapt division orientation and cell fate to the specific properties of the epithelium.     

Electron microscopy analysis of Mycobacterium tuberculosis cell division

The ultrastructure of Mycobacterium tuberculosis cells undergoing division was examined by electron microscopy. Two features of cell division were observed and are described here. First, cells are capable of undergoing a type of "snapping" postfission movement. This movement is likely due to a multi-layered cell wall in which the inner layer participates in septum formation while the outer layer ruptures first on one side. A second feature related to cell division is the ability of dividing cells to form transient branching structures.     

恶性转化试验及其相关试验体系在环境致癌因素检测中的应用

恶性转化试验及在其基础上建立起来的相关试验体系是当前用于环境致癌因素检测的主要手段,本以各种试验方法为核心,以试验中应用的靶材料为依据,从体内,体外两个方面,对现有的环境致癌因素检测方法进行了综述。     

Abscisic acid switches cell division modes of asymmetric cell division and symmetric cell division in stem cells of protonemal filaments in the moss Physcomitrium patens

Multicellular organisms regulate cell numbers and cell fate by using asymmetric cell division (ACD) and symmetric cell division (SCD) during their development and to adapt to unfavorable environmental conditions. A stem cell self-renews and generates differentiated cells. In plants, various types of cells are produced by ACD or SCD; however, the molecular mechanisms of ACD or SCD and the cell division mode switch are largely unknown. The moss Physcomitrium (Physcomitrella) patens is a suitable model to study plant stem cells due to its simple anatomy. Here, we report the cell division mode switch induced by abscisic acid (ABA) in P. patens. ABA is synthesized in response to abiotic stresses and induces round-shape cells, called brood cells, from cylindrical protonemal cells. Although two daughter cells with distinct sizes were produced by ACD in a protonemal stem cell on ABA-free media, the sizes of two daughter cells became similar with ABA treatment. Actin microfilaments were spatially localized on the apices of apical stem cells in protonemata on ABA-free media, but the polar accumulation was lost under the condition of ABA treatment. Moreover, ABA treatment conferred an identical cell fate to the daughter cells in terms of cell division activity. Collectively, the results indicate ABA may suppress the ACD characteristics but evoke SCD in cells. We also noticed that ABA-induced brood cells not only self-renewed but regenerated protonemal cells when ABA was removed from the media, suggesting that brood cells are novel stem cells that are induced by environmental signals in P. patens.     

Oncoprotein BMI‐1 induces the malignant transformation of HaCaT cells

BMI‐1 (B‐cell‐specific Moloney murine leukemia virus integration site 1), a novel oncogene, has attracted much attention in recent years for its involvement in the initiation of a variety of tumors. Recent evidence showed that BMI‐1 was highly expressed in neoplastic skin lesions. However, whether dysregulated BMI‐1 expression is causal for the transformation of skin cells remains unknown. In this study, we stably expressed BMI‐1 in a human keratinocyte cell line, HaCaT. The expression of wild‐type BMI‐1 induced the malignant transformation of HaCaT cells in vitro. More importantly, we found that expression of BMI‐1 promoted formation of squamous cell carcinomas in vivo. Furthermore, we showed that BMI‐1 expression led to the downregulation of tumore suppressors, such as p16INK4a and p14ARF, cell adhesion molecules, such as E‐Cadherin, and differentiation related factor, such as KRT6. Therefore, our findings demonstrated that dysregulated BMI‐1 could indeed lead to keratinocytes transformation and tumorigenesis, potentially through promoting cell cycle progression and increasing cell mobility. J. Cell. Biochem. 106: 16–24, 2009. © 2008 Wiley‐Liss, Inc.     

The structure of FtsZ filaments in vivo suggests a force-generating role in cell division

In prokaryotes, FtsZ (the filamentous temperature sensitive protein Z) is a nearly ubiquitous GTPase that localizes in a ring at the leading edge of constricting plasma membranes during cell division. Here we report electron cryotomographic reconstructions of dividing Caulobacter crescentus cells wherein individual arc-like filaments were resolved just underneath the inner membrane at constriction sites. The filaments' position, orientation, time of appearance, and resistance to A22 all suggested that they were FtsZ. Predictable changes in the number, length, and distribution of filaments in cells where the expression levels and stability of FtsZ were altered supported that conclusion. In contrast to the thick, closed-ring-like structure suggested by fluorescence light microscopy, throughout the constriction process the Z-ring was seen here to consist of just a few short (approximately 100 nm) filaments spaced erratically near the division site. Additional densities connecting filaments to the cell wall, occasional straight segments, and abrupt kinks were also seen. An 'iterative pinching' model is proposed wherein FtsZ itself generates the force that constricts the membrane in a GTP-hydrolysis-driven cycle of polymerization, membrane attachment, conformational change, depolymerization, and nucleotide exchange.     

Themes and variations in prokaryotic cell division

Perhaps the biggest single task facing a bacterial cell is to divide into daughter cells that contain the normal complement of chromosomes. Recent technical and conceptual breakthroughs in bacterial cell biology, combined with the flood of genome sequence information and the excellent genetic tools in several model systems, have shed new light on the mechanism of prokaryotic cell division. There is good evidence that in most species, a molecular machine, organized by the tubulin-like FtsZ protein, assembles at the site of division and orchestrates the splitting of the cell. The determinants that target the machine to the right place at the right time are beginning to be understood in the model systems, but it is still a mystery how the machine actually generates the constrictive force necessary for cytokinesis. Moreover, although some cell division determinants such as FtsZ are present in a broad spectrum of prokaryotic species, the lack of FtsZ in some species and different profiles of cell division proteins in different families suggests that there are diverse mechanisms for regulating cell division.     

Acetyl phosphate and the phosphorylation of OmpR are involved in the regulation of the cell division rate in Escherichia coli

Carbon sources that can be converted to acetate were added to the growth medium of Escherichia coli wild-type cells. Cells responded with an increased cell division rate. The addition of acetate also caused a decreased synthesis of flagella. Mutants in phosphotransacetylase, which are incapable of synthesizing acetyl phosphate, and mutants in the osmoregulator OmpR divided at a lower rate than did wild-type cells. The mutants did not increase their cell division rate upon the addition of serine, as observed for wild-type cells. These data are consistent with the idea that the previously described effect of serine upon the cell division rate is mediated by acetyl phosphate and phosphorylation of OmpR. Received: 23 March 1998 / Accepted: 8 May 1998     

Topology of amino-phospholipids in the red cell membrane

The red cell membrane has an asymmetric arrangement of phospholipids. The amino-phospholipids are localized primarily on the inner surface of the membrane and the choline phospholipids are localized to a large extent on the outer surface of the membrane. Evidence is presented based on the use of covalent chemical probes in sequence that the red cell membrane contains heterogeneous domains of PE and PS and that the transport systems for Pi and K⁺ are asymmetrically arranged. Certain amino groups of PE, PS, and/or protein localized on the outer membrane surface are involved in Pi transport and certain amino groups of PE, PS, and/or protein localized on the inner surface of the membrane are involved in K⁺ transport. Cross-linking studies with DFDNB show that the cross-linked PE-PE molecules are rich in plasmalogens. This suggests that clusters of plasmalogen forms of PE occur in the membrane. Both PE and PS are cross-linked to membrane protein. These PE and PS molecules contain 24–28% 16:0 and 18:0 fatty acids and 12% fatty aldehydes. PE and PS molecules are cross-linked to a spectrin-rich fraction. It is proposed that the binding of spectrin to membrane PE and PS may help anchor spectrin to the inner surface of the membrane and regulate shape changes in the cell. K⁺-valinomycin forms a complex with TNBS and converts it from a non-penetrating proble to a penetrating probe. Valinomycin enhances K⁺ leak and Pi leak in the red cells. SITS inhibits completely the valinomycin-induced Pi leak and inhibits partially the valinomycin induced K⁺ leak. Valinomycin and IAA have additive effects on Pi leak. Ouabin has no effect on basal or valino-mycin-induced Pi leak. These data suggest that Pi leak and K⁺ leak occur by separate transport systems. In summary, the amino-phospholipids in the red cell membrane are asymmetrically arranged; some occur in clusters and some are closely associated with membrane proteins. Amino-phospholipids also are believed to bind spectrin to the inner surface of the membrane and also may play a role in cation and anion leak.