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PubMed2002

The Arabidopsis SPIKE1 gene is required for normal cell shape control and tissue development.

Regulated growth and cell shape control are fundamentally important to the function of plant cells, tissues, and organs. The signal transduction cascades that control localized growth and cell shape, however, are not known. To better understand the relationship between cytoskeletal organization, organelle positioning, and regulated vesicle transport, we conducted a forward genetic screen to identify genes that regulate cytoskeletal organization in plants. Because of the distinct requirements for microtubules and actin filaments during leaf trichome development, a trichome-based morphology screen is an efficient approach to identify genes that affect cytoplasmic organization. The seedling lethal spike1 mutant was identified based on trichome, cotyledon, and leaf-shape defects. The predicted SPIKE1 protein shares amino acid identity with a large family of adapter proteins present in humans, flies, and worms that integrate extracellular signals with cytoskeletal reorganization. Both the trichome phenotype and immunolocalization data suggest that SPIKE1 also is involved in cytoskeletal reorganization. The assembly of laterally clustered foci of microtubules and polarized growth are early events in cotyledon development, and both processes are misregulated in spike1 epidermal cells.

Amino Acid Sequence↗
PubMed1997

Changes in p53 expression can modify cell shape of ras-transformed fibroblasts and epitheliocytes.

p53 plays an important role in restriction of abnormal cell proliferation. Loss of this safeguard function induced by p53 mutations seems to be a key mechanism in oncogenesis. It cannot be excluded however, that in addition to elimination of p53-dependent checkpoints and/or apoptosis p53 mutations may cause additional effects that contribute to oncogenic transformation. In order to analyse the effects of wild-type (wt) and mutant p53 on expression of ras-induced morphological transformation we used the method of computer-assisted morphometry. The following parameters were determined: a) the area covered by the spread cells; b) dispersion and c) elongation of cell contours. The last two indices characterise cell shape. Elongation indicates the degree of bipolarity of cell contour and dispersion-the degree of its multipolarity. Transformation of Rat1 and mouse 10(3) fibroblasts by N-rasasp12 oncogene was accompanied by dramatic decrease of cell area and increase of dispersion and elongation. IAR-2 discoid epitheliocytes expressing exogenous ras oncogene transformed into polarised cells with decreased cell area. Fluorescent microscopic examination of actin cytoskeleton stained with rhodamine-phalloidin had shown that ras-induced transformation of IAR-2 cells is characterised by disappearance of circumferential actin bundle and straight fibers. Neither did we reveal actin stress-fibers in the ras-transformed Rat1 cells. Transduction of p53 cDNAs caused no significant changes in morphometric parameters of non-transformed parental Rat1, IAR-2 and 10(3) cells, but some of the p53 mutants modified cell shape of ras-transformed cells. p53-His273, unlike other tested p53 mutants (Tyr141, His194, Trp248), induced partial reversion of morphological transformation in both Rat1 fibroblasts and IAR-2 epitheliocytes. Its expression led to increase of average cell area, decrease of dispersion and elongation indices, and re-appearance of actin bundles. Exogenous wild-type p53 also caused some reversion of transformed phenotype of Rat/ras cells, but its effect was weaker than that of the p53-His273. In contrast, another p53 mutant p53-His175 was able to enhance ras-induced morphological transformation in p53-deficient murine 10(3) fibroblasts that is consistent with possible involvement of some gain of function activity of mutant p53 in modulation of cell shape. Possible pathways that might be responsible for p53-induced changes of cell morphology are discussed.

Animals↗
PubMed1994

Identification of Drosophila cytoskeletal proteins by induction of abnormal cell shape in fission yeast.

To clone metazoan genes encoding regulators of cell shape, we have developed a functional assay for proteins that affect the morphology of a simple organism, the fission yeast Schizosaccharomyces pombe. A Drosophila melanogaster cDNA library was constructed in an inducible expression vector and transformed into S. pombe. When expression of the Drosophila sequences was induced, aberrant cell shapes were found in 0.2% of the transformed colonies. Four severe phenotypes representing defects in cytokinesis and/or cell shape maintenance were examined further. Each displayed drastic and specific reorganizations of the actin cytoskeleton. Three of the cDNAs responsible for these defects appear to encode cytoskeletal components: the actin binding proteins profilin and cofilin/actin depolymerizing factor and a membrane-cytoskeleton linker of the ezrin/merlin family. These results demonstrate that a yeast phenotypic screen efficiently identifies conserved genes from more complex organisms and sheds light on their potential in vivo functions.

Actin Depolymerizing Factors↗
PubMed1987

Changes of vascular endothelial cell shape and of membrane potential in response to the ionophore A23187.

Endothelial cells lining the thoracic inferior vena cavae of guinea-pigs were depolarised by exposure in vitro to the ionophore A23187, as judged by intracellular glass microelectrodes. There was also a simultaneous rounding up of the cell, as demonstrated by electron microscopy. Both depolarisation and change of cell shape occurred in the absence of extracellular calcium ions. Prior exposure of the endothelium to verapamil prevented both the depolarisation and the change of cell shape induced by A23187. In contrast, pretreatment with indomethacin prevented the change of cell shape but not the depolarisation induced by A23187. Possible mechanisms of action of these substances on the endothelial cell are discussed.

Animals↗
PubMed2004

Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation.

1. During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H(4) but not H(3) receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2. Histamine (0.01-30 microm) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 microm histamine with EC(50) at 19 nm. After 60 min incubation with 1 microm histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 microm) also enhanced the eosinophil shape change induced by other chemokines. 3. Histamine-induced eosinophil shape change was mediated by the H(4) receptor. This effect was completely inhibited by H(4) receptor-specific antagonist JNJ 7777120 (IC(50) 0.3 microm) and H(3)/H(4) receptor antagonist thioperamide (IC(50) 1.4 microm), but not by selective H(1), H(2) or H(3) receptor antagonists. H(4) receptor agonists imetit (EC(50) 25 nm) and clobenpropit (EC(50) 72 nm) could mimic histamine effect in inducing eosinophil shape change. 4. Histamine (0.01-100 microm) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. This effect was mediated by the H(4) receptor and could be blocked by H(4) receptor antagonists JNJ 7777120 and thioperamide. 5. Histamine (0.01-10 microm) induced eosinophil chemotaxis with an EC(50) of 83 nm. This effect was mediated by the H(4) receptor and could be blocked by H(4) receptor antagonists JNJ 7777120 (IC(50) 86 nm) and thioperamide (IC(50) 519 nm). Histamine (0.5 microm) also enhanced the eosinophil shape change induced by other chemokines. 6. In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H(4) receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H(4) receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H(4) receptor antagonists.

Cell Adhesion Molecules↗
PubMed1995

Substratum surface topography alters cell shape and regulates fibronectin mRNA level, mRNA stability, secretion and assembly in human fibroblasts.

The regulation of cell shape, fibronectin mRNA level, secretion and assembly by substratum surface topography was investigated in early passage human gingival fibroblasts cultured on titanium-coated smooth or V-shaped grooved substrata produced by micromachining. Cells on grooved surfaces were significantly elongated and orientated along the grooves of the substratum, while cell height, measured using confocal scanning laser microscopy, was approximately 1.5-fold greater than that of cells on smooth surfaces. Northern hybridization analysis revealed that on a per cell basis the grooved surface increased the amounts of fibronectin mRNA/cell approximately 3.5-fold at 16 hours, approximately 1.9-fold at 40 hours and approximately 2.2-fold at 90 hours, while the mRNA levels of the house-keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPD) were constant. The amounts of secreted fibronectin on the grooved surface were increased approximately 2-fold for all time points. The stability of fibronectin mRNA was also altered by substratum surface topography. The half-life of fibronectin mRNA on smooth surfaces was estimated to be approximately 5 hours, but on the grooved surfaces the half-life of fibronectin mRNA showed a two-phase response: a rapid 60% reduction in the first half-life (t1/2 approximately 2 hours) and a 2.4-fold increase in the second half-life (t1/2 approximately 12 hours) relative to that observed on the smooth surface. The GAPD mRNA half-lives were essentially unaffected by the surface topography of the substrata. The grooved surface was also found to alter the amount of fibronectin assembled into the extracellular matrix, producing a approximately 2-fold increase in the cultures at all time points. It thus appears that substratum surface topography alters cell shape and modulates fibronectin at the transcriptional and post-transcriptional levels, as well as the amount of fibronectin assembled into extracellular matrix. Micromachining, which has the ability to precisely control surface topography over a wide range of dimensions and shapes, appears to be a useful technique in investigating the relationship between cell shape and function.

Adult↗
PubMed2005

Bacterial cell shape.

Bacterial species have long been classified on the basis of their characteristic cell shapes. Despite intensive research, the molecular mechanisms underlying the generation and maintenance of bacterial cell shape remain largely unresolved. The field has recently taken an important step forward with the discovery that eukaryotic cytoskeletal proteins have homologues in bacteria that affect cell shape. Here, we discuss how a bacterium gains and maintains its shape, the challenges still confronting us and emerging strategies for answering difficult questions in this rapidly evolving field.

Cell Membrane↗
PubMed1985

Regulation of cell shape in Euglena gracilis. III. Involvement of stable microtubules.

The role of cytoplasmic microtubules in a recently reported biological clock-controlled rhythm in cell shape of the alga Euglena gracilis (strain Z) was examined using indirect immunofluorescence microscopy. The resulting fluorescent patterns indicated that, unlike many other cell systems, Euglena cells apparently change from round to long to round cell shape without associated cytoplasmic microtubule assembly and disassembly. Instead, the different cell shapes were correlated with microtubule patterns, which suggested that movement of stable microtubules to accomplish cell shape changes. In live intact cells, these microtubules were demonstrated by immunofluorescence to be stable to lowered temperature and elevated intracellular Ca2+ levels, treatments that are commonly used to depolymerize microtubules. In cells extracted in detergent at low temperature or in the presence of elevated Ca2+ levels, the fluorescent image of the microtubules was disrupted. Transmission electron microscopy confirmed the loss of one subset of pellicle microtubules. The difference in microtubule stability to these agents between live intact cells and cells extracted in detergent suggested the presence of a microtubule-stabilizing factor in live cells, which is released from the cell by extraction with detergent, thereby permitting microtubule depolymerization by Ca2+ or lowered temperature. The calmodulin antagonist trifluoperazine prevented the Ca2+-induced disruption of the fluorescent microtubule pattern in cells extracted in detergent. These results implied the involvement of calmodulin in the sensitivity to Ca2+ of the microtubules of cells extracted in detergent.

Animals↗
PubMed2006

Coordinated cell-shape changes control epithelial movement in zebrafish and Drosophila.

Epithelial morphogenesis depends on coordinated changes in cell shape, a process that is still poorly understood. During zebrafish epiboly and Drosophila dorsal closure, cell-shape changes at the epithelial margin are of critical importance. Here evidence is provided for a conserved mechanism of local actin and myosin 2 recruitment during theses events. It was found that during epiboly of the zebrafish embryo, the movement of the outer epithelium (enveloping layer) over the yolk cell surface involves the constriction of marginal cells. This process depends on the recruitment of actin and myosin 2 within the yolk cytoplasm along the margin of the enveloping layer. Actin and myosin 2 recruitment within the yolk cytoplasm requires the Ste20-like kinase Msn1, an orthologue of Drosophila Misshapen. Similarly, in Drosophila, actin and myosin 2 localization and cell constriction at the margin of the epidermis mediate dorsal closure and are controlled by Misshapen. Thus, this study has characterized a conserved mechanism underlying coordinated cell-shape changes during epithelial morphogenesis.

Actins↗
PubMed2004

Characterization of the nuclear deformation caused by changes in endothelial cell shape.

We investigated the mechanotransduction pathway in endothelial cells between their nucleus and adhesions to the extracellular matrix. First, we measured nuclear deformations in response to alterations of cell shape as cells detach from a flat surface. We found that the nuclear deformation appeared to be in direct and immediate response to alterations of the cell adhesion area. The nucleus was then treated as a neo-Hookean compressible material, and we estimated the stress associated with the cytoskeleton and acting on the nucleus during cell rounding. With the obtained stress field, we estimated the magnitude of the forces deforming the nucleus. Considering the initial and final components of this adhesion-cytoskeleton-nucleus force transmission pathway, we found our estimate for the internal forces acting on the nucleus to be on the same order of magnitude as previously measured traction forces, suggesting a direct mechanical link between adhesions and the nucleus.

Animals↗
PubMed2005

Molecular dissection of PINCH-1 reveals a mechanism of coupling and uncoupling of cell shape modulation and survival.

How cells couple and uncouple regulation of cellular processes such as shape change and survival is an important question in molecular cell biology. PINCH-1, a widely expressed protein consisting of five LIM domains and a C-terminal tail, is an essential focal adhesion protein with multiple functions including regulation of the integrin-linked kinase (ILK) level, cell shape, and survival signaling. We show here that the LIM1-mediated interaction with ILK regulates all these three processes. By contrast, the LIM4-mediated interaction with Nck-2, which regulates cell morphology and migration, is not required for the control of the ILK level and survival. Remarkably, a short 15-residue tail C-terminal to LIM5 is required for both cell shape modulation and survival, albeit it is not required for the control of the ILK level. The C-terminal tail not only regulates PINCH-1 localization to focal adhesions but also functions after it localizes there. These findings suggest that PINCH-1 functions as a molecular platform for coupling and uncoupling diverse cellular processes via overlapping but yet distinct domain interactions.

Adaptor Proteins, Signal Transducing↗
PubMed1994

The effect of red cell shape on the measurement of red cell volume. A proposed method for the comparative assessment of this effect among various haematology analysers.

Shape changes of abnormally deformed red cells in aperture impedance haematology analysers are known to affect MCV, MCHC and haematocrit estimation. However, different counters vary in the manifestation of this effect. We performed a comparative study among five analysers. Three of them are based on impedance without hydrodynamic focusing (Coulter STKR, Cell-Dyn3000 Abbott and K-1000 Sysmex). The other two use hydrodynamic focusing, either with impedance (NE-8000 Sysmex) or two angle laser scatter (H*1 Bayer). A novel method of analysis was applied. Two hundred and three specimens with abnormal red cells and 50 normal specimens (according to ICSH criteria) were assayed. In all samples the PCV was estimated by the reference method without correction for trapped plasma. A true MCHC value was estimated from the mean haemoglobin value and the PCV. The shape effect was assessed by three linear regressions: 1) haematocrit deviations from PCV (corrected for any calibration bias) versus true MCHC; 2) analyser MCHC vs. true MCHC; 3) MCV vs. MCH. The regressions for the analysers with hydrodynamic focusing indicated no significant shape effect. Aperture impedance analysers without focusing varied in their behaviour. The Coulter STKR and the Cell-Dyn3000 both showed strong correlation of haematocrit deviations with true MCHC, poor MCHC correlations and linear MCV-MCH regressions. The K-1000 showed minor indications of such an effect. We conclude that comparative studies are needed to quantitate red cell shape effect errors among various impedance analysers.

Bias↗
PubMed1983

Cell shape and phenotypic expression in chondrocytes.

The relationship between cell shape, proliferation, and phenotypic expression was studied in human chondrocytes. Shape was controlled independent of serum concentration, anchorage, and cell density by alteration of substratum adhesiveness with poly(2-hydroxyethyl methacrylate) (poly[HEMA]). Cells that were held rounded displayed features of the chondrocyte phenotype; i.e., they were round, proliferated slowly, incorporated low levels of [3H]thymidine into DNA, and incorporated large amounts of 35SO4 into glycosaminoglycans. In contrast, cells that were held flat were fibroblast-like: they exhibited flattened morphology, more rapid growth, greater incorporation of [3H]thymidine, and less incorporation of 35SO4. These studies suggest that cell shape may play an important role in phenotypic expression in chondrocytes.

Cartilage↗
PubMed1989

Altered cell shapes in fibroblasts treated with 5'-deoxy-5'-methylthioadenosine: relation to morphogenesis of neural cells.

In the present study, mouse 3T3 fibroblasts and primary human foreskin fibroblasts exposed to MTA (5'-deoxy-5'-methylthioadenosine) were found to achieve neural-like cell shapes and to extend long, multipolar processes rapidly and reversibly. Time lapse recordings and pharmacologic studies revealed that process formation in MTA-treated fibroblasts was mechanistically related to the rapid-onset mode of neurite formation previously characterized in neural hybrid NG108-15 cells. These data, together with evidence presented elsewhere, indicate that MTA selectively reorganizes the mode of expression of a specific cytoplasmic machinery that is active in many types of cells, and which is involved in regulating cell shape and neurite formation in developing neurons.

Adenosine↗
PubMed1977

Cell shape and hexose transport in normal and virus-transformed cells in culture.

The rate of hexose transport was compared in normal and virus-transformed cells on a monolayer and in suspension. It was shown that: 1) Both trypsin-removed cells and those suspended for an additional day in methyl cellulose had decreased rates of transport and lower available water space when compared with cells on a monolayer. Thus, cell shape affects the overall rate of hexose transport, especially at higher sugar concentrations. 2) Even in suspension, the initial transport rates remained higher in transformed cells with reference to normal cells. Scanning electron micrographs of normal and transformed chick cells revealed morphological differences only in the flat state. This indicates that the increased rate of hexose transport after transformation is not due to a difference in the shape of these cells on a monolayer.

Animals↗
PubMed1985

Reversible oxidant-induced increases in albumin transfer across cultured endothelium: alterations in cell shape and calcium homeostasis.

To determine whether reactive oxygen molecules could directly and reversibly increase the transfer of albumin across an endothelial barrier, we measured albumin transfer across monolayers of endothelium cultured on micropore filters before and after exposure to xanthine and xanthine oxidase. Xanthine and xanthine oxidase increased endothelial albumin transfer in a dose-dependent fashion. Parallel phase contrast and fluorescence microscopy demonstrated retraction of adjacent cells from one another and disruption of the actin filaments. The oxidant-induced increases in albumin transfer and changes in cell shape were reversed by removing xanthine oxidase and then incubating the monolayers for 3 1/2 hours in tissue culture media enriched with fetal bovine serum. However, incubation in tissue culture media without serum resulted in progressive injury and cell death. Hence, the brief exposure to oxidants initiated a progressive injury process that was reversed by incubation in serum. Because intracellular and extracellular calcium are important determinants of cell shape, and because some oxidized membrane lipids act as calcium ionophores, we asked whether oxidants altered endothelial calcium homeostasis. Xanthine-xanthine oxidase increased release of 45Ca++ from preloaded cells. The calcium antagonist lanthanum chloride prevented xanthine-xanthine oxidase increases in endothelial albumin transfer and prevented the changes in cell shape; chelation of extracellular calcium inhibited lysis of endothelium by xanthine-xanthine oxidase; and the calcium ionophore A23187 increased endothelial albumin transfer and mimicked the oxidant-induced changes in cell shape. Lanthanum chloride inhibited these effects of A23187. These data suggest that oxygen radicals can reversibly increase endothelial permeability to macromolecules, that this is associated with reversible changes in endothelial cell shape and actin filaments, and that the changes in cell shape are related to oxidant-induced changes in endothelial calcium homeostasis.

Animals↗
PubMed1998

Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.

BACKGROUND: The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. AIMS: To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. METHODS: Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and alpha smooth muscle actin (alpha-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and alpha-SMA. RESULTS: In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for alpha-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for alpha-SMA. At 48 hours, cells were positive for alpha-SMA. CONCLUSIONS: Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.

Animals↗
PubMed2002

Benzylamide sulindac analogues induce changes in cell shape, loss of microtubules and G(2)-M arrest in a chronic lymphocytic leukemia (CLL) cell line and apoptosis in primary CLL cells.

Given our interest in cyclic nucleotide phosphodiesterase inhibitors in chronic lymphocytic leukemia (CLL), we studied the effects of sulindac sulfone (exisulind), a non- cyclooxygenase-inhibitory end metabolite of the NSAID sulindac that has been reported to inhibit cGMP phosphodiesterases. We focused on a novel benzylamide analogue of sulindac sulfone, CP461, which is in clinical trials as a chemotherapeutic agent. As previously reported for colon carcinoma cell lines, we found that CP461 induced a rise in cGMP levels and blocked cell proliferation in the CLL cell line WSU-CLL. Surprisingly, however, cell cycle analysis revealed that CP461 caused G(2)-M arrest with an EC(50) of 1.1 micro M. G(2)-M arrest was associated with phosphorylation of Bcl2 (but not BAD, Bax, or Bcl-XL): both of these end points were abrogated by treatment with a calcium chelator. Although CP461 induces p53 up-regulation, G(2)-M arrest and Bcl2 phosphorylation were independent of p53. Because microtubule-active drugs such as vincristine also induced G(2)-M arrest and Bcl2 phosphorylation in WSU-CLL, whereas the genotoxic drugs etoposide and doxorubicin did not, we examined the effect of CP461 on microtubules by indirect immunofluoresence microscopy. CP461 eliminated microtubules rapidly, with reduction detected within 30 min of drug treatment. CP461 also induced marked changes in cell shape. Neither sulindac sulfide (a cyclooxygenase inhibitor) nor sulindac sulfone induced G(2)-M arrest, Bcl2 phosphorylation, microtubule disassembly, or cell shape changes. Treatment with 30 micro M CP461 induced greater than 50% apoptosis in 10 of 10 primary CLL leukemic cell samples, whereas the same drug concentration had only marginal effects (14% apoptosis) on whole mononuclear cells. Our work demonstrates that addition of a benzylamide moiety to sulindac compounds results in markedly altered pharmacological properties that may be of use in the therapy of lymphoid malignancies.

Antineoplastic Agents↗