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PubMed2001

The alphaVbeta6 integrin regulates its own expression with cell crowding: implications for tumour progression.

Expression of the growth-promoting integrin alphavbeta6 in colon cancer cells induces gelatinase B secretion and activation, the inhibition of which abolishes alphavbeta6-mediated tumour cell growth within a collagen matrix. Herein, we show that high cell density selectively enhances alphavbeta6 expression in a protein kinase C (PKC)-dependent manner in preference to other beta integrin subunits, resulting in a marked increase in gelatinase B secretion as cells reach confluence. Moreover, PKC activity increases with cell confluence, and the rise in PKC activity is much greater for alphavbeta6-expressing cells than for colon cancer cells which lack alphavbeta6. We propose a self-perpetuating system of colon cancer progression in which the integrin alphavbeta6 provides a means of sustaining tumour cell proliferation. In this model, alphavbeta6 regulates its own expression via a PKC-mediated signalling pathway as tumour cells become crowded and quiescent. The alphavbeta6-mediated induction of gelatinase B secretion facilitates peri-cellular matrix degradation, which helps overcome crowding and restores cell proliferation.

Antigens, Neoplasm↗

PubMed1993

Macromolecular crowding and molecular recognition.

The effects of macromolecular crowding upon macromolecular associations in solution, and upon binding of a macromolecular ligand to a surface site, are reviewed. It is demonstrated, by means of two examples, that crowding may lead to significant alterations of biochemical or biological recognition processes at the molecular level.

Binding Sites↗

PubMedDate not supplied

Crowding and the polymerization of sickle hemoglobin.

Under physiological conditions, sickle hemoglobin, a natural mutant of human hemoglobin A with a surface hydrophobic valine in place of a negatively charged glutamic acid, polymerizes at high volume occupancy. Equilibrium solubility of sickle hemoglobin entails activity coefficients that can approach 10(3) at high concentrations. Polymerization occurs by homogeneous and heterogeneous nucleation mechanisms, which are both profoundly sensitive to crowding; homogeneous nucleation rates for example are enhanced by 10(10) when the initial concentration is augmented by 50% non-polymerizing hemoglobin. A molecular description of the reaction therefore entails substantial corrections for molecular crowding which are all very accurately described by excluded volume corrections, treating hemoglobin as a hard sphere with volume consistent with the molecular structure of the molecule, and involving no further adjustable parameters. These effects and the descriptions that rationalize this behavior are described.

Anemia, Sickle Cell↗

PubMedDate not supplied

Neutron scattering measurements of intact cells show changes after heat shock consistent with an increase in molecular crowding.

Molecular crowding has been shown to be important in many cellular processes. The crowded environment in the cell results in a significant proportion of the cellular water being in contact with macromolecules such as proteins and DNA. These interfacial water molecules show a reduced dynamic motion that has been observed with isolated macromolecules using several biophysical techniques. Previously we investigated the inelastic neutron scattering properties of water closely associated with isolated biomolecules, and showed that interfacial water is strongly perturbed, as judged by its energy transfer spectrum. Here we have probed living cells using inelastic and quasielastic neutron scattering. We have found that mild heat stress ('heat shock'), which causes some proteins to become unfolded in the cell, results in changes in the inelastic neutron scattering in the librational region (45-130 meV). Heat shock also causes a narrowing of the quasielastic scattering peak. These changes can be understood in terms of an increase in the proportion of interfacial water molecules, and a net reduction in proton dynamics.

Diffusion↗

PubMedDate not supplied

Crowding-induced organization in cells: spontaneous alignment and sorting of filaments with physiological control points.

Under sufficiently crowded conditions, elongated particles spontaneously align along a common axis and separate from particles with dissimilar packing parameters. Clarifying the relevance of these entropy-driven phenomena to intact cells has required the development of theoretical approaches that tractably take into account daunting physiological complexities including the extreme crowding of the cytosol, the complex mixture of macromolecules present, the process of filament self-assembly, and the characteristic widths, flexibilities and charges of filaments formed by different proteins. This review summarizes the approaches taken, including their validation by observations of simpler systems, and the insights that have been gained into the means by which cells can modulate and capitalize upon spontaneous ordering.

Animals↗

PubMedDate not supplied

Crowding effects in binary mixtures of rod-like and spherical particles.

Crowding effects relevant to the phase stability of binary mixtures of rod-like and spherical particles are investigated by means of Monte Carlo simulations in the isobaric NPT ensemble. The two types of particles are represented, respectively, by freely rotating hard spherocylinders of a moderate aspect ratio (L/sigma = 5) and hard spheres of the same diameter sigma. Molar fractions of spheres ranging xHS = 0.00-0.37 are considered with the aim of characterizing the crowding effects on the liquid crystal phases of the hard spherocylinder fluid induced by the spherical component as depleting agent. We find that the addition of the spherical crowder is beneficial for the stabilization of the layers of the rod-like particles characteristic of the smectic phase. On the contrary, the addition of spheres has a negative impact upon the stability of the nematic phase, where the rod-like particles tend to align collectively parallel to each other. Interestingly, the spheres tend to arrange forming rod-like clusters in the nematic phase and lamellar structures in the smectic phase, which is compensated by the entropy gained by the spherocylinder particles in each phase. The main results are in qualitative agreement with recent experimental and theoretical studies and serve to test the prediction of current equations of state for these types of binary mixtures.

Macromolecular Substances↗

PubMedDate not supplied

Chaperonin function--effects of crowding and confinement.

Chaperonins assist in the acquisition of native protein structure in the cell by providing a shielded environment for a folding polypeptide chain, generated by the interior surface of their cylindrical structure. The folding chain is isolated from the highly crowded cytoplasm, but at the same time confined within the chaperonin folding cage. Both confinement and macromolecular crowding can affect folding kinetics and yields, the modus operandi of chaperonins and their interaction with their protegés. Recent experimental data, as well as computer simulations, provide increasing evidence that the particular physico-chemical conditions prevailing in the cellular interior have to be taken into account when trying to unravel the processes of cellular protein folding.

Archaea↗

PubMedDate not supplied

Fluorescence anisotropy as a probe to study tracer proteins in crowded solutions.

Fluorescence anisotropy has been widely used to study the dynamics and interactions of biomolecules in diluted solutions. Comparable studies on single tracer macromolecules at the cellular level are now feasible because of the recent development of non-invasive fluorescence markers, like the growing family of the green fluorescence proteins (GFPs), and the advances in time-resolved fluorescence microscopy instrumentation. The interpretation of fluorescence polarization data in terms of dynamics and biological function of the macromolecular complexes in these physiological environments requires a deep understanding of the tracer rotational diffusion in such complex media. In this work we have studied the rotational diffusion of a tracer protein, apomyoglobin labeled with 1-anilino-8-naphthalene sulfonate, in crowded solutions of an unrelated protein, ribonuclease A. We have evaluated the deviation of the different tracer rotational motions from the Stokes-Einstein-Debye diffusion behavior, and its relation to the properties of the transient molecular cavities where the tracer is rotating in the fluorescence lifetime window. Finally, we have analyzed the application of fluorescence polarization methods to determine the apparent equilibrium constants of homo and hetero-associations of macromolecules in crowded conditions.

Anilino Naphthalenesulfonates↗

PubMed1994

Autocrine transforming growth factor-beta 1 and beta 2 expression is increased by cell crowding and quiescence in colon carcinoma cells.

Although a great deal is known about the cellular effects of exogenous transforming growth factor-beta (TGF-beta) treatment and the effects of various exogenous agents (including TGF-beta's themselves) on TGF-beta expression, studies of cellular controls for autocrine TGF-beta expression and function have been rare. Since exogenous TGF-beta treatment blocks progression through the cell cycle, it seemed likely that autocrine TGF-beta activity would be induced by growth states in which there was little or no cell division such as confluency or quiescence. Specific TGF-beta 1 or beta 2 neutralizing antibody treatment of a colon carcinoma cell line designated CBS showed that autocrine TGF-beta activity could be demonstrated in quiescent cells but not in preconfluent cells. Studies of kinetics of TGF-beta 1 and beta 2 mRNA levels during the establishment of quiescence revealed a significant increase of both isoforms in quiescent cells. The quiescent cells also secreted three- to fourfold and four-to fivefold higher levels of total (latent plus active) TGF-beta 1 and beta 2 protein in the conditioned media than the confluent cells and preconfluent cells, respectively. There was no detectable active form of either TGF-beta isoform in the conditioned media of preconfluent cells, whereas a significant amount of active TGF-beta 1 and beta 2 was detected in the conditioned media of quiescent cells. Quantitative RNase protection assays were developed to compare the effects of cell crowding vs quiescence on TGF-beta expression. TGF-beta 1 was primarily induced by quiescence. TGF-beta 2 was induced by both quiescence and cell crowding. Increased TGF-beta 1 mRNA levels appeared to be exclusively due to an increase in stability, while increased TGF-beta 2 mRNA levels were due to increased transcription. This growth state-related induction of TGF-beta's was also observed in two other colon carcinoma cell lines. These studies show that TGF-beta 1 and beta 2 are autocrine-negative factors which can be situationally expressed by cells as a function of their growth state. Autocrine expression of the TGF-beta's in this model system appears not to affect exponentially growing cells, but rather to function by maintaining a quiescent state and/or by blocking progression through the cell cycle.

Carcinoma↗

PubMed1995

Effects of macromolecular crowding on nuclear size.

The concentration of macromolecules inside cells is high, and the resultant crowding of cytoplasm can be expected to affect many interactions involving macromolecular assemblies. Here, we have examined the effect of solute size and concentration on nuclear volume in saponin-permeabilized macrophages. Nuclei swelled in the presence of small solutes and shrank reversibly in the presence of larger permeant solutes. Remarkably, the smallest solutes capable of shrinking the nucleus were not excluded by the pores in the nuclear envelope. Indeed, nuclei shrank in the presence of such solutes even after the nuclear envelope had been sheared mechanically or permeabilized with detergent. Nuclei extracted with 1% Triton X-100 shrank in the presence of very high concentrations of small solute molecules (30% w/v) as well as in lower concentrations of larger solutes. Consistent with a macromolecular crowding effect, changes in nuclear volume were dependent on solute size and not simply dependent on the colligative properties of solutes or the exclusion of solutes by the nuclear envelope. Solute size-dependent changes in nuclear volume were independent of the chemical nature of the solutes and of the activity of the ions in the buffer. Together, these observations indicate that high concentrations of macromolecules such as those found inside cells can influence the size of the nucleus by directly affecting nuclear structure.

Animals↗

PubMed1997

Stabilization of compact spermidine nucleoids from Escherichia coli under crowded conditions: implications for in vivo nucleoid structure.

Nucleoids from Escherichia coli were isolated in the presence of spermidine at low salt concentrations. The nucleoids denature at relatively low temperatures or salt concentrations, yielding broad slowly sedimenting zones and/or macroscopic aggregates upon sucrose gradient centrifugation. Denaturation is accompanied by a loss of a characteristically compact shape as visualized by light and electron microscopy. Addition of polyethylene glycol or dextran prevents these changes, extending the range of stability of the isolated nucleoids to temperatures and ionic conditions like those which commonly occur in vivo. The effects of the polymers are consistent with stabilization by macromolecular crowding. Enzymatic digestion of the nucleoid DNA primarily releases three small proteins (H-NS, FIS, and HU) and RNA polymerase, as well as residual lysozyme from the cell lysis procedure. If isolated nucleoids are extracted with elevated salt concentrations under crowded, stabilized conditions, two of the proteins (HU and lysozyme) are efficiently removed and the compact form of the nucleoids is retained. These extracted nucleoids maintain their compact form upon reisolation into the initial uncrowded low-salt medium, indicating that HU, the most common "histone-like" protein of E. coli, is not a necessary component for maintaining compaction in these preparations.

Bacterial Proteins↗

PubMed1997

Nucleosomes: a solution to a crowded intracellular environment?

The emergence of eukaryotes was accompanied by two major events that concern their genome and are of crucial significance when considered in terms of macromolecular crowding: (i) a substantial increase in the amount of DNA, and (ii) its confinement within a defined space. The resulting highly crowded environment would have strongly promoted DNA self-assembly processes, leading to extremely condensed and thermodynamically stable DNA aggregates. Such structural transitions have indeed been observed in vitro, as well as in virtually all cellular systems in which a nucleosomal assembly is absent. In this appear we raise the hypothesis that upon transition from prokaryotic systems to eukaryotes, the nucleosomes were rendered essential in order to negate extensive DNA condensation processes that would have resulted from excluded volume effects. By suppressing such processes, the nucleosomes act to maintain and regulate the conformational space of the DNA, thus enabling conformational flexibility and reversible structural modulations.

Animals↗

PubMed1999

Self-organized criticality in termite architecture: a role for crowding in ensuring ordered nest expansion

A cellular automaton model of the vertical and lateral growth that occurs in a termite nest expansion is formulated. The model consists of a lattice of building sites permeated by a trail network of termites. Termites are recruited from the network to build at these sites by an attractive pheromone which emanates from building pellets. The experimentally observed behaviour in which termites halt and then retreat from overcrowded sites is also incorporated along with the assumption that termites which retreat then build on nearby sites. Simulations without this response to crowding result in disordered, unrealistic nest structures, while its inclusion qualitatively reproduces two previously unexplained features of nest expansion. First, the active surface formed by joining the tips of growing pillars maintains a smooth appearance through time. Second, the model explains how building activity spreads laterally over the building domain. The competition between the attractive pheromone and inhibitory crowding stimuli drives the system to a critical state where the correlation length (distance over which building sites interact) diverges, i.e. all building sites interact with each other. An explicit mapping of a particular case of the model onto the sandpile model of self-organized criticality is exhibited. The criticality of the model determines power-law scalings of the system's dependence on the density of termites on the trail network and the size of the building domain. The model makes several experimentally testable predictions. Copyright 1999 Academic Press.

Journal Article↗

PubMed1985

Transplacental induction of myeloschisis associated with hindbrain crowding and other malformations in the central nervous system in Long-Evans rats.

Nine groups of 66 pregnant rats, grouped by gestation days 11 to 19, were subjected to a single, intragastric administration of ethylenethiourea (ETU). Cesarean section was performed on gestation day 20. No dam died following the ETU treatment, although a mortality as high as 21.2% was noted among the fetuses in this group; the remaining live fetuses were found to suffer from a high incidence of myeloschisis associated with hindbrain crowding. Exencephaly and abnormally enlarged head with occipital bossing due to the herniation of the mesencephalic tectum, with and without dilation of the mesencephalic and 4th ventricles, were induced among the fetuses of the dams given ETU at gestation days 12 and 13. Various degrees of hydranencephaly and dysplastic hydrocephalus were found among the fetuses of dams treated by ETU from gestation days 14 to 18. From the histological features of these malformations of the central nervous system (CNS), a possible mechanism in the induction of myeloschisis with hindbrain crowding induced by ETU is discussed, and compared with the previously reported similar malformations induced by trypan blue.

Abnormalities, Multiple↗

PubMed2000

Periodontal relevance of anterior crowding.

The periodontal relevance of anterior and posterior crowding concerns 3 main aspects: 1. oral hygiene/plaque retention, 2. altered topography of gingiva, septum and orofacial alveolar bone and 3. periodontal therapy (scaling, root planing, regenerative approaches). These aspects are discussed with regard to the literature and to the author's own clinical and histological findings. Present-day knowledge suggests that the following positive periodontal effects can be expected from correction of orthodontic crowding: better access for oral hygiene, improved morphology of soft and hard periodontal tissues; future research has to substantiate the value of this benefit, simplified mechanical and surgical therapy (scaling, root planing, curettage), more favorable conditions for periodontal regeneration.

Cuspid↗

PubMed2006

Task set determines the amount of crowding.

The present study deals with the question of how crowding effects, which are interactions among adjacent features or characters, emerges automatically or by so-called higher level controlled processing. Two experiments are presented comparing performances during detecting, localizing, and identifying a flanked target in same strings when the target was defined on the basis of either its form or its category. Detection and localization performances were better for form- relative to category-defined targets whereas the reverse was observed for identification performance. This shows that the interacting information is indeed high level in that it is affected by task settings like the defining target feature and the observers' task set. The results suggest that crowding effects do not emerge due to processes depending on the parameters of stimulus presentation, but due to processes activated by certain task sets.

Humans↗

PubMed2005

Fluorescence dynamics of DNA condensed by the molecular crowding agent poly(ethylene glycol).

Condensation of extended DNA into compact structures is encountered in a variety of situations, both natural and artificial. While condensation of DNA has been routinely carried out by the use of multivalent cations, cationic lipids, detergents, and polyvalent cationic polymers, the use of molecular crowding agents in condensing DNA is rather striking. In this work, we have studied the dynamics of plasmid DNA condensed in the presence of a molecular crowding agent, polyethylene glycol (PEG). Steady-state and time-resolved fluorescence of the recently established condensation-indicating DNA binder, YOYO-1 [G. Krishnamoorthy, G. Duportail, and Y. Mely (2002), Biochemistry 41, 15277-15287] was used in inferring the dynamic aspects of DNA condensates. It is shown that DNA condensed by PEG is more flexible and less compact when compared to DNA condensed by binding agents such as polyethyleneimine. The relevance of such differences in dynamics toward functional aspects of condensed DNA is discussed.

Benzoxazoles↗

PubMed1982

Crowding of the peripheral nasal isopters in glaucoma.

We studied 300 visual fields of 153 consecutive patients who had glaucoma or increased intraocular pressures. All the visual fields were plotted with the same technique on a Goldmann perimeter. Crowding of the peripheral nasal isopters was said to be present when the nasal isopter, outlined with the peripheral threshold target, was less than 55 degrees from fixation and within 5 degrees of the nasal isopter plotted with the V4e (largest, most intense) target. This finding was detected in 65 visual fields; in 12 of these it was the only abnormality. Crowding of the peripheral nasal isopters is important in the early detection of glaucoma; the V4e target, or equivalent, is useful in examining the nasal periphery in screening protocols for glaucoma.

Adolescent↗