Showing papers in "BioEssays in 1996"
TL;DR: Two cascades activated preferentially by the inflammatory cytokines TNF‐α and IL‐1‐β, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc, are defined.
Abstract: Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal-regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF-alpha and IL-1-beta, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the "stress activated' protein kinases (SAPKs, also termed Jun N-terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF-alpha actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells.
730 citations
TL;DR: The formation of basement membranes requires cooperation between different cell types since nidogen, for example, is usually synthesized by cells other than those exposed to the basement membranes.
Abstract: Basement membranes are thin sheets of extracellular proteins situated in close contact with cells at various locations in the body. They have a great influence on tissue compartmentalization and cellular phenotypes from early embryonic development onwards. The major constituents of all basement membranes are collagen IV and laminin, which both exist as multiple isoforms and each form a huge irregular network by self assembly. These networks are connected by nidogen, which also binds to several other components (proteoglycans, fibulins). Basement membranes are connected to cells by several receptors of the integrin family, which bind preferentially to laminins and collagen IV, and via some lectin-type interactions. The formation of basement membranes requires cooperation between different cell types since nidogen, for example, is usually synthesized by cells other than those exposed to the basement membranes. Thus many molecular interactions, of variable affinities, determine the final shape of basement membranes and their preferred subanatomical localization.
694 citations
TL;DR: Mass-produced microarrays provide a new tool for genome expression analysis that may revolutionize genetic dissection, drug discovery and human disease diagnostics.
Abstract: Advances in biochemistry, chemistry and engineering have enabled the development of a new gene expression assay. This 'chip-based' approach utilizes microscopic arrays of cDNAs printed on glass as high-density hybridization targets. Fluorescent probe mixtures derived from total cellular messenger RNA (mRNA) hybridize to cognate elements on the array, allowing accurate measurement of the expression of the corresponding genes. Array densities of > 1,000 cDNAs per cm2 enable quantitative expression monitoring of a large number of genes in a single hybridization. A two-color fluorescence detection scheme allows rapid and simultaneous differential expression analysis of independent biological samples. Mass-produced microarrays provide a new tool for genome expression analysis that may revolutionize genetic dissection, drug discovery and human disease diagnostics.
364 citations
TL;DR: A better understanding of the action of the glucocorticoid receptor is provided and opportunities for the design of steroidal compounds that could function more effectively as anti‐inflammatory drugs are offered.
Abstract: Glucocorticoid hormones are effective in controlling inflammation, but the mechanisms that confer this action are largely unknown. Recent advances in this field have shown that both positive and negative regulation of gene expression are necessary for this process. The genes whose activity are modulated in the anti-inflammatory process code for several cytokines, adhesion molecules and enzymes. Most of them do not carry a classical binding site for regulation by a glucocorticoid receptor, but have instead regulatory sequences for transcription factors such as AP-1 or NF-kappa B. This makes them unusual targets for glucocorticoid action and emphasizes the need for novel regulatory mechanisms. Recent studies describe an important contribution by protein-protein interactions, in which several domains of the receptor participate; these studies provide a better understanding of the action of the receptor and offer opportunities for the design of steroidal compounds that could function more effectively as anti-inflammatory drugs.
308 citations
TL;DR: Recent data dealing with the topographical heterogeneity of expression of these connexins in the different cardiac tissues and the unique conductance properties of the channels they form are reviewed.
Abstract: In heart, the propagation of electrical activity is mediated by intercellular channels, referred to as junctional channels, aggregated into gap junctions and localised between myocytes. These channels consist of structurally related transmembrane proteins, the connexins, three of which (CX43, CX40 and CX45) have been shown to be associated with the myocytes of mammalian heart; a fourth, CX37, was detected exclusively in endothelial cells. In this paper, we review the recent data dealing with the topographical heterogeneity of expression of these connexins in the different cardiac tissues and the unique conductance properties of the channels they form, and attempt to assess the role played by each connexin and the consequences of their multiplicity in the propagation of action potentials.
304 citations
TL;DR: The use of Pax‐6 for expression of different crystallin genes provides a new link at the developmental and transcriptional level among the diverse crystallins and may lead to new insights into their evolutionary recruitment as refractive proteins.
Abstract: The vertebrate eye lens has been used extensively as a model for developmental processes such as determination, embryonic induction, cellular differentiation, transdifferentiation and regeneration, with the crystallin genes being a prime example of developmentally controlled, tissue-preferred gene expression. Recent studies have shown that Pax-6, a transcription factor containing both a paired domain and homeodomain, is a key protein regulating lens determination and crystallin gene expression in the lens. The use of Pax-6 for expression of different crystallin genes provides a new link at the developmental and transcriptional level among the diverse crystallins and may lead to new insights into their evolutionary recruitment as refractive proteins.
291 citations
TL;DR: PH domains are discussed in detail and it is concluded that they form a versatile family of membrane binding and protein localization modules.
Abstract: Pleckstrin homology (PH) domains are a family of compact protein modules defined by sequences of roughly 100 amino acids. These domains are common in vertebrate, Drosophila, C. elegans and yeast proteins, suggesting an early origin and fundamental importance to eukaryotic biology. Many enzymes which have important regulatory functions contain PH domains, and mutant forms of several such proteins are implicated in oncogenesis and developmental disorders. Numerous recent studies show that PH domains bind various proteins and inositolphosphates. Here I discuss PH domains in detail and conclude that they form a versatile family of membrane binding and protein localization modules.
289 citations
TL;DR: This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysOSomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins.
Abstract: Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the cell surface and endocytosis, others exit the trans-Golgi network in clathrin-coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins.
284 citations
TL;DR: There is evidence that UVB irrradiation of skin can activate the expression of proteins including immunomodulating cytokines, ornithine decarboxylase and, to a limited extent, nuclear oncogene products, as well as lead to stabilisation of p53.
Abstract: Ultraviolet radiation activates the expression of a wide variety of genes, by pathways which differ between the short non-solar ultraviolet C (UVC) wavelengths, which are strongly absorbed by nucleic acids, and the long solar ultraviolet A (UVA, 320-380 nm) wavelengths, which generate active oxygen intermediates. Intermediate solar ultraviolet (UV) wavelengths in the UVB (290-320 nm) range also contain an oxidative component, but more closely resemble UVC in their gene activating properties. Short wavelength UV, in common with other extracellular stimuli including growth factors, activates signal transduction events that involve both stress- and mitogen-activated protein kinase cascades. The extrapolation of the complex modulation of gene expression that ensues to the consequences of natural UV exposure requires careful attention to the details of doses and wavelength employed in the model experiments. Nevertheless, there is evidence that UVB irradiation of skin can activate the expression of proteins including immunomodulating cytokines, ornithine decarboxylase and, to a limited extent, nuclear oncogene products, as well as lead to stabilisation of p53. Non-cytotoxic doses of UVA radiation also lead to the strong activation of several genes which would be expected to have functional relevance in vivo.
236 citations
TL;DR: There is every reason to expect trypanosomes to provide further surprises and insights into the evolution of genetic regulatory mechanisms.
Abstract: Among pathogenic micro-organisms that evade the mammalian immune responses, Trypanosoma brucei has developed the most elaborate capacity for antigenic variation. Trypanosomes branched early during eukaryotic evolution. They are characterized by many aberrations, ranging from the unusual compartmentation of metabolic pathways to the heresy of RNA editing. The ubiquitous phenomenon of glycosylphosphatidylinositol-anchoring of eukaryotic plasma membrane proteins and RNA trans-splicing (trypanosome genes contain no introns), which adds an identical leader sequence to all trypanosome mRNAs, were first defined during studies of antigenic variation. Genetic transformation of trypanosomes and the high efficiency of gene targeting provide new opportunities to investigate the regulation of antigenic variation. There is every reason to expect trypanosomes to provide further surprises and insights into the evolution of genetic regulatory mechanisms.
TL;DR: An overview of the most relevant properties of hnRNPs is presented and some emerging ideas on theiir roles are discussed.
Abstract: In eukaryotic cells, messenger RNAs are formed by extensive post-transcriptional processing of primary transcripts, assembled with a large number of proteins and processing factors in ribonucleoprotein complexes. The protein moiety of these complexes mainly constitutes a class of about 20 major polypeptides called heterogeneous nuclear ribonucleoproteins or hnRNPs. The function and the mechanism of action of hnRNPs is still not fully understood, but the identification of RNA binding domains and RNA binding specificities, and the development of new functional assays, has stimulated interest in them. In contrast to previous models that hypothesised a mere structural (histone-like) function, a more diversified and dynamic role for these proteins is now emerging. In fact, they can be viewed as a subset of the trans-acting pre-mRNA maturation factors. They might actively participate in post-transcriptional events such as regulated splicing and mRNA export. Moreover, recent data suggest an involvement of some of these proteins in molecular diseases. Here we present an overview of the most relevant properties of hnRNPs and discuss some emerging ideas on their roles.
TL;DR: The discovery of connexin mutations associated with human diseases and the study of knockout mice have illustrated the vital role of cell‐cell communication in a diverse array of tissue functions.
Abstract: Most cells communicate with their immediate neighbors through the exchange of cytosolic molecules such as ions, second messengers and small metabolites. This activity is made possible by clusters of intercellular channels called gap junctions, which connect adjacent cells. In terms of molecular architecture, intercellular channels consist of two channels, called connexons, which interact to span the plasma membranes of two adjacent cells and directly join the cytoplasm of one cell to another. Connexons are made of structural proteins named connexins, which compose a multigene family. Connexin channels participate in the regulation of signaling between developing and differentiated cell types, and recently there have been some unexpected findings. First, unique ionic- and size-selectivities are determined by each connexin; second, the establishment of intercellular communication is defined by the expression of compatible connexins; third, the discovery of connexin mutations associated with human diseases and the study of knockout mice have illustrated the vital role of cell-cell communication in a diverse array of tissue functions.
TL;DR: Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure in vitro and in vivo.
Abstract: Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure, in vitro and in vivo. Protein kinases involved in cell signaling and those activated in mitosis dynamically control spatial and temporal organization of intracellular IF phosphorylation. Thus, IF phosphorylation appears to be one of the most predominant strategies in coordinating intracellular organization of the IF network.
TL;DR: Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells, and the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate.
Abstract: The formation of DNA photoproducts by ultraviolet (UV) light is responsible for induction of mutations and development of skin cancer. To understand UV mutagenesis, it is important to know the mechanisms of formation and repair of these lesions. Cyclobutane pyrimidine dimers and (6-4)photoproducts are the two major classes of UV-induced DNA lesions. Their distribution along DNA sequences in vivo is strongly influenced by nucleosomes and other DNA binding proteins. Repair of UV photoproducts is dependent on the transcriptional status of the sequences to be repaired and on the chromatin environment. Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells. With the aid of in vitro systems, the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate. Future work will focus on the development of in vitro assays for transcription-coupled repair and repair in chromatin.
TL;DR: The kinesins arose early in eukaryotic evolution and gene duplication has allowed functional specialization to occur, resulting in a surprisingly large number of different classes of these proteins adapted for intracellular transport of vesicles and organelles, and for assembly and force generation in the meiotic and mitotic spindles.
Abstract: The cellular processes of transport, division and, possibly, early development all involve microtubule-based motors. Recent work shows that, unexpectedly, many of these cellular functions are carried out by different types of kinesin and kinesin-related motor proteins. The kinesin proteins are a large and rapidly growing family of microtubule-motor proteins that share a 340-amino-acid motor domain. Phylogenetic analysis of the conserved motor domains groups the kinesin proteins into a number of subfamilies, the members of which exhibit a common molecular organization and related functions. The kinesin proteins that belong to different subfamilies differ in their rates and polarity of movement along microtubules, and probably in the particles/organelles that they transport. The kinesins arose early in eukaryotic evolution and gene duplication has allowed functional specialization to occur, resulting in a surprisingly large number of different classes of these proteins adapted for intracellular transport of vesicles and organelles, and for assembly and force generation in the meiotic and mitotic spindles.
TL;DR: A recently developed autoregulatory senescence‐inhibition system targets cytokinin production quantitatively, spatially and temporally, and results in transgenic plants that exhibit significantly delayedsenescence without abnormalities.
Abstract: Three approaches have been used to investigate the inhibitory role of the cytokinin class of phytohormones in plant senescence: external application of cytokinins, measurement of endogenous cytokinin levels before and during senescence, and manipulation of endogenous cytokinin production in transgenic plants. In transgenic plant studies, endogenous cytokinin levels are manipulated by expression of IPT, a gene encoding isopentenyl transferase. Transgenic plants expressing IPT from a variety of promoters exhibit developmental and morphological alterations and often display retarded leaf senescence. A recently developed autoregulatory senescence-inhibition system targets cytokinin production quantitatively, spatially and temporally, and results in transgenic plants that exhibit significantly delayed senescence without abnormalities. These transgenic studies not only confirm the regulatory role of cytokinins in plant senescence, but also provide a way to manipulate senescence for potential agricultural applications.
TL;DR: This review discusses how all of these molecuar components coordinate to induce amphibian metamorphosis in a correct spatial and temporal manner.
Abstract: Amphibian metamorphosis is a post-embryonic process that systematically transforms different tissues in a tadpole Thyroid hormone plays a causative role in this complex process by inducing a cascade of gene regulation While natural metamorphosis does not occur until endogenous thyroid hormone has been synthesized, tadpoles are competent to respond to exogenous thyroid hormone shortly after hatching In addition, even though the metamorphic transitions of individual organs are all controlled by thyroid hormone, each occurs at distinct developmental stages Recent molecular studies suggest that this competence of premetamorphic tadpoles to respond to the hormone and the developmental stage-dependent regulation of tissue-specific transformations are determined in part by the levels of thyroid hormone receptors and the concentrations of cellular free thyroid hormone In addition, at least two genes, encoding a cytosolic thyroid hormone binding protein and a 5-deiodinase, respectively, are likely to be critical players in regulating cellular free thyroid hormone concentrations This review discusses how all of these molecuar components coordinate to induce amphibian metamorphosis in a correct spatial and temporal manner These studies provde us with general clues as to how and why tissues become competent to respond to hormonal signals
TL;DR: The accessibility of multiple differentiated cell lineages in mice suggests that they may provide a tool for dissecting the role of chromatin-mediated silencing in cell differentiation and tissue-specific gene expression.
Abstract: Expression of transgenes in mice, when examined with assays that can distinguish individual cells, is often found to be heterocellular, or variegated. Line-to-line variations in expression of a transgene may be due largely to differences in the proportion of cells in which it is expressed. Variegated silencing by centromeric heterochromatin is well described, but other factors may also affect transgene silencing in mice. Tandem arrays of transgenes themselves form heterochromatin, and some cell lineages may tend to silence transgenes because of extensive facultative heterochromatin in their nuclei. The cis-acting transcriptional control elements within a transgene inhibit silencing, and strain-specific differences in chromatin proteins may strongly influence the extent of variegation. The accessibility of multiple differentiated cell lineages in mice suggests that they may provide a tool for dissecting the role of chromatin-mediated silencing in cell differentiation and tissue-specific gene expression.
TL;DR: It is argued that although developmental genetic data can help identify homologous structures, they are neither necessary nor sufficient, and do not in any case justify a new definition of homology.
Abstract: The concept of homology arose from classical studies of comprative morphology, and took on a new signficance with the advent of evolutionary theory. It is currentlyl undergoing antoher metamorphosis: many developmental geneticists now dfine homology as shared patterns of gene expression. However, this ne usage conflaes difinition with criteri, and fails to recognize the meaninful asignments of homology must speify a biologcal level. We argue the although developmental genetic data can help identify homologus structures. they are niether necessary nor sufficient, and do not in any case jutify a new definition of homology.
TL;DR: It is suggested that a thermosensitive factor intervenes, directly or indirectly, in the transcriptional regulation of the aromatase gene in reptiles with temperature‐dependent sex determination.
Abstract: In many species of reptiles, sex is determined at fertilization by zygotic sex chromosome composition. In other species, including all crocodilians, most turtles and some lizards, sex is determined by temperature during the earlier stages of gonadal differentiation. The effects of exogenous estrogens, antiestrogens and aromatase inhibitors at different temperatures have unambiguously demonstrated the involvement of estrogens in sexual differentiation of the gonads. Aromatase is the enzyme that converts androgens to estrogens. Gonadal aromatase activity is well correlated with gonadal structure. It increases exponentially in differentiating ovaries, whereas it remains low in differentiating testes. Moreover, there is a high correlation between the thermosensitive periods for both ovary differentiation and increase in aromatase activity. We suggest that a thermosensitive factor intervenes, directly or indirectly, in the transcriptional regulation of the aromatase gene in reptiles with temperature-dependent sex determination.
TL;DR: Dynamin would be the first GTPase identified that acts as a structural protein with mechano‐chemical function, and a concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force.
Abstract: Dynamin is a GTPase that regulates late events in clathrin-coated vesicle formation. Our current working model suggests that dynamin is targeted to coated pits in its unoccupied or GDP-bound form, where it is initially distributed uniformly throughout the clathrin lattice. GTP/GDP exchange triggers its release from these sites and its assembly into short helices that encircle the necks of invaginated coated pits like a collar. GTP hydrolysis, which is required for vesicle detachment, presumably induces a concerted conformation change, tightening the collar. Unlike most of its GTPase cousins that serve as molecular switches, dynamin has a low affinity for GTP, a very high intrinsic rate of GTP hydrolysis and functions as a homo-oligomer. A concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force. In this case, dynamin would be the first GTPase identified that acts as a structural protein with mechano-chemical function.
TL;DR: The role of proteins in the minichromosome maintenance (MCM) family is discussed, which may hold the key to understanding how DNA is replicated once, and only once, per cell cycle.
Abstract: The regulatory mechanism which ensures that eukaryotic chromosomes replicate precisely once per cell cycle is a basic and essential cellular property of eukaryotes. This fundamental aspect of DNA replication is still poorly understood, but recent advances encourage the view that we may soon have a clearer picture of how this regulation is achieved. This review will discuss in particular the role of proteins in the minichromosome maintenance (MCM) family, which may hold the key to understanding how DNA is replicated once, and only once, per cell cycle.
TL;DR: It is proposed that lysosomes are maintained within cells by a repeated series of kiss and run, transient fusion and fission processes with the late endosome/prelysosome compartment.
Abstract: Molecules are transferred to lysosomes, the major, acid pH, digestive compartment in eukaryotic cells, by a complex series of pathways that converge at a late endosome/prelysosomal compartment. Here, we discuss the relationship between this compartment and the lysosome. We propose that lysosomes are maintained within cells by a repeated series of kiss and run, transient fusion and fission processes with the late endosome/prelysosome compartment. Directionality to these processes may be conferred by pH gradients and retrieval mechanisms. The future challenge in testing this and any other proposed hypothesis for lysosomal biogenesis will be the establishment of molecular mechanisms.
TL;DR: Evidence indicates that the neutral theory cannot explain key features of protein evolution, patterns of biased codon usage in certain species, and is likely to remain an integral part of the quest to understand molecular evolution.
Abstract: The neutral theory of molecular evolution has been instrumental in organizing our thinking about the nature of evolutionary forces shaping variation at the DNA level. More importantly, it has provided empiricists with a strong set of testable predictions and hence, a useful null hypothesis against which to test for the presence of selection. Evidence indicates that the neutral theory cannot explain key features of protein evolution nor patterns of biased codon usage in certain species. Whereas we now have a reasonable model of selection acting on synonymous changes in Drosophila, protein evolution remains poorly understood. Despite limitations in the applicability of the neutral theory, it is likely to remain an integral part of the quest to understand molecular evolution.
TL;DR: Systemin and its precursor prosystemin provide prototypes for the emerging possibilities that polypeptide hormones may have broad roles in signalling environmental stress responses, and in regulating plant growth and development as well.
Abstract: Insect and pathogen attacks activate plant defense genes within minutes in nearby cells, and within hours in leaves far distant from the sites of the predator attacks. A search for signal molecules involved in both the localized and distal signalling has resulted in the identification of an 18-amino-acid polypeptide, called systemin, that activates defense genes in leaves of tomato plants when supplied at levels as low as fmols/plant. Several lines of evidence support a role for systemin as a wound hormone. As with animal polypeptide hormones, systemin is derived from a larger precursor protein, called prosystemin, by limited proteolysis. Systemin has been shown by autoradiography to be phloemmobile and, by antisense technology, to be an essential component of the wound-inducible, systemic signal transduction system leading to the transcriptional activation of the defensive genes. A search for the receptor of systemin has led to the identification in plant plasma membranes of a systemin-binding protein. However, this protein has properties not of a receptor, but of a furin-like proteinase that cleaves systemin into smaller polypeptides. Systemin and its precursor prosystemin provide prototypes for the emerging possibilities that polypeptide hormones may have broad roles in signalling environmental stress responses, and in regulating plant growth and development as well.
TL;DR: The new findings suggest that in terms of ligand binding the FGFRs might be an even more promiscuous family of receptor tyrosine kinases than was already appreciated.
Abstract: Fibroblast growth factor receptors (FGFRs) have been implicated in many developmental and regenerative events, including axial organisation, mesodermal patterning, keratinocyte organisation and brain development. The consensus view that this reflects a role for one or other of the nine known members of the fibroblast growth factor family in these processes has recently been challenged by the suggestion that FGFRs might be directly activated by a much wider range of ligands, including heparan sulphate proteoglycans and neural cell adhesion molecules. In addition, two novel soluble ligands for FGFRs have been identified using yeast two-hybrid technology. Overall, the new findings suggest that in terms of ligand binding the FGFRs might be an even more promiscuous family of receptor tyrosine kinases than was already appreciated.
TL;DR: The evidence that TSP-1 promotes tumor progression is discussed and a hypothetical scheme for its mechanism of action is presented.
Abstract: Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
TL;DR: A reappraisal of cell signalling, taking into account the protein interactions with the membrane electrostatic profile, suggests that an electrical dimension is deeply involved in this fundamental aspect of cell biology.
Abstract: Membrane proteins possess certain features that make them susceptible to the electric fields generated at the level of the plasma membrane. A reappraisal of cell signalling, taking into account the protein interactions with the membrane electrostatic profile, suggests that an electrical dimension is deeply involved in this fundamental aspect of cell biology. At least three types of potentials can contribute to this dimension: (1) the potential across the compact layer of water adherent to membrane surfaces; this potential is affected by classical inducers of cell differentiation, like dimethylsulfoxide and hexamethylenebisacetamide; (2) the potential across the Gouy-Chapman double layer, which accounts for the effects of extracellular cations in the modulation of differentiation; and (3) the resting potential. This last potential and its governing ion currents can be exploited in localised mechanisms of cell signalling centred on the functional association of integrin receptors with ion channels.
TL;DR: This review will examine some of the current information linking adhesion receptors to control of mitogenesis and differentiation and investigates the mechanistic basis for the cooperation between anchorage signals and signals from soluble growth and differentiation factors.
Abstract: Recently it has become clear that integrins and other adhesive receptors play an important role in the control of cell growth and differentiation. In various cell types, anchorage to the extracellular matrix via integrins strongly influences the ability of the cell to respond to soluble mitogens or to differentiation factors. Thus adhesive receptors must generate signals that influence cell behavior. Some of the pathways of adhesion receptor signaling are now beginning to be worked out, but there is still much to learn. In particular, the mechanistic basis for the cooperation between anchorage signals and signals from soluble growth and differentiation factors remains ill-defined. This review will examine some of the current information linking adhesion receptors to control of mitogenesis and differentiation.