Showing papers in "BioEssays in 1994"
TL;DR: The homology of the yeast vps34 with the mammalian phosphatidylinositol 3‐kinase has suggested a role for this pathway in vesicular trafficking, and the 3‐phosphoinositide pathway has been implicated in growth factor‐dependent mitogenesis, membrane ruffling and glucose uptake.
Abstract: Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol-specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the generation of two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. The 3-phosphoinositide pathway involves protein-tyrosine kinase-mediated recruitment and activation of phosphatidylinositol 3-kinase, resulting in the production of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. The 3-phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3-phosphoinositide pathway has been implicated in growth factor-dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3-kinase has suggested a role for this pathway in vesicular trafficking. In this review the different mechanisms employed by protein-tyrosine kinases to activate phosphatidylinositol 3-kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined.
746 citations
TL;DR: Based on taxonomy and molecular analysis of gene expression patterns it is possible to deduce a putative sequence of acquisition of the different branches of the biosynthetic pathway and their regulators.
Abstract: Summary Flavonoids ar€ a class of low molecular rveight phenolic compounds that is widely distributed in th€ ptant kingdom. They exhibit a divers€ spectrum of biologicat functions and play an important role in the int€raction betwe€n plants and their environment. Flavonoids not only protect the plant from the harmful effec0s of UV irrsdiation but also play a crucial role in the serxal reproduction process. A special class of tlavonoid potyme.s, th€ tannins, plays a structural role in the ptant. Y€t other classes of flavonoids, flavonols and anthocyaninsj have been implicated in the attraction of pollinators. Certain flavonoids participAte in the inte.action b€tween plants and other organisms such as symbiotic bacteria and parasites. This rais€s the intriguing question as to how thes€ different compounds arose and evolved, Bas€d on taxonomy aId molecular analysis of g€n€ expression patterns it is possible to d€duce a putative sequence of acq sition of the different branches of fhe biosvnthetic pathway and th€ir regulato.s, lnlroduction Plants arc well,known producers ofa large anay of low mol eculal weighi compounds. Most of rhesc compounds were initially classified as secondary meIaboliles because they seemed to have no clear finction for rhe orgrinisn. To man, however. these compounds have had a long hisrory of use as, for instance. precursors of medicines, liavours, fragrances. dyes and various subslances for the cheD ical indusrrv. I livonoids are probably lhe moq inren,iret) \rudied ,ec ondary metabolites of plants. Although their widespread presence in lhe plant kingdom was known for nany years. originally tbey were considered to be of lirlle bioloqical imporlance. Ne\enhele\'. rla!unoid, hare r'adiriona y Eeen favourite research objects lor chemists. enzymologists and genelicists. For exanple, the laws ofMendel and rhe discovery of transposable elemeDts by Mcclintock are based ir parr on the analyses oi anthocyanin pigmentation mulants. Today, flavonoid biosynthesis is one of rhe be$ slsLems available for the study ofregularion ofplanr gcne expression. Although this research often addresses issues other than the biological functions offlavonoids, it has helped to nake us awaIe of the wide variety of important biological functions that flavonoids exert in tbe planr.
713 citations
TL;DR: Human spermatozoa appear to use reactive oxygen species for a physiological purpose and have the difficult task of ensuring the balanced generation of these potentially harmful, but biologically important, modulators of cellular function.
Abstract: Although the generation of reactive oxygen species is an activity normally associated with phagocytic leucocytes, mammalian spermatozoa were, in fact, the first cell type in which this activity was described. In recent years it has become apparent that spermatozoa are not the only nonphagocytic cells to exhibit a capacity for reactive oxygen species production, because this activity has been detected in a wide variety of different cells including fibroblasts, mesangial cells, oocytes, Leydig cells, endothelial cells, thyroid cells, adipocytes, tumour cells and platelets. Since the capacity to generate reactive oxygen species is apparently so widespread, the risk-benefit equation for these potentially pernicious molecules becomes a matter of intense interest. In the case of human spermatozoa, the risk of manufacturing reactive oxygen metabolites is considerable because these cells are particularly vulnerable to lipid peroxidation. Indeed, there is now good evidence to indicate that oxygen radicals are involved in the initiation of peroxidative damage to the sperm plasma membrane, seen in many cases of male infertility. This risk is off-set by recent data suggesting that superoxide anions and hydrogen peroxide also participate in the induction of key biological events such as hyperactivated motility and the acrosome reaction. Thus, human spermatozoa appear to use reactive oxygen species for a physiological purpose and have the difficult task of ensuring the balanced generation of these potentially harmful, but biologically important, modulators of cellular function.
561 citations
TL;DR: Significant progress has been made in the understanding of the ATP-dependent mechanisms used by the Hsp70 and chaperonin families of molecular chaperones, which can cooperate to assist in folding new polypeptide chains.
Abstract: The discovery of “molecular chaperones” has dramatically changed our concept of cellular protein folding. Rather than folding spontaneously, most newly synthesized polypeptide chains seem to acquire their native conformation in a reaction mediated by these versatile helper proteins. Understanding the structure and function of molecular chaperones is likely to yield useful applications for medicine and biotechnology in the future.
512 citations
TL;DR: The Y‐box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals and range from the control of the E. coli cold‐shock stress response to the translational masking of messenger RNA in vertebrate gametes.
Abstract: The Y-box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals. The central nucleic acid binding domain of the vertebrate proteins is 43% identical to a 70-amino-acid-long protein (CS7.4) from E. coli. The structure of this domain consists of an antiparallel five-stranded beta-barrel that recognizes both DNA and RNA. The diverse biological roles of these Y-box proteins range from the control of the E. coli cold-shock stress response to the translational masking of messenger RNA in vertebrate gametes. This review discusses the organization of the prokaryotic and eukaryotic Y-box proteins, how they interact with nucleic acids, and their biological roles, both proven and potential.
363 citations
TL;DR: Much evidence reviewed here implicates free oxygen radicals (FORs) in the process of arrest and the arrest or delay of most embryos in vitro can be reduced or prevented experimentally by addition of metal chelators to limit hydroxy radical formation and lipid hydroperoxidation.
Abstract: A major obstacle to the study of mammalian development, and to the practical application of knowledge gained from it in the clinic during therapeutic in vitro fertilisation and embryo transfer (IVF-ET), is the propensity of embryos to become retarded or arrested during their culture in vitro. The precise developmental cell cycle in which embryos arrest or delay is characteristic for the species and coincides with the earliest period of embryonic gene expression. Much evidence reviewed here implicates free oxygen radicals (FORs) in the process of arrest. Thus, studies on the development of mouse preimplantation embryos in vitro have shown that (i) FORs are elevated in vitro, but not in vivo, at the time at which embryos become arrested or delayed, (ii) systems for removing reactive oxygen species to limit the formation of hydroxy radicals are present, although they have not yet been assessed quantitatively and may differ qualitatively from those in adult cells, (iii) metabolic and possibly genetic adaptations to oxidative damage are evident, (iv) published procedures for overcoming in vitro arrest are explicable in terms of FOR-mediated damage or responses and (v) the arrest or delay of most embryos in vitro can be reduced or prevented experimentally by addition of metal chelators to limit hydroxy radical formation and lipid hydroperoxidation.
348 citations
TL;DR: The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6-methylguanine and 6-thioguanine in DNA as discussed by the authors.
Abstract: DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6-methylguanine and 6-thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of this defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers.
304 citations
TL;DR: This work and similar efforts in eukaryotic cells, although far from complete, have established that DNA helicases are essential components of the machinery that interacts with the DNA molecule.
Abstract: DNA helicases catalyze the disruption of the hydrogen bonds that hold the two strands of double-stranded DNA together. This energy-requiring unwinding reaction results in the formation of the single-stranded DNA required as a template or reaction intermediate in DNA replication, repair and recombination. A combination of biochemical and genetic studies have been used to probe and define the roles of the multiple DNA helicases found in E. coli. This work and similar efforts in eukaryotic cells, although far from complete, have established that DNA helicases are essential components of the machinery that interacts with the DNA molecule.
292 citations
TL;DR: The present review offers a scheme of endothelial cell differentially expressed endothelialcell molecules as targets for directed therapeutic intervention, with the exception that endothelial cells maintain transdifferentiating competence.
Abstract: Endothelial cells line the inside of all blood vessels, forming a structurally and functionally heterogeneous population of cells. Their complexity and diversity has long been recognized, yet very little is known about the molecules and regulatory mechanisms that mediate the heterogeneity of different endothelial cell populations. The constitutive organ- and microenvironment-specific phenotype of endothelial cells controls internal body compartmentation, regulating the trafficking of circulating cells to distinct vascular beds. In contrast, surface molecules associated with the activated cytokine-inducible endothelial phenotype play a critical role in pathological conditions including inflammation, tumor angiogenesis, and wound healing. Differentiation of the endothelial cell phenotypes appears to follow similar mechanisms to the differentiation of hematopoietic cells, with the exception that endothelial cells maintain transdifferentiating competence. The present review offers a scheme of endothelial cell differentiation and discusses the possible applications of differentially expressed endothelial cell molecules as targets for directed therapeutic intervention.
288 citations
TL;DR: Observations lead to the proposal that cells may have evolved a post‐replicative mechanism for the elimination and/or repair of large DNA secondary structures.
Abstract: Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intra-strand base-pairing. This intra-strand base-pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, suggesting that if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post-replicative mechanism for the elimination and/or repair of large DNA secondary structures.
263 citations
TL;DR: Both prokaryotic and eukaryotic transcription factors that respond to ROIs will be described that are activated by either exposure to antioxidants, which reduce the intracellular ROI concentration, or by hypoxia, the absence of oxygen.
Abstract: The respiration of oxygen, while essential to aerobic organisms for the generation of energy, leads to the formation of reactive oxygen intermediates (ROIs) as harmful byproducts. ROIs damage nucleic acids, lipids and proteins. Therefore, protective mechanisms against elevated intracellular ROI levels, referred to as oxidative stress, have evolved. These include the activation of transcription factors which elevate the expression of protective enzymes. Eukaryotic cells have also evolved the ability to specifically generate ROIs following stimulation with various agents. In these cases, ROIs are used as second messengers to activate gene expression. Here we will discuss both prokaryotic and eukaryotic transcription factors that respond to ROIs. In addition, transcription factors will be described that are activated by either exposure to antioxidants, which reduce the intracellular ROI concentration, or by hypoxia, the absence of oxygen.
TL;DR: The P19 mouse embryonal carcinoma cell line is a suitable model system with which to analyze regulation of neuronal differentiation and proteins that play a key role in the neuronal differentiation of P19 cells are beginning to be identified.
Abstract: The differentiation of mammalian neurons during development is a highly complex process involving regulation and coordination of gene expression at multiple steps. The P19 mouse embryonal carcinoma cell line is a suitable model system with which to analyze regulation of neuronal differentiation. These multipotential cells can be maintained and propagated in tissue culture in an undifferentiated state. Exposure of aggregated P19 cells to retinoic acid results in the differentiation of cells with many fundamental phenotypes of mammalian neurons. Undifferentiated P19 cells are amenable to genetic manipulations such as transfection and establishment of stable clonal cell lines expressing introduced genes. Proteins that play a key role in the neuronal differentiation of P19 cells are beginning to be identified. These include retinoic acid receptors, the epidermal growth factor receptor and the transcription factors Oct-3 and Brn-2. The biological and technical advantages of this system should facilitate deeper analysis of the activities of proteins that play a role in neuronal differentiation.
TL;DR: The mechanism(;s) by which growth factors may inhibit apoptosis is discussed, which represents a mechanism of cell clearance in many physiological situations where deletion of cells is required.
Abstract: Apoptosis is now widely recognized as a common form of cell death and represents a mechanism of cell clearance in many physiological situations where deletion of cells is required. Peptide growth factors, initially characterised as stimulators of cell proliferation, have now been shown to inhibit death in many cell types. Deprivation of growth factors leads to the induction of apoptosis, i.e. condensation of chromatin and degradation in oligonucleosome-sized fragments, formation of plasma and nuclear membrane blebs and cell fragmentation into apoptotic bodies which can be taken up by neighbouring cells. Here we discuss the mechanism(s) by which growth factors may inhibit apoptosis.
TL;DR: The RAD6 pathway of budding yeast, Saccharomyces cerevisiae, is responsible for a substantial fraction of this organism's resistance to DNA damage, and also for induced mutagenesis, and the pathway appears to incorporate two different recovery processes, both regulated by RAD6.
Abstract: The RAD6 pathway of budding yeast, Saccharomyces cerevisiae, is responsible for a substantial fraction of this organism's resistance to DNA damage, and also for induced mutagenesis. The pathway appears to incorporate two different recovery processes, both regulated by RAD6. The error-prone recovery process accounts for only a small amount of RAD6-dependent resistance, but probably all induced mutagenesis. The underlying mechanism for error-prone recovery is very likely to be translesion synthesis. The error-free recovery process accounts for most of RAD6-dependent resistance, but its mechanism is less clear; it may entail error-free bypass by template switching and/or DNA gap filling by recombination. RAD6 regulates these activities by ubiquitinating target proteins, but the identities of these target proteins, and the roles they play in error-free and error-prone recovery, have not yet been established.
TL;DR: Very limited data indicate that transposon‐mediated chromosome restructuring is occurring in natural populations of Drosophila, which suggests thattransposable elements may help to shape the structure of the Drosophile genome and implies that they may have a similar role in other organisms.
Abstract: A combination of cytogenetic and molecular analyses has shown that several different transposable elements are involved in the restructuring of Drosophila chromosomes. Two kinds of elements, P and hobo, are especially prone to induce chromosome rearrangements. The mechanistic details of this process are unclear, but, at least some of the time, it seems to involve ectopic recombination between elements inserted at different chromosomal sites; the available data suggest that these ectopic recombination events are much more likely to occur between elements in the same chromosome than between elements in different chromosomes. Other Drosophila transposons also appear to mediate chromosome restructuring by ectopic recombination; these include the retrotransposons BEL, roo, Doc and I and the foldback element FB. In addition, two retrotransposons, HeT-A and TART, have been found to be associated specifically with the ends of Drosophila chromosomes. Very limited data indicate that transposon-mediated chromosome restructuring is occurring in natural populations of Drosophila. This suggests that transposable elements may help to shape the structure of the Drosophila genome and implies that they may have a similar role in other organisms.
TL;DR: It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton.
Abstract: One of the earliest structural changes observed in cells in response to many extracellular factors is membrane ruffling: the formation of motile cell surface protrusions containing a meshwork of newly polymerized actin filaments. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton. The small GTP-binding protein Rac is a key regulator of membrane ruffling, and proteins that can regulate Rac activity, such as Bcr, are likely to act on this signalling pathway. In addition, several previously characterized signal transducing molecules are implicated in the membrane-ruffling response, including Ras, the adaptor protein Grb2, phosphatidyl inositol 3-kinase, phospholipase A2 and phorbol ester-responsive proteins. Changes in polyphosphoinositide metabolism and intracellular Ca2+ levels may also play a role. A number of actin-binding and organizing proteins localize to membrane ruffles and are potential targets for these signal transducing molecules.
TL;DR: This work has shown that interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways.
Abstract: Despite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its extreme importance in cell function. So far, three ligands for profilin have been well-characterized in vitro: actin monomers, membrane polyphosphoinositides and poly-L-proline. In the years following its discovery, profilin's role in vivo progressed from that of a simple actin-binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways.
TL;DR: Analysis of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation, and further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs.
Abstract: The link between oncogenesis and normal development is well illustrated by the study of the Wnt family of proteins. The first Wnt gene (int-1) was identified over a decade ago as a proto-oncogene, activated in response to proviral insertion of a mouse mammary tumor virus. Subsequently, the discovery that Drosophila wingless, a developmentally important gene, is homologous to int-1 supported the notion that int-1 may have a role in normal development. In the last few years it has been recognized that int-1 and Wingless belong to a large family of related glyco-proteins found in vertebrates and invertebrates. In recognition of this, members of this family have been renamed Wnts, an amalgam of int and Wingless. Investigation of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation. Further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs. In addition, a genetic approach has identified some of the molecules required for the transmission and reception of the Wingless signal. We will review recent data which have contributed to our growing understanding of the function and mechanism of Drosophila Wingless signaling in cell fate determination, growth and specification of pattern.
TL;DR: Findings suggest that paxillin may be an important intermediary in these pathways mediated through the activation of tyrosine kinases concentrated at the sites of adhesion.
Abstract: Paxillin is a recently identified member of the complex of cytoskeletal proteins that is found concentrated in cultured cells and in vivo at the cytoplasmic face of regions of cell attachment to the extracellular matrix. These sites, in view of their close proximity to the extracellular matrix, are well positioned to act as signal-transducing centers to 'report on' changes in the cells, immediate environment. Recent findings indicate that such signals are in part mediated through the activation of tyrosine kinases concentrated at the sites of adhesion. Changes in the phosphotyrosine content of paxillin accompanying this elevation in kinase activity suggest that paxillin may be an important intermediary in these pathways.
TL;DR: The nucleosomes must be perturbed in response to an activation signal in order for the trans‐acting factors to gain access to cis‐acting elements; a chromatin remodeling process which forms DNase I hypersensitive sites must occur.
Abstract: The DNA in a eukaryotic nucleus is packaged into a nucleosome array, punctuated by variations in the regular pattern. The local chromatin structure of inducible genes appears to fall into two categories: preset and remodeling. Preset genes are those in which the binding sites for trans-acting factors are accessible (;i.e. in a non-nucleosomal, DNase I hypersensitive configuration) prior to activation. In response to the activation signal, positive factors bind to cis-acting regulatory elements and trigger transcription with no major alterations in the chromatin structure of the promoter region. In contrast, remodeling genes are those in which some of the required cis-acting regulatory elements are packaged into nucleosomes. The nucleosomes must be perturbed in response to an activation signal in order for the trans-acting factors to gain access to cis-acting elements; a chromatin remodeling process which forms DNase I hypersensitive sites must occur. In both cases, precise positioning of nucleosomes along the promoter region of a gene appears to be critical for appropriate regulation of expression.
TL;DR: The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly.
Abstract: A complex structure, visible by electron microscopy, surrounds each chromosome during mitosis. The organization of this structure is distinct from that of the chromosomes and the cytoplasm. It forms a perichromosomal layer that can be isolated together with the chromosomes. This layer covers the chromosomes except in centromeric regions. The perichromosomal layer includes nuclear and nucleolar proteins as well as ribonucleoproteins (RNPs). The list of proteins and RNAs identified includes nuclear matrix proteins (perichromin, peripherin), nucleolar proteins (perichro-monucleolin, Ki-67 antigen, B23 protein, fibrillarin, p103, p52), ribosomal proteins (S1) and snRNAs (U3 RNAs). Only limited information is available about how and when the perichromosomal layer is formed. During early prophase, the proteins extend from the nucleoli towards the periphery of the nucleus. Thin cordon-like structures reach the nuclear envelope delimiting areas in which chromosomes condense. At telophase, the proteins are associated with the part of the chromosomes remaining condensed and accumulate in newly formed nucleoli in regions where chromatin is already decondensed. The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly.
TL;DR: Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed.
Abstract: The rate-limiting step in the uptake and metabolism of D-glucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin-coated pits and vesicles, early endosomes, and tubulo-vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3-kinase, is discussed.
TL;DR: The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances.
Abstract: The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position-effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white gene variegation, pairing-dependent effects and insertional targeting.
TL;DR: A review of recent studies that elucidate a role for tensin in maintenance of cellular structure and signal transduction, and demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential are discussed.
Abstract: Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate a role for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential.
TL;DR: The DNA primary structure features that are pertinent to the formation of these conformers are summarized and data concerning the occurrence of these sequences in the eukaryotic genome is presented.
Abstract: Extensive studies of DNA secondary structure during the past decade have shown that DNA is a dynamic molecule, whose structure depends on the underlying nucleotide sequence and is influenced by the environment and the overall DNA topology. Three major non-B-DNA structures have been described (Z-DNA, triplex DNA and cruciform DNA) which are stabilized by unconstrained negative supercoiling and can be formed under physiological conditions. In this essay we summarize the DNA primary structure features that are pertinent to the formation of these conformers and present data concerning the occurrence of these sequences in the eukaryotic genome. The evidence in favor of the existence of these unusual DNA structures in vivo is discussed. The effect of alternative non-B-DNA structures on the way DNA is organized in chromatin is considered, and this is followed by evaluation of the data relating these structures to eukaryotic transcription. Some possible mechanisms by which the effect of non-B structures on transcription might be exerted are proposed.
TL;DR: Six collagen genes are now known to encode cuticular collagens, a finding that confirms the importance of this group of structural proteins to the formation of the cuticle and the role of the Cuticle as an exoskeleton in shaping the worm.
Abstract: The cuticle of the nematode Caenorhabditis elegans forms the barrier between the animal and its environment. In addition to being a protective layer, it is an exoskeleton which is important in maintaining and defining the normal shape of the nematode. The cuticle is an extracellular matrix consisting predominantly of small collagen-like proteins that are extensively crosslinked. Although it also contains other protein and non-protein compounds that undoubtedly play a significant part in its function, the specific role of collagen in cuticle structure and morphology is considered here. The C. elegans genome contains between 50 and 150 collagen genes, most of which are believed to encode cuticular collagens. Mutations that result in cuticular defects and grossly altered body form have been identified in more than 40 genes. Six of these genes are now known to encode cuticular collagens, a finding that confirms the importance of this group of structural proteins to the formation of the cuticle and the role of the cuticle as an exoskeleton in shaping the worm. It is likely that many more of the genes identified by mutations giving altered body form, will be collagen genes. Mutations in the cuticular collagen genes provide a powerful tool for investigating the mechanisms by which this group of proteins interact to form the nematode cuticle.
TL;DR: It is suggested that many developmental changes in beta thymosin levels within cells and tissues may be related to changes in G‐actin pool size.
Abstract: The beta thymosins are a highly conserved family of strongly polar 5 kDa polypeptides that are widely distributed among vertebrate classes; most are now known to bind to monomeric actin and inhibit its polymerization. One beta thymosin, beta four, (T beta 4) is the predominant form in mammalian cells, present at up to 0.5 mM. Many species are known to produce at least two beta thymosin isoforms, in some cases in the same cell. Their expression can be separately regulated. When present outside the cell, the N-terminal tetrapeptide of beta four appears to affect cell cycle regulation; beta thymosins or smaller fragments derived from them may have additional regulatory functions. We suggest that many developmental changes in beta thymosin levels within cells and tissues may be related to changes in G-actin pool size.
TL;DR: The cloning of two regions at which chromosome breakage can be induced has in each case uncovered an unstable CG-rich triplet repeat which becomes methylated when fully expanded, suggesting a common basis to the observed phenotypes.
Abstract: Trinucleotide repeat expansions are now a well-established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar muscular atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG-rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3' untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed.
TL;DR: This work has identified numerous examples of gene redundancy and has highlighted the need to consider metabolic differences between man and mouse in disease modelling, and Gene targeting could also make a contribution to improved protocols for gene therapy.
Abstract: Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider metabolic differences between man and mouse in disease modelling. More sophisticated gene-targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site-specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy.
TL;DR: The amphitelic orientation of univalents in metaphase I and pairing of the chromatids in meiosis II appear to ensure correct segregation as well, as well as the possibility that the spindlepossibly joining forces with the kinetochores‐carries out the faithful segregation ofunivalents which are not directly physically attached to one another.
Abstract: The chromosomes which segregate in anaphase I of meiosis are usually physically bound together through chiasmata. This association is necessary for proper segregation, since univalents sort independently from one another in the first meiotic division and this frequently leads to genetically unbalanced offspring. There are, however, a number of species where genetic exchanges in the form of meiotic cross-overs, the prerequisite of the formation of chiasmata, are routinely missing in one sex or between specific chromosomes. These species nevertheless manage to segregate these non-exchange chromosomes. There are four direct modes for associating achiasmatic chromosomes: (a) modified SC, (b) adhesion of chromatids comparable to somatic pairing, (c) 'stickiness' of heterochromatin or (d) specific 'segregation bodies', consisting of material structurally different from chromatin. There is also the possibility that the spindle-possibly joining forces with the kinetochores--carries out the faithful segregation of univalents which are not directly physically attached to one another. Finally, amphitelic orientation of univalents in metaphase I and pairing of the chromatids in meiosis II appear to ensure correct segregation as well.