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Transduction Cascades (transduction + cascade)
Kinds of Transduction Cascades Selected AbstractsNeuropeptide Y in the olfactory microvillar cellsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2006Giorgia Montani Abstract This paper examines a possible role of microvillar cells in coordinating cell death and regeneration of olfactory epithelial neurons. The olfactory neuroepithelium of mammals is a highly dynamic organ. Olfactory neurons periodically degenerate by apoptosis and as a consequence of chemical or physical damage. To compensate for this loss of cells, the olfactory epithelium maintains a lifelong ability to regenerate from a pool of resident multipotent stem cells. To assure functional continuity and histological integrity of the olfactory epithelium over a period of many decades, apoptosis and regeneration require to be precisely coordinated. Among the factors that have been implicated in mediating this regulation is the neuropeptide Y (NPY). Knockout mice that lack functional expression of this neurogenic peptide show defects in embryonic development of the olfactory epithelium and in its ability to regenerate in the adult. Here we show that, in postnatal olfactory epithelia, NPY is exclusively expressed by a specific population of microvillar cells. We previously characterized these cells as a novel type of putative chemosensory cells, which are provided with a phosphatidyl-inositol-mediated signal transduction cascade. Our findings allow for the first time to suggest that microvillar cells are involved in connecting apoptosis to neuronal regeneration by stimulus-induced release of NPY. [source] DNA damage-induced gene expression in Saccharomyces cerevisiaeFEMS MICROBIOLOGY REVIEWS, Issue 6 2008Yu Fu Abstract After exposure to DNA-damaging agents, both prokaryotic and eukaryotic cells activate stress responses that result in specific alterations in patterns of gene expression. Bacteria such as Escherichia coli possess both lesion-specific responses as well as an SOS response to general DNA damage, and the molecular mechanisms of these responses are well studied. Mechanisms of DNA damage response in lower eukaryotes such as Saccharomyces cerevisiae are apparently different from those in bacteria. It becomes clear that many DNA damage-inducible genes are coregulated by the cell-cycle checkpoint, a signal transduction cascade that coordinates replication, repair, transcription and cell-cycle progression. On the other hand, among several well-characterized yeast DNA damage-inducible genes, their effectors and mechanisms of transcriptional regulation are rather different. This review attempts to summarize the current state of knowledge on the molecular mechanisms of DNA damage-induced transcriptional regulation in this model lower eukaryotic microorganism. [source] Gq,-linked phospholipase C,1 and phospholipase C, are essential components of the pheromone biosynthesis activating neuropeptide (PBAN) signal transduction cascadeINSECT MOLECULAR BIOLOGY, Issue 4 2010J. J. Hull Abstract Sex pheromone production for most moths is regulated by pheromone biosynthesis activating neuropeptide (PBAN). In Bombyx mori, PBAN binding triggers the opening of store-operated Ca2+ channels, suggesting the involvement of a receptor-activated phospholipase C (PLC). In this study, we found that PLC inhibitors U73122 and compound 48/80 reduced sex pheromone production and that intracellular levels of 3H-inositol phosphate species increased following PBAN stimulation. In addition, we amplified cDNAs from pheromone glands corresponding to PLC,1, PLC,4, PLC, and two G protein , subunits, Go and Gq. In vivo RNA interference-mediated knockdown analyses revealed that BmPLC,1, BmGq1, and unexpectedly, BmPLC,, are part of the PBAN signal transduction cascade. [source] A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2005Liliane Goetsch Abstract Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its ,-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor. [source] The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memoryJOURNAL OF NEUROCHEMISTRY, Issue 1 2001J. David Sweatt The mitogen-activated protein kinase (MAP kinase, MAPK) cascade, as the name implies, was originally discovered as a critical regulator of cell division and differentiation. As further details of this signaling cascade were worked out, it became clear that the MAPK cascade is in fact a prototype for a family of signaling cascades that share the motif of three serially linked kinases regulating each other by sequential phosphorylation. Thus, a revised nomenclature arose that uses the term MAPK to refer to the entire superfamily of signaling cascades (comprising the erks, the JNKs and the p38 stress activated protein kinases), and specifies the prototype MAPK as the extracellular signal-regulated kinase (erk). The two erk MAPK isoforms, p44 MAPK and p42 MAPK, are referred to as erk1 and erk2, respectively. The erks are abundantly expressed in neurons in the mature central nervous system, raising the question of why the prototype molecular regulators of cell division and differentiation are present in these non-dividing, terminally differentiated neurons. This review will describe the beginnings of an answer to this question. Interestingly, the general model has begun to emerge that the erk signaling system has been co-opted in mature neurons to function in synaptic plasticity and memory. Moreover, recent insights have led to the intriguing prospect that these molecules serve as biochemical signal integrators and molecular coincidence detectors for coordinating responses to extracellular signals in neurons. In this review I will first outline the essential components of this signal transduction cascade, and briefly describe recent results implicating the erks in mammalian synaptic plasticity and learning. I will then proceed to outline recent results implicating the erks as molecular signal integrators and, potentially, coincidence detectors. Finally, I will speculate on what the critical downstream effectors of the erks are in neurons, and how they might provide a readout of the integrated signal. [source] A che -like signal transduction cascade involved in controlling flagella biosynthesis in Rhodospirillum centenumMOLECULAR MICROBIOLOGY, Issue 5 2005James E. Berleman Summary Rhodospirillum centenum is a photosynthetic bacterium capable of undergoing swim cell to swarm cell differentiation that allows this species to be motile on both liquid and solid media. Previous experiments have demonstrated that the che1 operon is required for the control of chemotactic and phototactic behaviour of both swim and swarm cells. In this report, we analyse the function of a second che -like gene cluster in R. centenum, the che2 gene cluster. In-frame deletion mutants of cheW2, cheB2, cheR2, cheY2, and of the entire che2 operon, exhibit defects in swim and swarm cell motility. Analysis of these strains demonstrates that they are non-motile, and that the non-motile phenotype is resulting from reduced polar and lateral flagella synthesis. Additionally, mutations in mcp2, ORF204, cheA2 and ORF74 remain chemotacticly and phototacticly competent at both high and low growth temperatures. Mutations in these che2 genes result in elevated levels of flagellin proteins giving rise to a hyperflagellate phenotype. We propose a model in which R. centenum utilizes a che -like signal transduction pathway (che2) for regulating flagellum synthesis in order to optimize swim cell-swarm cell differentiation in response to changing environmental conditions. [source] A Phytochrome-like Protein AphC Triggers the cAMP Signaling Induced by Far-red Light in the Cyanobacterium Anabaena sp.PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2004Strain PCC7120 ABSTRACT In the filamentous, nitrogen-fixing cyanobacterium Anabaena sp. PCC7120, red light (630 nm) decreased, whereas far-red light (720 nm) increased cellular adenosine 3,,5,-cyclic monophosphate (cAMP) content. To find a red and far-red light photoreceptor that triggers the cAMP signal cascade, we disrupted 10 open reading frame having putative chromophore-binding GAF domains. The response of the cellluar cAMP concentration to red and far-red light in each open reading frame disruptant was determined. It was found that only the mutant of the gene all2699 failed to respond to far-red light. The open reading frame named as aphC encoded a protein with 920 amino acids including GAF domains similar to those involved in Cph2, a photoreceptor of Synechocystis sp. PCC6803. To determine which adenylate cyclase (AC) is responsible for far-red light signal, we disrupted all AC genes and found that CyaC was the candidate. The enzymatic activity of CyaC might be controlled by a far-red light photoreceptor through the phosphotransfer reaction. The site-specific mutant of the Asp59 residue of the receiver (R1) domain of CyaC lost its light-response capability. It was suggested that the far-red light signal was received by AphC and then transferred to the N-terminal response regulator domain of CyaC. Then its catalytic activity was stimulated, which increased the cellular cAMP concentration and drove the subsequent signal transduction cascade. [source] Ret-PCP2 colocalizes with protein kinase C in a subset of primate ON cone bipolar cellsTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 7 2010Pyroja Sulaiman Abstract Purkinje cell protein 2 (PCP2), a member of the family of guanine dissociation inhibitors and a strong interactor with the G-protein subunit G,o, localizes to retinal ON bipolar cells. The retina-specific splice variant of PCP2, Ret-PCP2, accelerates the light response of rod bipolar cells by modulating the mGluR6 transduction cascade. All ON cone bipolar cells express mGluR6 and G,o, but only a subset expresses Ret-PCP2. Here we test the hypothesis that Ret-PCP2 contributes to shaping the various temporal bandwidths of ON cone bipolar cells in monkey retina. We found that the retinal splice variants in monkey and mouse are similar and longer than the cerebellar variants. Ret-PCP2 is strongly expressed by diffuse cone bipolar type 4 cells (DB4; marked with anti-PKC,) and weakly expressed by midget bipolar dendrites (labeled by antibodies against G,o, G,13, or mGluR6). Ret-PCP2 is absent from diffuse cone bipolar type 6 (DB6; marked with anti-CD15) and blue cone bipolar cells (marked with anti-CCK precursor). Thus, cone bipolar cells that terminate in stratum 3 of the inner plexiform layer (DB4) express more Ret-PCP2 than those that terminate in strata 3 + 4 (midget bipolar cells), and these in turn express more than those that terminate in stratum 5 (DB6 and blue cone bipolar cells). This expression pattern approximates the arborization of ganglion cells (GC) with different temporal bandwidths: parasol GCs stratifying near stratum 3 are faster than midget GCs stratifying in strata 3 + 4, and these are probably faster than the sluggish GCs that arborize in stratum 5. J. Comp. Neurol. 518:1098,1112, 2010. © 2009 Wiley-Liss, Inc. [source] Discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes,THE JOURNAL OF PATHOLOGY, Issue 2 2009Andreas R Klatt Abstract We deciphered constituent parts of a signal transduction cascade that is initiated by collagen II and results in the release of various pro-inflammatory cytokines, including interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released collagen II fragments and pro-inflammatory cytokines. We previously proposed discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of osteoarthritis, our study further investigates the hypothesis that discoidin domain receptor 2 is a candidate receptor for collagen II, and that transcription factor NF,B, lipid kinase PI3K, and the MAP kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with collagen II, and observed the outcome, specifically the changes in interleukin-6 release. Knockdown was performed by siRNA-mediated gene silencing in the case of discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes and that MAP kinases p38, JNK and ERK, as well as transcription factor NF,B, are integral components of intracellular collagen II signalling. Given the detrimental role of these molecules in osteoarthritis, our findings provide new targets for more specific therapeutics, which may have fewer side effects than those currently applied. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Inhibition of ,7-containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slicesTHE JOURNAL OF PHYSIOLOGY, Issue 5 2009Jian-xin Shen Cys-loop ligand-gated nicotinic ACh receptors (nAChRs) and G protein-coupled muscarinic ACh receptors (mAChRs) are expressed on rat hippocampal interneurones where they can regulate excitability, synaptic communication and cognitive function. Even though both nAChRs and mAChRs appear to co-localize to the same interneurones, it is not clear whether there is crosstalk between them. We utilized patch-clamp techniques to investigate this issue in rat hippocampal CA1 interneurones in slices under conditions where synaptic transmission was blocked. The ,7 nAChR-mediated currents were activated by choline, and when the activation of this receptor was preceded by the activation of the M1 mAChR subtype, the amplitude of ,7 responses was significantly reduced in a rapidly reversible and voltage-independent manner, without any change in the kinetics of responses. This M1 mAChR-mediated inhibition of ,7 nAChRs was through a PLC-, calcium- and PKC-dependent signal transduction cascade. These data show that M1 mAChRs and ,7 nAChRs are functionally co-localized on individual rat hippocampal interneurones where the activation of these particular mAChRs inhibits ,7 nAChR function. This information will help to understand how these cholinergic receptor systems might be regulating neuronal excitability in the hippocampus in a manner that has relevance for synaptic plasticity and cognition. [source] Modulation by phytochrome of the blue light-induced extracellular acidification by leaf epidermal cells of pea (Pisum sativum L.): a kinetic analysisTHE PLANT JOURNAL, Issue 5 2000J. Theo M. Elzenga Summary Blue light induces extracellular acidification, a prerequisite of cell expansion, in epidermis cells of young pea leaves, by stimulation of the proton pumping-ATPase activity in the plasma membrane. A transient acidification, reaching a maximum 2.5,5 min after the start of the pulse, could be induced by pulses as short as 30 msec. A pulse of more than 3000 ,mol m,2 saturated this response. Responsiveness to a second light pulse was recovered with a time constant of about 7 min. The fluence rate-dependent lag time and sigmoidal increase of the acidification suggested the involvement of several reactions between light perception and activation of the ATPase. In wild-type pea plants, the fluence response relation for short light pulses was biphasic, with a component that saturates at low fluence and one that saturates at high fluence. The phytochrome-deficient mutant pcd2 showed a selective loss of the high-fluence component, suggesting that the high-fluence component is phytochrome-dependent and the low-fluence component is phytochrome-independent. Treatment with the calmodulin inhibitor W7 also led to the elimination of the phytochrome-dependent high-fluence component. Simple models adapted from the one used to simulate blue light-induced guard cell opening failed to explain one or more elements of the experimental data. The hypothesis that phytochrome and a blue light receptor interact in a short-term photoresponse is endorsed by model calculations based upon a three-step signal transduction cascade, of which one component can be modulated by phytochrome. [source] TRPM1: The endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cellsBIOESSAYS, Issue 7 2010Catherine W. Morgans Abstract For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders. [source] Binding characteristics of chondroitin sulfate proteoglycans and laminin-1, and correlative neurite outgrowth behaviors in a standard tissue culture choice assayDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2002Diane M. Snow Abstract Neuronal growth cones are capable of sophisticated discrimination of environmental cues, on cell surfaces and in the extracellular matrix, to accomplish navigation during development (generation) and following nervous system injury (regeneration). Choices made by growth cones are commonly examined using tissue culture paradigms in which molecules of interest are purified and substratum-bound. From observations of growth cone behaviors using these paradigms, assertions are made about choices neuronal growth cones may make in vivo. However, in many cases, the binding, interactions, and conformations of these molecules have not been determined. In the present study, we investigated the binding characteristics of two commonly studied outgrowth regulatory molecules: chondroitin sulfate proteoglycans (CSPGs), which are typically inhibitory to neurite outgrowth during development and following nervous system injury, and laminin, which is typically outgrowth promoting for many neuronal types. Using a novel combination of radiolabeling and quantitative fluorescence, we determined the precise concentrations of CSPGs and laminin-1 that were bound separately and together in a variety of choice assays. For identically prepared cultures, we correlated neurite outgrowth behaviors with binding characteristics. The data support our working hypothesis that neuronal growth cones are guided by the ratio of outgrowth-promoting to outgrowth-inhibiting influences in their environment, i.e., they summate local molecular cues. The response of growth cones to these molecular combinations is most likely mediated by integrins and subsequent activation of signal transduction cascades in growth cones. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 285,301, 2002 [source] A common gene exclusion mechanism used by two chemosensory systemsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2009Luca Capello Abstract Sensory coding strategies within vertebrates involve the expression of a limited number of receptor types per sensory cell. In mice, each vomeronasal sensory neuron transcribes monoallelically a single V1R pheromone receptor gene, chosen from a large V1R repertoire. The nature of the signals leading to this strict receptor expression is unknown, but is apparently based on a negative feedback mechanism initiated by the transcription of the first randomly chosen functional V1R gene. We show, in vivo, that the genetic replacement of the V1rb2 pheromone receptor coding sequence by an unrelated one from the odorant receptor gene M71 maintains gene exclusion. The expression of this exogenous odorant receptor in vomeronasal neurons does not trigger the transcription of odorant receptor-associated signalling molecules. These results strongly suggest that despite the different odorant and vomeronasal receptor expression sites, function and transduction cascades, a common mechanism is used by these chemoreceptors to regulate their transcription. [source] Group I metabotropic glutamate receptors regulate the frequency,response function of hippocampal CA1 synapses for the induction of LTP and LTDEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2004Els J. M. Van Dam Abstract Synaptically released glutamate binds to ionotropic or metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and can be divided into three subclasses (Group I,III) depending on their pharmacology and coupling to signal transduction cascades. Group I mGluRs are coupled to phospholipase C and are implicated in several important physiological processes, including activity-dependent synaptic plasticity, but their exact role in synaptic plasticity remains unclear. Synaptic plasticity can manifest itself as an increase or decrease of synaptic efficacy, referred to as long-term potentiation (LTP) and long-term depression (LTD). The likelihood, degree and direction of the change in synaptic efficacy depends on the history of the synapse and is referred to as ,metaplasticity'. We provide direct experimental evidence for an involvement of group I mGluRs in metaplasticity in CA1 hippocampal synapses. Bath application of a low concentration of the specific group I agonist 3,5-dihydroxyphenylglycine (DHPG), which does not affect basal synaptic transmission, resulted in a leftward shift of the frequency,response function for the induction of LTD and LTP in naďve synapses. DHPG resulted in the induction of LTP at frequencies which induced LTD in control slices. These alterations in the induction of LTD and LTP resemble the metaplastic changes observed in previously depressed synapses. In addition, in the presence of DHPG additional potentiation could be induced after LTP had apparently been saturated. These findings provide strong evidence for an involvement of group I mGluRs in the regulation of metaplasticity in the CA1 field of the hippocampus. [source] Promoter regulation in Candida albicans and related speciesFEMS YEAST RESEARCH, Issue 1 2009Sabine E. Eckert Abstract Regulation of gene expression has been studied extensively in Saccharomyces cerevisiae and Schizosaccharomyces pombe. Some, but by far not all, of the findings are also applicable to Candida albicans, an important ascomycete fungal pathogen of humans. Areas of research in C. albicans include the influence of key signal transduction cascades on morphology, and the response to host-generated influences, such as host immune effector cells, blood, pH or elevated carbon dioxide. The resistance to antifungal agents and response to stress are also well researched. Conditional gene expression and reporter genes adapted to the codon usage of C. albicans are now widely used in C. albicans. Here we present a comprehensive overview of the current techniques used to investigate regulation mechanisms for promoters in C. albicans and other Candida species. In addition, we discuss reporter genes used for the study of gene expression. [source] Calcineurin phosphatase in signal transduction: lessons from fission yeastGENES TO CELLS, Issue 7 2002Reiko Sugiura Calcineurin (protein phosphatase 2B), the only serine/threonine phosphatase under the control of Ca2+/calmodulin, is an important mediator in signal transmission, connecting the Ca2+ -dependent signalling to a wide variety of cellular responses. Furthermore, calcineurin is specifically inhibited by the immunosuppressant drugs cyclosporin A and tacrolimus (FK506), and these drugs have been a powerful tool for identifying many of the roles of calcineurin. Calcineurin is enriched in the neural tissues, and also distributes broadly in other tissues. The structure of the protein is highly conserved from yeast to man. The combined use of powerful genetics and of specific calcineurin inhibitors in fission yeast Schizosaccharomyces pombe (S. pombe) identified new components of the calcineurin pathway, and defined new roles of calcineurin in the regulation of the many cellular processes. Recent data has revealed functional interactions in which calcineurin phosphatase is involved, such as the cross-talk between the Pmk1 MAP kinase signalling, or the PI signalling. Calcineurin also participates in membrane traffic and cytokinesis of fission yeast through its functional connection with members of the small GTPase Rab/Ypt family, and Type II myosin, respectively. These findings highlight the potential of fission yeast genetic studies to elucidate conserved elements of signal transduction cascades. [source] Caspase-activation pathways in apoptosis and immunityIMMUNOLOGICAL REVIEWS, Issue 1 2003Emma M. Creagh Summary:, Members of the caspase family of cysteine proteases have been firmly established to play key roles in signal transduction cascades that culminate in apoptosis (programmed cell death). Caspases are normally expressed as inactive precursor enzymes (zymogens) that become activated during apoptosis and proceed to dismantle the cell from within. To date, three major apoptosis-associated pathways to caspase activation have been elucidated. Certain caspases, such as caspase-1, also occupy important positions in signaling pathways associated with immune responses to microbial pathogens. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as interleukin-1, (IL-1,) and IL-18, and not apoptosis per se. Here, we discuss the current understanding of how caspases are activated during apoptosis and inflammation and the roles these proteases play in either context. [source] Fibronectin, integrins, and growth controlJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2001Erik H.J. Danen Cell proliferation is controlled not only by soluble mitogens but also by components of the extracellular matrix (ECM) such as fibronectin, to which cells adhere via the integrin family of transmembrane receptors. Input from both growth factor receptors and integrins is required to stimulate progression through the G1 phase of the cell cycle, via induction of G1 cyclins and suppression of inhibitors of the G1 cyclin-dependent kinases. Extensive crosstalk takes place between integrin and growth factor receptor signaling pathways, and mitogenic signaling is weak and transient in the absence of integrin-mediated cell adhesion. In normal untransformed cells, all of the important mitogenic signal transduction cascades, namely those downstream of the Ras and Rho family small GTPases and the phosphoinositide 3-OH kinase-PKB/Akt pathway, are regulated by integrin-mediated cell adhesion. As a result, these cells are anchorage-dependent for growth. In contrast, constitutive activity of each of these pathways has been reported in cancer cells, which not only reduces their mitogen dependence but also allows these cells to grow in an anchorage-independent fashion. © 2001 Wiley-Liss, Inc. [source] Development of the force field parameters for phosphoimidazole and phosphohistidineJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 11 2004Yuri A. Kosinsky Abstract Phosphorylation of histidine-containing proteins is a key step in the mechanism of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage in a wide variety of signal transduction cascades in bacteria, yeast, higher plants, and mammals. Studies of structural and dynamical aspects of such enzymes in the phosphorylated intermediate states are important for understanding the intimate molecular mechanisms of their functioning. Such information may be obtained via molecular dynamics and/or docking simulations, but in this case appropriate force field parameters for phosphohistidine should be explicitly defined. In the present article we describe development of the GROMOS96 force field parameters for phosphoimidazole molecule,a realistic model of the phosphohistidine side chain. The parameterization is based on the results of ab initio quantum chemical calculations with subsequent refinement and testing using molecular mechanics and molecular dynamics simulations. The set of force constants and equilibrium geometry is employed to derive force field for the phosphohistidine moiety. Resulting parameters and topology are incorporated into the molecular modeling package GROMACS and used in molecular dynamics simulations of a phosphohistidine-containing protein in explicit solvent. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1313,1321, 2004 [source] Anatomical Markers of Activity in Neuroendocrine Systems: Are we all ,Fos-ed out'?JOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2002G. E. Hoffman Abstract It has now been nearly 15 years since the immediate early gene, c -fos, and its protein product, Fos, were introduced as tools for determining activity changes within neurones of the nervous system. In the ensuing years, this approach was applied to neuroendocrine study with success. With it have come advances in our understanding of which neuroendocrine neurones respond to various stimuli and how other central nervous system components interact with neuroendocrine neurones. Use of combined tract-tracing approaches, as well as double-labelling for Fos and transmitter markers, have added to characterization of neuroendocrine circuits. The delineation of the signal transduction cascades that induce Fos expression has led to establishment of the relationship between neurone firing and Fos expression. Importantly, we can now appreciate that Fos expression is often, but not always, associated with increased neuronal firing and vice versa. There are remaining gaps in our understanding of Fos in the nervous system. To date, knowledge of what Fos does after it is expressed is still limited. The transience of Fos expression after stimulation (especially if the stimulus is persistent) complicates design of experiments to assess the function of Fos and makes Fos of little value as a marker for long-term changes in neurone activity. In this regard, alternative approaches must be sought. Useful alternative approaches employed to date to monitor neuronal changes in activity include examination of (i) signal transduction intermediates (e.g. phosphorylated CREB); (ii) transcriptional/translational intermediates (e.g. heteronuclear RNA, messenger RNA (mRNA), prohormones); and (iii) receptor translocation. Another capitalizes on the fact that many neuroendocrine systems show striking stimulus-transcription coupling in the regulation of their transmitter or its synthetic enzymes. Together, as we move into the 21st Century, the use of multiple approaches to study activity within neuroendocrine systems will further our understanding of these important systems. [source] Specificity of the second messenger pathways involved in basic fibroblast growth factor-induced survival and neurite growth in chick ciliary ganglion neuronsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2009Alessandra Gilardino Abstract Basic fibroblast growth factor (bFGF) exerts multiple neurotrophic actions on cultured neurons from the ciliary ganglion of chick embryo, among them promotion of neuronal survival and of neurite outgrowth. To understand the specificity of the signal transduction cascades involved in the control of these processes, we used pharmacological inhibitors of the three main effectors known to act downstream of the bFGF receptor (FGFR): phospholipase C, (PLC,), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3-K). Neuronal survival was assessed at 24 and 48 hr; neurite growth was analyzed both on dissociated neurons and on explants of whole ganglia. Our data show that only the PI3-K pathway is involved in the survival-promoting effect of bFGF; on the other hand, all three effectors converge on the enhancement of neurite outgrowth, both on isolated neurons and in whole ganglia. © 2009 Wiley-Liss, Inc. [source] The cytoplasmic tail of the ,3 integrin subunit promotes neurite outgrowth in PC12 cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2005Nadja Mechai Abstract Binding of integrins to proteins of the extracellular matrix (ECM) provides structural and signaling information for biological processes such as cell proliferation, migration, neurite outgrowth, and differentiation. Integrins represent a family of heterodimeric transmembrane cell surface receptors. Besides connecting the ECM with the cytoskeleton, integrins also induce various signaling pathways in response to ligand binding. Integrin ligation leads to cytoplasmic protein,protein interactions requiring both integrin cytoplasmic tails. These sequences are initiation points for focal adhesion formation and subsequent signal transduction cascades. In this study, we addressed the question of whether the short cytoplasmic tail of the ,3 integrin subunit of ,3,1 integrin is required for ,3,1 integrin-dependent processes. For this purpose, cDNA representing the extracellular and transmembrane domain of the interleukin 2 receptor (IL2R) , subunit and the cytoplasmic sequence of the ,3 integrin subunit was transfected into PC12 cells. Autonomous expression of the cytoplasmic ,3 tail does not affect attachment but leads to inhibition of neuronal differentiation on laminin 5. This indicates that the cytoplasmic ,3 sequence is not required for cell attachment but is necessary for long-term adhesion and for the reorganization of the cytoskeleton that precedes neuronal differentiation. Inhibition of neurite outgrowth by chimeric IL2R-,3 can be rescued by treatment of transfected cells with the pharmacological inhibitor Y27632, which inhibits the RhoA downstream effector Rho kinase ,. © 2005 Wiley-Liss, Inc. [source] Stem cell biology of the central nervous systemJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2002Hideyuki Okano Abstract Neural stem cells (NSCs) are multipotential progenitor cells that have self-renewal activities. A single NSC is capable of generating various kinds of cells within the central nervous system (CNS), including neurons, astrocytes, and oligodendrocytes. Because of these characteristics, there is increasing interest in NSCs and neural progenitor cells from the aspects of both basic developmental biology and therapeutic applications to the damaged brain. This special issue, dedicated to understanding the nature of the NSCs present in the CNS, presents an introduction to several avenues of research that may lead to feasible strategies for manipulating cells in situ to treat the damaged brain. The topics covered by these studies include the extracellular factors and signal transduction cascades involved in the differentiation and maintenance of NSCs, the population dynamics and locations of NSCs in embryonic and adult brains, prospective identification and isolation of NSCs, the induction of NSCs to adopt particular neuronal phenotypes, and their transplantation into the damaged CNS. © 2002 Wiley-Liss, Inc. [source] v-Ha- ras mitogenic signaling through superoxide and derived reactive oxygen speciesMOLECULAR CARCINOGENESIS, Issue 4 2002Ji-Qin Yang Abstract The ras proto-oncogene is frequently mutated in human tumors and functions to constitutively stimulate signal transduction cascades, resulting in unchecked proliferation and malignant transformation. In certain cells, superoxide functions as a signal-transduction messenger, mediating the downstream effects of ras and rac. We demonstrated previously that v-Ha -ras,transfected rat kidney epithelial cells (RECs) overproduced superoxide anion and that this superoxide production was mediated by ras. In the present study, we further demonstrated that v-Ha -ras overexpression transformed immortal nonmalignant RECs into malignant cancer cells; v-Ha -ras,transfected cells formed clones in soft agar, had high plating efficiency, and formed tumors in nude mice. Our data suggest that superoxide radical plays a role in ras-induced transformation; modulation of intracellular superoxide level by overexpression of manganese-containing superoxide dismutase or copper- and zinc-containing superoxide dismutase inhibited ras-induced transformation, as evidenced by in vitro studies of plating efficiency and by in vivo studies of tumor formation in nude mice. Overexpression of catalase (CAT) alone was found to have little effect on tumor cell growth, but overexpression of glutathione peroxidase 1 (GPx1) completely suppressed tumor cell growth in nude mice. This finding suggests that peroxides removed by GPx1, but not by CAT, are also involved in ras-induced transformation. © 2002 Wiley-Liss, Inc. [source] Enhancing endocrine response with novel targeted therapies,CANCER, Issue S3 2008Why have the clinical trials to date failed to deliver on the preclinical promise? Abstract Acquired resistance to endocrine therapies has severely limited their long-term effectiveness in breast cancer. In recent years a clear rationale has developed for combining signal transduction inhibitors (STIs) with endocrine therapies to delay the emergence of acquired resistance and enhance endocrine responsiveness. A variety of biologic agents have been developed to target key proteins along the EGFR, HER2, MAPK, and P13K/Akt signal transduction cascades. While several of these agents have shown early promise in selected breast cancer models, translating these data into convincing clinical results has been generally disappointing to date. By applying more rigorous trial design and tumor selection criteria to future trials, it is much more likely that adding the new generation of targeted therapies can fulfill its promise in enhancing endocrine responsiveness and our ability to treat breast cancer patients. Cancer 2008. © 2007 American Cancer Society. [source] Fluorescence (Förster) resonance energy transfer imaging of oncogene activity in living cellsCANCER SCIENCE, Issue 1 2006Etsuko Kiyokawa A hallmark of cancer cells is their uncontrolled activation of growth signal transduction cascades comprised of oncogene products. Overexpression and activating mutations of the growth factor receptors Ras and Raf are frequently observed in human cancer cells. Several research groups, including our own, have been developing probes based on the principle of fluorescence (Förster) resonance energy transfer (FRET) to visualize how signaling molecules, including oncogene products, are regulated in normal and cancerous cells in the living state. In this review, we will briefly introduce the principle of FRET-based probes, present an overview of the probes reported to date, and discuss the perspectives of these probes and fluorescent imaging systems in cancer biology. (Cancer Sci 2006; 97: 8,15) [source] Introduction on the multifaceted roles of nitric oxide in the retinaACTA OPHTHALMOLOGICA, Issue 2009NN OSBORNE Multifaceted roles of nitric oxide in the retina. N.N. Osborne. Nuffield Lab of Ophthalmology, University of Oxford, Oxford, United Kingdom Nitric oxide (NO), a free radical gas with a half-life of a few seconds is implicated in various physiological and pathophysiological roles associated with the retina and its vasculature. Generated by a family of nitric oxide synthetases (NOS), NO has been shown to bind to soluble guanylyl cyclase and to mitochondrial cytochrome c oxidase to activate defined signalling cascades. Different types of NOS exist and can be activated by calcium dependent (NOS1 and NOS3) or independent (NOS2) mechanisms. Generally, NOS1 is located to neurones while NOS2 and NOS3 are in glial and endothelial cells, respectively. NO is involved in communication between different neurones, glial cells and neurones, and in the interactions of endothelial cells with pericytes and neurones. As a consequence, a reduction in the generation of endogenous NO in the healthy retina can result in vasoconstriction; the consequences of such an affect on the retina and alterations in visual processing may alter the photoreceptor transduction mechanism and communication between retinal cells. The binding of NO to mitochondrial cytochrome c oxidase to effectively compete with oxygen has been suggested be involved in a number of processes. NO-elicited events act as triggers by which mitochondrial signal transduction cascades become involved in the induction of cellular defence mechanisms and adaptive responses. Moreover, the effect of NO on the electron transport chain might lead to mitochondrial dysfunction and pathology. NO clearly has a multifaceted role in the healthy and unhealthy retina. 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