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Dissertations / Theses on the topic 'Signal transduction'
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Lioubin, Mario N. "Fms signal transduction, p150S̳h̳i̳p̳ : a signal transduction molecule with inositol 5-phosphatase activity /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/6339.
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Stefansson, Anne. "Mechanisms of Integrin Signal Transduction." Doctoral thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8221.
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<p>Integrins are a protein family of cell surface receptors, expressed in all cell types in the human body, except the red blood cells. Besides their importance in mediating physical connections with the surrounding environment, the integrin family members are also vital signalling mediators. They have no intrinsic kinase activity; instead the signals are transduced through conformational changes. </p><p>In this thesis, work is presented which is focused on molecular mechanisms of integrin signal transduction. The signal transduction was first studied from a structural point of view, determining the transmembrane domain borders of a few selected integrin family members and ruling out a signalling model involving a “piston-like” movement. </p><p>Then, downstream signalling events involved in the beta1 integrin-induced activation of Akt via the PI3kinase family were characterized. Our results identify a novel pathway for PI3K/Akt activation by beta1 integrins, which is independent of focal adhesion kinase (FAK), Src and EGF receptor. Furthermore, both beta1 integrins and EGF receptors induced phosphorylation of Akt at the regulatory sites Thr308 and Ser473, but only EGF receptor stimulation induced tyrosine phosphorylation of Akt.</p><p>Finally, signals from beta1 integrins underlying the morphologic changes during cell spreading were studied. A rapid integrin-induced cell spreading dependent on actin polymerisation was observed by using total internal reflection fluorescence (TIRF) microscopy. This integrin-induced actin polymerisation was shown to be dependent on PI3K p110alpha catalytic subunit and to involve the conserved Lys756 in the beta1-integrin membrane proximal part.</p>
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Ghislain, Julien Johannes. "Type I interferon signal transduction." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0015/NQ27652.pdf.
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Partch, Carrie L. Sancar Aziz. "Signal transduction mechanisms of cryptochrome." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,267.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.<br>Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics." Discipline: Biochemistry and Biophysics; Department/School: Medicine.
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Vieira, Elaine. "Signal Transduction of Glucagon Secretion." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6319.
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Priestley, Alistair James. "Signal transduction pathways in plants." Thesis, Lancaster University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250567.
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James, L. R. "Calcium signal transduction in astrocytes." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605022.
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Ca<sup>2+</sup> signals can exhibit great spatiotemporal complexity, leading to the hypothesis that the dynamics of Ca<sup>2+</sup> signals may allow astrocytes to discriminate between stimuli. An <i>in vitro</i> model system of primary cerebellar and cortical astrocytes was tailored to test this hypothesis, by comparing the kinetics of the Ca<sup>2+</sup> signal evoked by different receptor agonists. It was found that known physiological agonists triggered highly heterogeneous responses, but there were no systematic trends in the specific kinetic parameters of Ca<sup>2+</sup> signals that depended on the agonists which triggered them. These results suggest that the encoding of information as to agonist identity in the timing of the Ca<sup>2+</sup> signal is unlikely to be feasible. However, different agonists vary in the efficacy with which they trigger cell-wide Ca<sup>2+</sup> signals suggesting that there is a discrete probability that cultured astrocytes will respond to a given agonist with an all-or-none Ca<sup>2+</sup> signal. The probability of triggering a response can be enhanced by the neuromodulator nitric oxide (NO), acting through its receptor, soluble guanylyl cyclase (sGC). The mechanism of this “gain modulation” involves activation of PKG and PKC modulating an aspect of the G<sub>q</sub> signalling pathway in a manner that increases Ca<sup>2+</sup> excitability. Further investigations revealed complex crosstalk between the NO and Ca<sup>2+</sup> signalling pathways at multiple levels. In summary, the kinetics of Ca<sup>2+</sup> signalling in cultured astrocytes while heterogeneous, do not appear to vary predictably between physiological stimuli. Instead, the probability of response does vary according to receptor agonist, and can be enhanced by co-stimulation with NO. Given the close proximity between the astrocytic endfeed and CNS capillary and neuronal networks, but of which generate NO, there is potential for this crosstalk to modulate the activity of astrocytes <i>in vivo</i>.
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Simonson, Michael Scott. "Signal Transduction in Diabetic Nephropathy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1343145610.
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Pat, Betty Kila. "Signal transduction pathways in renal fibrosis /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17739.pdf.
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Sundström, Magnus. "Signal Transduction in Mast Cell Migration." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1474.
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<p>Mast cells are essential effector cells in the immune system as they release several inflammatory mediators. An accumulation of mast cells has been described in inflammatory conditions such as asthma and allergic rhinitis. Increased mast cell number, in the skin and other organs, is also a characteristic in mastocytosis, a disease without an effective treatment. One explanation for the increase in mast cell number is migration of mast cells in the tissue. In our studies we utilised mast cell lines, including HMC-1; cell lines transfected with the <i>c-kit</i> gene; and <i>in vitro</i> developed mast cells.</p><p>Our aim was to characterise, two variants of the HMC-1 cell line; the signalling pathways essential for mast cell migration towards TGF-β and SCF; and the mechanism regulating mast cell accumulation in mastocytosis.</p><p>Our results help to explain inconsistent findings regarding mast cell biology when HMC-1 cells have been used as a model system. The two variants, which we name HMC-1<sup>560</sup> and HMC-1<sup>560, 816</sup>, are used in different laboratories around the world. HMC-1<sup>560</sup> and HMC-1<sup>560, 816</sup> exhibited different characteristics regarding their karyotype, phenotype as well as their set of activating point mutations in the Kit receptor. Furthermore, divergent signalling pathways are of importance for mast cell migration towards TGF-β and SCF. The classical MAP kinase-signalling cascade was found to be of major relevance for TGF-β-induced migration. In contrast, this pathway had a modest impact on SCF-induced migration, which instead was highly dependent on p38 MAP kinase signalling. Finally, one mechanism for mast cell accumulation in mastocytosis appeared to be an activating point mutation in the gene for the Kit receptor. This mutation appeared to prone transfected cells and mast cell progenitors to a higher rate of migration towards SCF if compared with cells expressing wt Kit receptor.</p><p>In conclusion, our results show the importance of two different MAP kinase signalling pathways and mutations in the Kit receptor for mast cell migration induced by various types of stimuli. This knowledge helps us to understand the mechanism </p>
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Valdimarsdóttir, Gudrun. "TGFβ Signal Transduction in Endothelial Cells". Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4284.
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<p>Transforming growth factor β (TGFβ) is a multifunctional cytokine that is involved in many biological effects, such as proliferation, migration, differentiation and cell survival. TGFβ regulates cellular responses by binding to a heteromeric complex of type I and type II serine/threonine kinase receptors. The type I receptor, termed activin receptor-like kinase (ALK), acts downstream of the type II receptor and propagates the signal to the nucleus by phosphorylating receptor regulated Smads (R-Smads). The activated R-Smads can associate with the common partner Smad, Smad4, and this complex translocates to the nucleus where it participates in transcriptional regulation of target genes. TGFβ plays an important role in vascular morphogenesis. The aim of this study was to obtain more insight into the mechanisms by which TGFβ can act as an inhibitor or stimulator of angiogenesis Our findings show that in endothelial cells (ECs), TGFβ can activate two distinct type I receptor/Smad signalling pathways with opposite cellular responses. In most cell types, TGFβ signals via the TGFβ type I receptor, ALK5. However, ECs express a predominant endothelial type I receptor, named ALK1. Whereas the TGFβ/ALK1 signalling leads to activation, the TGFβ/ALK5 pathway results in an inhibition of the activation state. This suggests that TGFβ regulates the activation state of the endothelium via a fine balance between these two pathways. We identified genes that are specifically induced by TGFβ mediated ALK1 or ALK5 activation. Id1 was found to be the target gene of the ALK1/Smad1/5 pathway while induction of plasminogen activator inhibitor-1 was activated only by ALK5/Smad2 pathway. Furthermore, ALK1 activated ECs are highly invasive but this property is lost if Id1 expression is specifically knocked-down. ECs invasiveness is highly dependent on αv integrin binding to its extracellular matrix (ECM) protein partner and the invasion requires proteolytic cleavage of the ECM by metalloproteases (MMPs). Hence, TGFβ/ALK1/Id1 pathway may promote invasion by modulating the expression or activity of integrins and MMPs that are well known components of the ECM. Timing and duration of TGFβ signalling are important specificity determinants for its effect on cellular behaviour. After binding to ALK1, TGFβ induces a transient phosphorylation of Smad1/5 but a stable phosphorylation of Smad2 via ALK5. Our studies indicate that Smad7 is potently induced by ALK1 signalling and may recruit a PP1α/TIMAP phosphatase complex to ALK1 to dephosphorylate the receptor and thereby turning off phosphorylation resulting in a temporal activation of TGFβ/ALK1-induced Smad1/5 pathway. This mechanism enables an efficient and tightly temporally controlled activation resulting in the dominance of ALK5 upon prolonged exposure to TGFβ. Bone morphogenetic protein (BMP) is a member of the TGFβ superfamily and signals through Smad1/5. The BMP/Smad1/5 pathway was found to potently activate the endothelium. Id1 was identified as an important BMP target gene in ECs and was sufficient and necessary for BMP-induced EC migration. These studies not only provide new insights into possible molecular mechanisms that underlie activation and quiescence of ECs during physiological angiogenesis but may also explain the vascular phenotypes observed in mice and humans with perturbed TGFβ signalling pathways.</p>
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Ulrich, Luke. "Comparative Genomics of Microbial Signal Transduction." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/7632.
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High-throughput genome processing, sophisticated protein sequence analysis, programming, and information management were used to achieve two major advances in the comparative genomics of microbial signal transduction. First, an integrated and flexible bioinformatics platform and the Microbial Signal Transduction database (MiST) were developed, which facilitated the genome-wide analysis of bacterial signal transduction. This platform was used successfully for the high-throughput identification and classification of signal transduction proteins in more than 300 archaeal and bacterial organisms. Second, analysis of information encoded in prokaryotic genomes revealed that the majority of signal transduction systems consist of one-component systems a single protein containing both input and output domains but lacking phosphotransfer domains typical of two-component systems. The prevalence of one-component systems is a paradigm-shifting discovery because two-component systems are currently viewed as the primary mode of signal transduction in prokaryotes. One-component systems are more widely distributed among bacteria and archaea and display a greater diversity of domains than two-component systems. Additionally, in-depth bioinformatic analyses were performed that further characterized the function of two, input, signaling domains. In summary, this systematic, high-throughput delineation of microbial signal transduction is another step forward in our understanding of the genomic basis of life.
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Dukkipati, Abhiram. "Signal transduction by short-wavelength opsins." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2006. http://proquest.umi.com/login?COPT=REJTPTU0NWQmSU5UPTAmVkVSPTI=&clientId=3739.
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Lennartsson, Johan. "Stem Cell Factor Induced Signal Transduction." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5291-4/.
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Sundström, Magnus. "Signal transduction in mast cell migration /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5130-6/.
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McKay, Jodi Ho-Jung. "HRas intracellular trafficking and signal transduction." [Ames, Iowa : Iowa State University], 2007.
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Brownlie, Zoe. "Regulation of signal transduction by RGS4." Connect to e-thesis, 2007. http://theses.gla.ac.uk/124/.
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Thesis (Ph.D.) - University of Glasgow, 2007.<br>Ph.D. thesis submitted to the Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, 2007. Includes bibliographical references.
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Kim, Hyun Ji. "Development and signal transduction in Dictyostelium." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:4ed80c6e-adc8-46d6-aeaf-c853cef7af77.
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Dictyostelium, is a simple eukaryote that multiplies as separate amoebae. However when nutrients are no longer available it embarks on a developmental programme in which the amoebae collect together by chemotaxis and the resulting aggregates eventually transform into fruiting bodies consisting of a cluster of spores held up on a cellular stalk. The entire process of development normally takes about 24 hours. However there are mutants, termed rapidly developing mutants (rde) which complete development in about two-thirds of this time. RdeA null mutants have been reported to have elevated levels of cyclic AMP that may lead to increased activity of the enzyme, cAMP dependent protein kinase (PKA). I started my work by measuring total cAMP levels in an rdeA mutant along with an aca-/rdeA- double mutant that is expected to have very low level of cAMP due to the absence of the adenylyl cyclase, AC A. Two Dictyostelium adenylyl cyclases were known at the beginning of my work; one is AC A the aggregative enzyme, and the other ACG, expressed only during spore germination. Contrary to expectation, I detected cAMP in aca-/rdeA cells. This raised the question of which enzyme was responsible for producing this cAMP. In collaboration with Dr.Pauline Schaap, I discovered a novel adenylyl cyclase that I initially detected in rdeA and regA mutants but not in wild-type cells. The product of the rdeA gene, RDEA was thought to be an H2-module histidine phosphotrasferase of the kind acting in multi-step phosphorelays. Similarly REGA was believed to be a response regulator associated with a cAMP-phosphodiesterase. It had been proposed that RDEA phosphorylates REGA in a multi-step phosphorelay and it had been shown that it is the phosphorylated form of REGA that is active as a cAMP-PDE. I therefore thought that cAMP produced by the novel AC could be protected in rdeA mutants by the absence of the REGA cAMP-PDE activity and this idea was supported by my finding that the enzyme activity could also be detected in wild-type (aca-) cells when REGA-PDE was inhibited by IBMX. In order to investigate further the proposed phosphorelay model, I tested for possible interaction between RDEA and REGA using the yeast two-hybrid system and also measured intracellular cAMP-phosphodiesterase activity in rdeA and regA mutants. I found that the interaction between RDEA and REGA appeared to be too transient to be detected in the two-hybrid system. In addition rdeA and regA mutants seemed to have levels of intracellular cAMP-phosphodiesterase activity similar to wild type. However REGA-PDE activity measured specifically by immuno-precipitation was completely absent in the regA mutant. It therefore appeared that there is another intracellular cAMP-phosphodiesterase, in addition to the REGA PDE, in Dictyostelium and that the latter cannot be easily detected in total cell lysates. One possible explanation is that the novel adenylyl cyclase exists together with REGA in a complex (that may also include PKA) and that REGA PDE preferentially destroys the cAMP made by the novel adenylyl cyclase. I conclude that rdeA and regA mutants may develop rapidly due to high PKA activity induced by the accumulation of cAMP made by the novel AC when the REGA cAMP-PDE activity is absent.
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Brownlie, Zoe M. "Regulation of signal transduction by RGS4." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/124/.
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In the present study, the function and the mechanism of action of RGS4, a member of a family of proteins called Regulators of G protein Signalling (RGS) was investigated. A C-terminal fluorescent tag on RGS4 confirmed that transiently transfected RGS4 was predominantly cytosolic and underwent translocation to the plasma membrane of HEK293T cells following co-expression of Gi1, the 2A-adrenoceptor, or agonist activated 2A-adrenoceptor. This translocation of RGS4 to the plasma membrane was most pronounced with the co-expression of the constitutively active GTPase deficient Gi1 Q204L. High-affinity GTPase experiments indicated that RGS4S30C had enhanced GAP activity towards Go1 compared to wild type RGS4. This approach also demonstrated a simultaneous significant decrease in potency of both adrenaline and UK14304 to increase 2A-arenoceptor-activated high-affinity GTPase activity of Go1 in the presence of RGS4 and a further significant decrease in potency of both ligands in the presence of RGS4S30C. This enhanced GAP activity and observed decrease in agonist potency was also transferable to RGS16, an RGS protein closely related to RGS4. The selectivity of the G subunit was also investigated. The enhanced GAP activity and simultaneous significant decrease in potency of adrenaline and UK14304 to increase 2A-arenoceptor-activated high-affinity GTPase activity of RGS4S30C and RGS16S30C was selective for Go1 over Gi1. RGS4S30K and RGS4S30F also demonstrated higher GAP activity than wild type RGS4 but no consensus side chain could be identified that conferred a specific enhancement or loss of GAP activity. The ability to inhibit intracellular calcium release by an activated 1b-adrenoceptor-G11 fusion protein was used in order to investigate the GAP activity of RGS4N88S, RGS4N128A and RGS4N88S,N128A. All three mutants had ablated GAP activity towards G11 and therefore failed to inhibit intracellular calcium release. A novel role for the RGS insensitive mutation G188S was also observed when despite similar expression, G11 G188S significantly reduced agonist-stimulated [35S]GTPS binding compared to wild type G11. RGS4 represents a novel target for pharmaceutical drug development and the study of its regulation of signal transduction is an important area of investigation. These results highlight specific areas of RGS4 research with great pharmaceutical potential.
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Lillemeier, Bjorn Freimut. "Signal transduction through JAKS and STATS." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368696.
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Broughton, Nicola Ann. "Specificity in JAK/STAT signal transduction." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300540.
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Ainsworth, Paul. "Chemotaxis signal transduction in Campylobacter jejuni." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/28667.
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The bacterium Campylobacter jejuni is the most common cause of food borne disease in the UK, causing a 5-7 day enteritis including profuse watery diarrhoea, abdominal pain, fever, headache and occasionally vomiting. In rare cases leading to the paralysing autoimmune disease, Guillain-Barré syndrome. C. jejuni are highly motile cells, propelled through the environment by flagella, their motility is directed through a behaviour called chemotaxis. Cells are able to detect attractants or repellents and reposition the cell accordingly. Chemotaxis is central to C. jejuni colonisation as non-motile and non-chemotactic mutant strains poorly colonise their usual hosts. In Escherichia coli chemotaxis is regulated by the Che proteins which form a two component phospho relay system. In previous studies In silico comparison of E. coli Che proteins identified homologues in C. jejuni, which display altered chemotactic phenotypes in Δche mutant strains. Studies of interactions between the Che proteins using bacterial and yeast two hybrid systems, suggested ways in which the homologues may interact, but to further discern these mechanisms required in vitro study. For the purpose of this study the C. jejuni Che homologues were cloned, expressed and purified, for use in in vitro experiments. Radiolabelled Phosphotransfer assays confirmed CheA as a histidine kinase, and demonstrated Pi transfer to the response regulators of CheY, CheV and CheA, in that order of preference. Affinity tag pull-down assays found the predicted decrease in affinity between phosphorylated CheY and CheA, but also an increase in the affinity of phosphorylated CheV for the receptor, TLP[subscript 1]. The results of this study confirm the two component backbone of the C. jejuni Che model, and suggest how CheV may regulate methylation adaption in a system devoid of a CheB response regulator.
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Wang, Haojie. "Na+/K+-ATPase and Signal Transduction." University of Toledo Health Science Campus / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=mco1147300366.
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Coelho, Edgar Duarte de Jesus Valente Marques. "Synaptosomal signal transduction in Alzheimer's disease." Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/7418.
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Mestrado em Biomedicina Molecular<br>Alzheimer’s Disease (AD) is characterized by the presence of amyloid plaques
(APs) and neurofibrillary tangles (NFTs), which consist of Abeta aggregates
and hyperphosphorylated tau, respectively. It is known that increasing Abeta
concentrations precede NFT production. Moreover, several lines of evidence
suggest that the increase in APP and tau phosphorylation is the result of Abeta
neurotoxicity. Although, the precise effects of the neurotoxic peptide on APP
and tau phosphorylation remain yet to be fully elucidated. Synapses exhibit
high concentrations of protein kinases (PKs) and protein phosphatases (PPs).
Therefore, it is essential to adopt a model system that mimics what happens at
the synapse. Synaptosomes are actually recognized as “in vitro synapses” and
for that reason were the model system used.
Our data revealed that there was a considerable enrichment of pre- and postsynaptic
markers in the synaptosomal fraction after synaptosome isolation.
Given these results, we went on to test the effects of Abeta on synaptosomal
viability, which was found to be slightly decreased, confirming the high viability
of synaptosomes. In addition, we observed the increase of APP and tau
phosphorylation after Abeta treatment, while holo-APP and total tau levels were
maintained, independently of Abeta concentrations. These results suggest that
Abeta can actually induce APP and tau hyperphosphorylation. The conclusions
attained from this dissertation are important to comprehend the pathways
related to the pathogenesis of Alzheimer’s disease.<br>A doença de Alzheimer (DA) caracteriza-se pela presença de placas amilóides
e de tranças neurofibrilares, que consistem em acumulações de Abeta e tau
hiperfosforilada, respectivamente. Concentrações crescentes de Abeta
precedem o aparecimento de tranças neurofibrilares. Além disso, vários
estudos sugerem que o aumento da fosfoforilação da APP e da tau no decorrer
da DA é consequência da neurotoxicidade do Abeta. No entanto, os efeitos
específicos do Abeta na fosforilação da APP e da tau ainda não foram
estabelecidos. Há grande abundância de cinases e fosfatases nas sinapses,
sendo portanto fundamental adoptar um modelo de estudo que as mimetize.
De facto, os sinaptossomas são actualmente reconhecidos como “sinapses in
vitro”, e por esse motivo foram o modelo de estudo utilizado.
Os dados obtidos mostraram um considerável enriquecimento de proteínas
pré- e pós-sinápticas na fracção sinaptossomal, após o isolamento de
sinaptossomas. Posto isto, testámos os efeitos do Abeta na viabilidade
sinaptossomal, tendo-se observado a sua diminuição generalizada, o que
confirma a toxicidade do péptido. Foi também observado o aumento da
fosforilação da APP e da tau após o tratamento com Abeta, enquanto que os
níveis de APP e tau totais permaneceram inalterados, independentemente das
concentrações de Abeta. Estes resultados sugerem que o Abeta pode
realmente induzir a hiperfosforilação da APP e da tau. As conclusões retiradas
desta dissertação são importantes para compreender melhor as vias
relacionadas com a patogénese da DA.
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Atherton, Philip James. "Signal transduction in skeletal muscle mediating responses to phenotype altering signals." Thesis, University of Central Lancashire, 2005. http://clok.uclan.ac.uk/8584/.
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Skeletal muscle phenotype, size and function respond to exercise, disease and ageing. The aim of this thesis was to investigate the signal transduction pathways responsible for selected skeletal muscle phenotype and size changes. Myostatin, recently identified as a negative regulator of muscle mass was exposed at 10 ng ml 4 to C2C12 cells, and using cDNA genome-wide profiling, was shown to act as a transcriptional suppressor. Furthermore, in these cells myostatin significantly (n8, p<0.05) reduced phosphorylation of components in the P1-3K pathway: PKB Ser473 -30 %, mTOR Ser2448 -50 %, p70 S6K Thr389 -60 %, whereas 4E-BP1 Thr37/46 remained unaffected. These data provide insights in to the mechanisms by which myostatin controls muscle mass, through negatively affecting transcription and translation. Differences in the concentrations of signalling proteins often alter cellular function and phenotype, as is evident from numerous heterozygous knock-out models. Whilst the levels of metabolic enzymes differ between fibre types, and are regulable by exercise, it is not known if this is also true of signal transduction proteins. Therefore, it was hypothesised that the relative levels of signalling proteins implicated in the adaptation to exercise in both fast rat extensor digitorum longus (EDL; 3% type I fibres) and slow Soleus (84% type I fibres) would be systematically different. Secondly, it was hypothesised that following 6 weeks of chronic electrical stimulation (CMNS) where the EDL undergoes a fast-to-slow transformation, the relative signalling protein concentrations between control EDL/stimulated EDL would mirror the differences shown in control EDL/Soleus. Finally, that CMNS would induce chronic signalling to produce, and maintain a slower phenotype. Western blots revealed that the concentrations of some proteins such as Calcineurin (2.6-fold) and p38 MAPK (1.36-fold) were higher in EDL, whilst others such as PGC-la (1.4-fold); and NFkB (3-fold) (all n=4, pc0.05) were higher in Soleus. CMNS of EDL also led to changes in protein levels between control EDL/stimulated EDL: AMPK which is higher in Soleus was actually 1.4-fold lower following stimulation of EDL, whereas other proteins such as PGC-la moved in the direction of that of Soleus. CMNS was also able to induce chronic phosphorylation of proteins involved in fibre type and mitochondrial biogenesis, such as AMPK 4 fold, and p38 -4.5-fold. These data show that signal transduction protein concentrations vary between fast and slow muscles, presumably reflecting differences at a fibre level. Furthermore, signalling proteins are regulated by CMNS of EDL, but do not always change in the direction of slow Soleus. Chronic phosphorylation of many signalling proteins can explain the characteristic phenotypic change in response to CMNS. Resistance training stimulates adaptive protein synthesis and hypertrophy whereas endurance training induces a partial fast-to-slow fibre phenotype transformation. To simulate these conditions, isolated rat muscles were stimulated at 25 °C with either high frequency (HFS; 6 x 10 repetitions, 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3 and 2.7-fold, respectively (n=6, p<0.05). LFS had no significant effect on protein synthesis 3 h after stimulation, but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA (n6, p<0.05). Only LFS increased AMPK phosphorylation significantly at Thr172 by 2-fold and increased POC- 1 a protein to 1.3-fold of control. LFS had no effect on PICB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3j3 at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 56k, 4E-BPI, eIF2B, and eEF2 (all n=8, p<0.05). This behaviour has been termed the AMPK-PICB switch, and is hypothesised to mediate specific adaptations to endurance and resistance training, respectively. Ageing is associated with a loss of muscle mass tenned sarcopenia. Essential amino acids (EAA) are potent stimulators of muscle protein synthesis (MPS), and therefore defects in EAA-induced anabolism might affect ability to maintain muscle mass in ageing and disease. MPS and signalling responses to EAA-stimulation of 20 fasted young versus 24 elderly subjects (age 28 ± 6 and 70 ± 6; BMI 24 ± 3, 25 ± 4 kg.m 2 respectively; means ± SD) and 8 fasted elderly versus 8 elderly with type II DM (age 66 ± 3 and 70 ± 6; BMI: 25 ± 4 vs. 32 ± 2 kg.m 2, respectively means ± SD) were measured using gas combustion mass spectrometry and Western blotting methods. Basal MPS rates were indistinguishable, but the elderly displayed a reduced anabolic responsiveness of MPS to EAA, possibly due to decreased intramuscular phosphorylation after EAA, of amino acid sensing/signalling proteins mTOR, p70 S6 kinase, 4E-BPI and eIF2Bs by —50 %. This was further exacerbated in elderly with type II DM whom exhibited reduced Ser2448 phosphorylation of mTOR by —50 %, reflecting decreased downstream signalling. Associated with the anabolic deficits were — 4-fold increases in NFiB protein, the inflammation-associated transcription factor, as well as —50 % and —20 % decreases in protein expression of p70 S6K of healthy elderly and elderly with type II DM, respectively. These results suggest that the elderly are unable to mount a full anabolic response to EAA and that this blunting is further pronounced in type II DM.
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Schlesner, Matthias. "The halobacterium salinarum taxis signal transduction network." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-102084.
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Weismüller, Marco [Verfasser]. "Simulation of signal transduction pathways / Marco Weismüller." Ulm : Universität Ulm. Fakultät für Informatik, 2004. http://d-nb.info/1015439071/34.
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Gong, Yunchen 1965. "Analyses of alternative cell signal transduction pathways." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85552.
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Living cells keep sensing the changes in their environments, mostly, via cell surface receptors for different ligands. Attachment-dependent cells are sensitive to alterations in extracellular matrix (ECM). ECM is not only required for cell survival, but also prerequisite for epidermal growth factor (EGF) to stimulate cell proliferation. The receptors for the majority of ECM components are integrins and the receptor for EGF is EGF receptor (EGFR). When bound by their ligands, integrins and EGFR induce signal transduction cascades composed of alternative pathways. A quantitative assessment of relative contributions of alternative pathways to one final cell signaling will help understand designing principles of the network. Unfortunately, a methodology for such assessment is still not available, partly because of lack of relatively mature mathematical models. On the other hand, in most biochemical cascades, existence of alternative pathways increases the complexity and thus the robustness of networks. The relationships between the topology and robustness of large-scale biochemical networks have been studied intensively recently. In small-scale networks, while feedback has been revealed as an important contributor for adaptation and robustness, the quantitative correlation between the topology/pathway redundancy of small networks and their robustness remains unknown.<br>In this thesis, apoptosis of bovine mammary gland epithelial cells was demonstrated to be induced when fibronectin, one of the major components of ECM, was degraded by overexpressed tPA via two potential ways: deprivation of attachment and the effects of fibronectin fragments. Secondly, a mathematical model for EGFR activation of the MAPK cascade, in which alternative pathways exist, was explored and it was found that the Shc-dependent pathway is both redundant and dominant. We hypothesize that the Shc-dependent pathway is important for EGFR to compete with other receptors, which need Shc to transduce cell signals; and this pathway is not aimed to increase the robustness of the EGFR cascade. Finally, for the general importance of alternative pathways to the network topology and robustness, several concepts have been proposed to decompose and quantitatively characterize the networks. We demonstrate that the pathnet score is a better assessment for robustness than the molecular connectivity.
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Cieslak, Alicja. "Two-component signal transduction in Actinobacillus actinomycetemcomitans." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101710.
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While some strains of Actinobacillus actinomycetemcomitans serve as causative agents of Localized Aggressive Periodontitis (LAP), there are strains of A. actinomycetemcomitans that live as members of the microflora in the oral cavities of periodontally healthy individuals. Two-component signal transduction is an important determinant of bacterial behaviour and plays an essential role in the regulation of virulence factors. Hence, our study investigates the two-component systems (TCSs) among A. actinomycetemcomitans strains of varying virulence levels. Among the groups of highly and mildly virulent strains that were studied, we found there to be significant differences in the ygiX/ygiY TCS. In the most virulent strains, the genes encoding the ygiX/ygiY TCS are part of an operon that includes 4 phage-related genes and a gene homologous to ygiW a gene that encodes a periplasmic protein. Hence, considering the importance of TCS in the regulation of virulence, we hypothesize that the ygiX/ygiY TCS might play a significant role in the regulation of virulence factors in highly virulent strains of A. actinomycetemcomitans . Further characterization of the ygiX/ygiY TCS will determine whether it indeed regulates the expression of genes that encode virulence factors.
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Whitworth, Emma Jane. "Adrenocortical proliferation and signal transduction 'in vitro'." Thesis, Queen Mary, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415058.
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Valejev, Najl V. "In silico analysis of signal transduction proteins." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432258.
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Chang, Wen-Tsan. "Molecular studies of signal transduction and development." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360212.
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Dixon, Mark. "Signal transduction mechanisms involved in hepatocyte proliferation." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245710.
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Bellamy, Tomas Cynric. "Nitric oxide signal transduction in the cerebellum." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367871.
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Onley, Catherine Mary. "Glycoprotein VI signal transduction in human platelets." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615707.
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Yu, Xiang. "Wingless signal transduction during Drosophila embryonic development." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624339.
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May, Michael Jonathan. "Cytokine-induced signal transduction in endothelial cells." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339150.
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Latimer, Heather Ruth. "Mechanisms of H₂O₂-induced signal transduction." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3671.
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Reactive oxygen species (ROS), including H2O2, are produced as unavoidable by-products of aerobic respiration, leading to oxidative stress and the initiation and development of many diseases, particularly age-associated diseases. Cells have evolved antioxidant and repair enzymes to protect against ROS, including the 2-Cys peroxiredoxins (Prx) family, a group of extremely abundant, highly conserved peroxidases. H2O2 initiates protective cell responses that include increasing expression of these enzymes. Counterintuitively, typical 2-Cys Prx have also been shown to have important roles in promoting stress-induced signal transduction, and as molecular chaperones, independent of their thioredoxin peroxidase activity. Although H2O2’s function as a signalling molecule is now well-established, the targets of H2O2 signals and the mechanisms by which these targets are regulated are poorly characterised. Studies in yeast models have provided some of the best evidence to date for the positive signalling roles of low levels of H2O2 to drive adaptive responses to limit damage. For example, in the fission yeast Schizosaccharomyces pombe, different levels of H2O2 activate distinct signal transduction pathways and transcriptional responses that protect cells against the toxic effects of increased ROS. Previous work has established that the single typical 2-Cys Prx, Tpx1, is essential for H2O2-induced gene expression. In S. pombe, Tpx1 is needed to promote the H2O2-induced activation of the AP-1-like transcription factor Pap1 and the p38/JNK related mitogen activated protein kinase (MAPK), Sty1, by mechanisms involving oxidation of cysteine residues. The overall aim of this project was to use biochemical and genetic approaches to investigate the molecular mechanisms underlying H2O2- sensing in the genetically amenable model organism, S. pombe. In this study we have identified that Tpx1 stimulates inactivation of the protein tyrosine phosphatase (PTP) Pyp1, to promote activation of the Sty1 pathway in response to low concentrations of H2O2. We have identified that Pyp1 undergoes multiple post-translational modifications, including oxidation and 4 phosphorylation in response to H2O2. We have examined the role of these modifications in regulating H2O2-induced activation of Sty1, identifying that H2O2-induced formation of a disulphide with thioredoxin, and stress-induced phosphorylation by the MAPKK Wis1, are important for maintaining Pyp1 function in cells exposed to increasingly stressful conditions. Moreover, we have also investigated the relationship between related PTP in the control of H2O2-induced Sty1 activation, identifying an unexpected role for Pyp1 in promoting the expression of the stress-induced PTP, Pyp2. Oxidation of the catalytic cysteine in the glycolytic GAPDH enzyme, Tdh1, has previously been shown to be important for H2O2-induced activation of Sty1. Indeed, GAPDH’s susceptibility to H2O2-induced oxidation of its catalytic cysteine has been proposed to have evolved as an important protective response to H2O2. Here we show that although a second cysteine in the active site of Tdh1 is important for the H2O2-induced oxidation of Tdh1 and oxidative stress resistance, this oxidation is not important for the H2O2-induced activation of Sty1. Having found that Tpx1 is required for the oxidation of Pap1, Sty1, Pyp1 and Tdh1, we have also investigated whether Tpx1 act as direct H2O2 transducers to promote the oxidation of these and other proteins. This has provided further insight into the mechanisms involved in activation of Pap1, and also identified many potential new candidates for Tpx1-dependent regulation by H2O2. These include a conserved MAPK activated kinase, Srk1, that we show inhibits cell cycle progression by a mechanism that is partially dependent on Tpx1. In summary, this study has identified new mechanisms involved in protective responses to increases in H2O2. In particular, it has provided new insight into how cells regulate the activity of stress-activated MAPK and GAPDH to coordinate appropriate responses to rises in ROS.
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Manne, Bhanu Kanth. "CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/340495.
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Physiology<br>Ph.D.<br>Platelets are involved in many processes ranging from fighting microbial infections and triggering inflammation to promoting tumor angiogenesis and metastasis. Nevertheless, the primary physiological function of platelets is to act as essential mediators in maintaining homeostasis of the circulatory system by forming hemostatic thrombi that prevent blood loss and maintain vascular integrity. CLEC-2 is a C-type lectin-like receptor that is highly expressed in platelets and lesser extent, in other cell types such as activated dendritic cells and B cells. Rhodocytin was the first ligand used to identify CLEC-2 receptor and it’s signaling on platelets. In the first chapter we identified a new agonist for CLEC-2 receptor. Fucoidan, a sulfated polysaccharide from fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration-dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylation of Syk and Phospholipase Cγ−2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRγ chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets. Lipid rafts are distinct areas of the plasma membrane implicated in the regulation of signaling in a variety of cells including platelets. A previous study C-type lectin like receptor 2 (CLEC-2) has been reported to activate platelets through a lipid raft-dependent manner. Secreted ADP potentiates CLEC-2-mediated platelet aggregation. We have investigated whether the decrease in CLEC-2-mediated platelet aggregation, previously reported in platelets with disrupted rafts, is a result of the loss of agonist potentiation by ADP. We disrupted platelet lipid rafts with methyl-β-cyclodextrin (MβCD) and measured signaling events downstream of CLEC-2 activation. Lipid raft disruption decreases platelet aggregation induced by CLEC-2 agonists. The inhibition of platelet aggregation by the disruption of lipid rafts was rescued by the exogenous addition of epinephrine but not 2-methylthioadenosine diphosphate (2MeSADP), which suggests that lipid raft disruption effects P2Y12-mediated Gi activation but not Gz. Phosphorylation of Syk (Y525/526) and PLCγ2 (Y759), were not affected by raft disruption in CLEC-2 agonist-stimulated platelets. Furthermore, tyrosine phosphorylation of the CLEC-2 hemi-ITAM was not effected when MβCD disrupts lipid rafts. Lipid rafts do not directly contribute to CLEC-2 receptor activation in platelets. The effects of disruption of lipid rafts in in vitro assays can be attributed to inhibition of ADP feedback that potentiates CLEC-2 signaling. Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an Immune Tyrosine Activation Motif (ITAM) and hemi-ITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the intracellular domain. The mechanisms by which this receptor activates Syk are not completely understood. In chapter 3, we identified a novel signaling mechanism in CLEC-2-mediated Syk activation. CLEC-2-mediated, but not GPVI-mediated, platelet activation and Syk phosphorylation were abolished by inhibition of PI3-Kinase, which demonstrates that PI3-Kinase regulates Syk downstream of CLEC-2. Ibrutinib, a Tec family kinase inhibitor, also completely abolished CLEC-2-mediated aggregation and Syk phosphorylation in human and murine platelets. Furthermore, embryos lacking both Btk and Tec exhibited cutaneous edema associated with blood-filled vessels in a typical lymphatic pattern similar to CLEC-2 or Syk-deficient embryos. Thus our data show, for the first time, that PI3-Kinase and Tec family kinases play a crucial role in the regulation of platelet activation and Syk phosphorylation downstream of CLEC-2 receptor.<br>Temple University--Theses
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Haberl, Florian Max. "Molecular modeling studies on signal transduction proteins." kostenfrei, 2008. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2008/1083/.
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Hung, Hiu Wai. "Signal transduction mechanism in xenopus presynaptic differentiation /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202003%20HUNG.
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Tomsett, Michael. "Signal transduction in helical oligomers and polymers." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.742998.
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Legewie, Stefan. "Systems biological analyses of intracellular signal transduction." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/16018.
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An der Interpretation extrazellulärer Signale beteiligte Regulationsnetzwerke sind von zentraler Bedeutung für alle Organismen. Extrazelluläre Signale werden gewöhnlich durch enzymatische Kaskaden innerhalb weniger Minuten in den Zellkern weitergeleitet, wo sie langsame Änderungen der Genexpression bewirken und so das Schicksal der Zelle beeinflussen. Im ersten Teil der Arbeit wird durch mathematische Modellierung untersucht, wie die MAPK Kaskade Signale von der Zellmembran in den Kern weiterleitet. Es wurden Netzwerkeigenschaften herausgearbeitet, die verhindern, dass die MAPK Kaskade fälschlicherweise durch genetische Mutationen aktiviert wird. Desweiteren wurde eine versteckte positive Rückkopplungsschleife identifiziert, welche die Aktivierung der MAPK Kaskade oberhalb eines gewissen Schwellwert-Stimulus verstärkt. Der zweite Teil der Arbeit konzentriert sich darauf, wie Änderungen der Genexpression auf langsamer Zeitskala in das Signalnetzwerk rückkoppeln. Eine systematische Genexpressionsdaten-Analyse ergab, dass transkriptionelle Rückkopplung in Eukaryoten generell über Induktion kurzlebiger Signalinhibitoren geschieht. Dynamische Modellierung und experimentelle Validierung von Modellvorhersagen ergab, dass das Inhibitorprotein SnoN als zentraler negativer Feedback Regulator im TGFbeta Signalweg fungiert. Der dritte Teil der Arbeit untersucht, wie die Genexpressionsmaschinerie intrazelluläre Signale interpretiert (“dekodiert“). Eine experimentelle und theoretische Analyse der cyanobakteriellen Eisenstress-Antwort ergab, dass IsrR, eine kleine regulatorische RNA, die Genexpression auf ausreichend starke und lange Stimulation beschränkt. Des Weiteren wurde ein “Reverse Engineering“-Algorithmus auf Hochdurchsatz-RNAi-Daten angewendet, um die Topologie eines krebsrelevanten Transkriptionsfaktornetzwerks abzuleiten. Zusammenfassend wurde in dieser Dissertation gezeigt, wie mathematische Modellierung die experimentelle Analyse biologischer Systeme unterstützen kann.<br>Intracellular regulatory networks involved in sensing extracellular cues are crucial to all living organisms. Extracellular signals are rapidly transmitted from the cell membrane to the nucleus by activation of enzymatic cascades which ultimately elicit slow changes in gene expression, and thereby affect the cell fate. In the first part of this thesis, the Ras-MAPK cascade transducing signals from the cell membrane to the nucleus is analyzed using mathematical modeling. Model analysis reveals network properties which prevent the MAPK cascade from being inappropriately activated by mutations. Moreover, the simulations unveil a hidden positive feedback loop which ensures strong amplification of MAPK signalling once extracellular stimulation exceeds a certain threshold. The second part of the thesis focuses on how slow gene expression responses feed back into the upstream signalling network. A systematic analysis of gene expression data gathered in mammalian cells demonstrates that such transcriptional feedback generally involves induction of highly unstable signalling inhibitors, thereby establishing negative feedback regulation. Dynamic data-based modelling identifies the SnoN oncoprotein as the central negative feedback regulator in the TGFbeta signalling pathway, and corresponding model predictions are verified experimentally in SnoN-depleted cells. The third part of the thesis focuses on how intracellular signals are decoded by the downstream gene expression machinery. A combined experimental and theoretical analysis of the cyanobacterial iron stress response reveals that small non-coding RNAs allow cells to selectively respond to sufficiently strong and sustained stimuli. Finally, a reverse engineering approach is applied to derive the topology of a complex mammalian transcription factor network from high-throughput knock-down data. In conclusion, this thesis demonstrates how mathematical modelling can support experimental analysis of biological systems.
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Young, Jared. "Carbon dioxide signal transduction in Arabidopsis guard cells." Diss., Connected to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3187824.
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Thesis (Ph. D.)--University of California, San Diego, 2005.<br>Title from first page of PDF file (viewed March 6, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Borowski, Peter. "Stochastic dynamics in olfactory signal transduction and development." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1159519135136-22697.
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The purpose of the senses of animals (and humans) is to translate information available in the external environment into internal information that can be processed by the brain. In the case of the olfactory sense -- the sense of smell -- this is information about the type and concentration of odourants. In the last 15 years major progress has been made in the experimental understanding of the first two stages of the olfactory sense: the signal transduction inside the cilia of the olfactory receptor neurons and the first 'relay station' in the brain, the olfactory bulb, as well as the connection between these two. Theoretical studies that classify the experimentally achieved knowledge or help in testing different biological hypotheses are only starting to be developed. The present work aims to contribute to the theoretical understanding of the first two stages of the olfactory sense. The first processing of the olfactory information, the olfactory signal transduction, is accomplished by a complex chemical network in the sensory cells with the task of coding the available information reliably over a wide range of stimulus strength. In the present work, methods from nonlinear dynamics combined with network theory (namely stoichiometric network analysis) are used to identify a specific negative feedback mechanism that accounts for a number of recently measured experimental results, e.g. oscillations in calcium concentration or the adaptation of the cell towards strong stimuli. This feedback is an experimentally well-established inhibition of cationic channels by the calcium-loaded form of the protein calmodulin. The results of the set of coupled nonlinear deterministic differential equations describing these dynamics agree quantitatively with experimental data. A bifurcation analysis of the system considered shows the robustness of the oscillatory solution against changes in parameters used. It also gives predictions that could serve as an experimental test of the proposed mechanism. Further abstraction and simplification of this specific signal transduction unit leads to a stochastic two-level system with negative feedback, that can not only be found in signalling systems but also in other branches of cell biology, e.g. regulated enzyme activity or in transcription dynamics. Whereas the description outlined above is fully deterministic, here the model system is intrinsically noisy. The influence of the feedback on the intrinsic noise as well as on the signalling properties of the module are analysed in detail by computing mean values, correlation and response functions of the two dynamical system variables using different analytical approaches. Common to all of them is that the intrinsic noise of the system is calculated from its dynamics rather than being introduced by hand. A master equation is used to get generally valid expressions for the mean values. Correlation and response functions for weak feedback are calculated within a path-integral description, and an easier self-consistent method with restricted validity is developed for future extensions of the module such as, e.g., the inclusion of diffusion. The results of the analytical methods are compared to each other and to the results of extended numerical simulations. The considered quantities allow for statements regarding the quality of the signal transduction properties of this module and the positive and negative effects of feedback on it. Going one step up in the information processing in the olfactory sense, another system is found that shows interesting dynamics during development and is influenced by stochastic effects: the formation of the neural map on the surface of the olfactory bulb -- stage two in the olfactory system. The dynamics of this very complex biological pattern formation process is studied mostly numerically focusing on three different aspects of axonal growth. Possible chemical guidance cues and the reaction of axonal growth cones to them are described using different levels of detail. There is strong experimental evidence for interactions among growing axons which is implemented in different ways into models. Finally, axon turnover is considered and used in the most promising simulation approach, where many axons grow as interacting directed random walkers. For each of these aspects, qualitative features of respective experiments are reproduced<br>Die Sinne der Tiere (und Menschen) dienen dazu, Informationen über die Aussenwelt in neuronale, ' interne' Information zu 'übersetzen'. Im Falle des Geruchssinns sind dies Informationen über die Art und Konzentration von Geruchsstoffen. In den letzten 15 Jahren wurden grosse Fortschritte im experimentellen Verständnis der ersten beiden Stufen des Geruchssinns gemacht, sowohl was die Signaltransduktion in den Zilien der Geruchszellen betrifft, als auch bezüglich der ersten 'Schaltstelle' im Gehirn, dem olfaktorischen Bulbus (sowie in der Verbindung dieser beiden Stufen). Die Entwicklung theoretischer Studien, die die experimentell gewonnenen Daten klassifizieren können, befindet sich dagegen erst am Anfang. Ziel der vorliegenden Arbeit ist es, zum theoretischen Verständnis dieser ersten beiden Stufen beizutragen. Die erste Verarbeitung der olfaktorischen Information, die olfaktorische Signaltransduktion, wird durch ein komplexes chemisches Netzwerk in den Sinneszellen bewerkstelligt. In dieser Dissertation werden Methoden der nichtlinearen Dynamik, kombiniert mit Netzwerktheorie (stöchiometrische Netzwerkanalyse) benutzt, um einen negativen Rückkopplungsmechanismus zu identifizieren, der einige in neuerer Zeit gewonnene experimentelle Ergebnisse erklären kann, u.a. Oszillationen der Kalziumkonzentration oder die Anpassung der Zelle an starke Reize. Bei dieser Rückkopplung handelt es sich um eine experimentell gut bestätigte Hemmung eines Kationenkanals durch den Kalziumkomplex des Proteins Calmodulin. Das Ergebnis der vier gekoppelten nichtlinearen deterministischen Differenzialgleichungen, die das dynamische Verhalten des Systems beschreiben, stimmt quantitativ mit experimentellen Daten überein. Eine Bifurkationsanalyse zeigt die Robustheit der oszillierenden Lösung gegenüber Veränderungen der verwendeten Parameter und macht Vorhersagen möglich, die als experimentelle Tests des vorgeschlagenen Mechanismus dienen können. Eine weitere Abstrahierung der oben beschriebenen Signaltransduktionseinheit führt zu einem stochastischen Zweiniveausystem mit negativer Rückkopplung, das nicht nur in Signalsystemen gefunden werden kann, sondern auch in anderen Bereichen der Zellbiologie. Im Gegensatz zu der oben beschriebenen, komplett deterministischen Beschreibung zeigt das hier betrachtete Modellsystem intrinsisches Rauschen. Der Einfluss der Rückkopplung auf das Rauschen sowie auf die Signalübertragungseigenschaften des Moduls werden detailliert analysiert, indem mit Hilfe verschiedener analytischer Methoden Mittelwerte, Korrelations- und Antwortfunktionen des Systems ausgerechnet werden. Diese Methoden habe alle gemein, dass das intrinsische Rauschen des Systems aus der Dynamik selbst berechnet wird und nicht ' von Hand' eingefügt wird. Um allgemeingültige Ausdrücke für die Mittelwerte zu bekommen, wird eine Mastergleichung aufgestellt und gelöst. Die Korrelations- und Antwortfunktionen werden für schwache Rückkopplung mit Hilfe einer Pfadintegralmethode ausgerechnet, und eine einfachere, selbstkonsistente Methode begrenzter Gültigkeit wird für mögliche Erweiterungen des Systems, z.B. die Berücksichtigung von Diffusion, entwickelt. Die Ergebnisse der verschiedenen analytischen Methoden werden miteinander und mit den Ergebnissen ausführlicher numerischer Simulationen verglichen. Die betrachteten Grössen ermöglichen Aussagen über die Qualität der Signaltransduktion dieses Moduls sowie über die positiven und negativen Effekte der Rückkopplung auf diese. Ein weiteres Beispiel für interessante und von stochastischen Effekten beeinflusste Dynamik findet man einen Schritt weiter in der olfaktorischen Signalverarbeitung: Die während der Entwicklung stattfindende Ausbildung der neuronalen Karte auf der Oberfläche des olfaktorischen Bulbus, der zweiten Stufe des olfaktorischen Systems. Die Dynamik dieser sehr komplexen biologischen Musterbildung wird mittels numerischer Simulationen untersucht, wobei der Schwerpunkt auf drei verschiedene Aspekte axonalen Wachstums gesetzt wird. Die Reaktion axonaler Wachstumskegel auf mögliche chemische Signalstoffe wird verschieden detailliert beschrieben. Es gibt deutliche experimentelle Hinweise auf Wechselwirkung zwischen Axonen, was in den Modellen auf verschiedene Arten implementiert wird. Schliesslich wird die Erneuerung der Axone betrachtet und im vielversprechendsten Modell, in dem viele Axone als wechselwirkende gerichtete random walkers simuliert werden, berücksichtigt und analysiert. Für jeden dieser drei Aspekte können entsprechende experimentelle Ergebnisse qualitativ reproduziert werden
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Adams-Phillips, Lori C. "Molecular analysis of ethylene signal transduction in tomato." Texas A&M University, 2003. http://hdl.handle.net/1969.1/1599.
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The plant hormone ethylene plays an important role in plant growth, development, and physiology. One of the critical components of the ethylene signal transduction pathway, ctr1 (constitutive triple response), was identified using a particularly useful seedling screen that takes advantage of the profound effects ethylene has on etiolated seedlings, known as triple response. CTR1 is one of six Arabidopsis MAPKKKs that are related to the Raf kinases, and acts as a negative regulator of ethylene response. In this study, isolation and characterization of a family of CTR1-like genes in tomato is reported. Based on amino acid alignments and phylogenetic analysis, the tomato CTR1-like (LeCTR) genes are more similar to Arabidopsis CTR1 (AtCTR1) than any other MAPKKK sequences in the Arabidopsis genome. The capacity of the LeCTR genes to function as negative regulators in ethylene signal transduction was tested through complementation of the Arabidopsis ctr1-8 mutant. Quantitative real-time PCR was carried out to generate an expression profile for the CTR1-like gene family during different stages of development marked by increased ethylene biosynthesis, including fruit ripening. The possibility of a multi-gene family of CTR1-like genes in other species besides tomato was examined through mining of EST and genomic sequence databases.
Based on nucleotide and amino acid identity, At4g24480 is most similar to AtCTR1 and could potentially represent a CTR1-like gene in Arabidopsis. Arabidopsis plants carrying a T-DNA insert in the At4g24480 locus were examined for abnormal ethylene response phenotypes including sensitivity to other hormones, signal molecules and abiotic stresses. Two mutant alleles, ctr1-1 and ctr1-8, containing mutations that disrupt kinase activity and receptor association, respectively, were examined for sensitivity to these same treatments in an effort to better characterize ethylene hormone and non-hormone interactions. They also served as controls to determine if At4g24480 indeed possessed CTR1-like function.
Arabidopsis and tomato represent species with very distinct fruit ripening/maturation programs. The critical dependence on ethylene for fruit ripening in tomato might have resulted in alteration or modification of the ethylene signal transduction pathway relative to Arabidopsis. Plans to characterize individual functions of the LeCTR genes through over-expression and reduced expression in tomato are outlined.
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Bergström, Rosita. "Epigenetic Regulation of Replication Timing and Signal Transduction." Doctoral thesis, Uppsala universitet, Molekylär cellbiologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8413.
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Upon fertilization the paternal and maternal genomes unite, giving rise to the embryo, with its unique genetic code. All cells in the human body are derived from the fertilized ovum: hence they all contain (with a few exceptions) the same genetic composition. However, by selective processes, genes are turned on and off in an adaptable, and cell type-specific, manner. The aim of this thesis is to investigate how signals coming from outside the cell and epigenetic factors residing in the cell nucleus, cooperate to control gene expression. The transforming growth factor-β (TGF-β) superfamily consists of around 30 cytokines, which are essential for accurate gene regulation during embryonic development and adult life. Among these are the ligands TGF-β1 and bone morphogenetic (BMP) -7, which interact with diverse plasma membrane receptors, but signal via partly the same Smad proteins. Smad4 is essential to achieve TGF-β-dependent responses. We observed that by regulating transcription factors such as Id2 and Id3 in a specific manner, TGF-β1 and BMP-7 achieve distinct physiological responses. Moreover, we demonstrate that CTCF, an insulator protein regulating higher order chromatin conformation, is able to direct transcription by recruiting RNA polymerase II to its target sites. This is the first mechanistic explanation of how an insulator protein can direct transcription, and reveals a link between epigenetic modifications and classical regulators of transcription. We also detected that DNA loci occupied by CTCF replicate late. The timing of replication is a crucial determinant of gene activity. Genes replicating early tend to be active, whereas genes replicating late often are silenced. Thus, CTCF can regulate transcription at several levels. Finally, we detected a substantial cross-talk between CTCF and TGF-β signaling. This is the first time that a direct interplay between a signal transduction pathway and the chromatin insulator CTCF is demonstrated.
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Roberts, Jonathan A. "Signal transduction of transfected and native P2Y receptors." Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/30614.
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This thesis looks at the turkey P2Y1, human P2Y2, human P2Y4 and rat P2Y6 receptors transfected into the human astrocytoma null cell line 1321N1 to investigate signalling pathways linking G protein receptor activation to tyrosine phosphorylation, MAPK and mitogenesis. This was compared with results for the native primary cell preparation of rat brain microvascular endothelial cells. Previous work by others and us has established that all 1321N1 transfected P2Y receptors are strongly linked to an increase in PLC activation. Neither the turkey P2Y1 or human P2Y2 receptors were coupled to an increase in overall tyrosine phosphorylation assessed by PY20 antibody western blot. Pervanadate alone gave large increases in tyrosine phosphorylation, but no further increase in tyrosine phosphorylation was observed with co-addition of 2MeSATP to the turkey P2Y1 transfectants. Co-addition of UTP and a sub-maximal concentration of prevanadate on the human P2Y2 receptor gave a reduction in tyrosine phosphorylation compared to pervanadate alone. This indicated possible activation of tyrosine phosphatase activity by the human P2Y1 and human P2Y2 receptors were both shown to activate p42/p44 MAPK assessed by phospho-MAPK antibody western blotting and a nonapeptide kinase assay. Both turkey P2Y1 and human P2Y2 receptor activation of MAPK was inhibited by the MEK inhibitor PD 98059. Human P2Y4 and rat P2Y6 receptors showed no activation of MAPK. Both turkey P2Y1 and human P2Y2 MAPK activation was PKC dependant; inhibited by Ro 31-8220 and Go 6850, but not Go 6976 a calcium sensitive PKC isoform inhibitor. PKC isoforms ( or ) may be involved in this signalling pathway. Some experiments investigating Pyk2 and Shc involvement in P2Y signalling are presented.
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Dikic, Inga. "Signal Transduction by Proline-Rich Tyrosine Kinase Pyk2." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5316-3/.
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Bergström, Rosita. "Epigenetic regulation of replication timing and signal transduction /." Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8413.
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