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Uschner, Friedemann. "Information processing in cellular signaling." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17660.
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Information spielt in der Natur eine zentrale Rolle. Als intrinsischer Teil des genetischen Codes ist sie das Grundgerüst jeder Struktur und ihrer Entwicklung. Im Speziellen dient sie auch Organismen, ihre Umgebung wahrzunehmen und sich daran anzupassen. Die Grundvoraussetzung dafür ist, dass sie Information ihrer Umgebung sowohl messen als auch interpretieren können, wozu Zellen komplexe Signaltransduktionswege entwickelt haben. In dieser Arbeit konzentrieren wir uns auf Signalprozesse in S.cerevisiae die von osmotischem Stress (High Osmolarity Glycerol (HOG) Signalweg) und der Stimulation mit α-Faktor (Pheromon Signalweg) angesprochen werden. Wir wenden stochastische Modelle an, die das intrinsische Rauschen biologischer Prozesse darstellen können, um verstehen zu können wie Signalwege die ihnen zur Verfügung stehende Information umsetzen. Informationsübertragung wird dabei mit einem Ansatz aus Shannons Informationstheorie gemessen, indem wir sie als einen Kanal in diesem Sinne auffassen. Wir verwenden das Maß der Kanalkapazität, um die Genauigkeit des Phosphorelays einschränken zu können. In diesem Modell, simuliert mit dem Gillespie Algorithmus, können wir durch die Analyse des Signalverhaltens den Parameterraum zusätzlich stark einschränken. Eine weitere Herangehensweise der Signalverarbeitung beschäftigt sich mit dem “Crosstalk” zwischen HOG und Pheromon Signalweg. Wir zeigen, dass die Kontrolle der Signalspezifizität vor allem bei Scaffold-Proteinen liegt, die Komponenten der Signalkaskade binden. Diese konservierten Motive zellulärer Signaltransduktion besitzen eine geeignete Struktur, um Information getreu übertragen zu können. Im letzten Teil der Arbeit untersuchen wir potentielle Gründe für die evolutionäre Selektion von Scaffolds. Wir zeigen, dass ihnen bereits durch die Struktur des Mechanismus möglich ist, Informationsgenauigkeit zu verbessern und einer verteilten Informationsweiterleitung sowohl dadurch als auch durch ihre Robustheit überlegen sind.<br>Information plays a ubiquitous role in nature. It provides the basis for structure and development, as it is inherent part of the genetic code. It also enables organisms to make sense of their environments and react accordingly. For this, a cellular interpretation of information is needed. Cells have developed sophisticated signaling mechanisms to fulfill this task and integrate many different external cues with their help. Here we focus on signaling that senses osmotic stress (High Osmolarity Glycerol (HOG) pathway) as well as α-factor stimulation (pheromone pathway) in S.cerevisiae. We employ stochastic modeling to simulates the inherent noisy nature of biological processes to assess how systems process the information they receive. This information transmission is evaluated with an information theoretic approach by interpreting signal transduction as a transmission channel in the sense of Shannon. We use channel capacity to both constrain as well as quantify the fidelity in the phosphorelay system of the HOG pathway. In this model, simulated with the Gillespie Algorithm, the analysis of signaling behavior allows us to constrain the possible parameter sets for the system severely. A further approach to signal processing is concerned with the mechanisms that conduct crosstalk between the HOG and the pheromone pathway. We find that the control for signal specificity lies especially with the scaffold proteins that tether signaling components and facilitate signaling by trans-location to the membrane and shielding against miss-activation. As conserved motifs of cellular signal transmission, these scaffold proteins show a particularly well suited structure for accurate information transmission. In the last part of this thesis, we examine the potential reasons for an evolutionary selection of the scaffolding structure. We show that due to its structure, scaffolds are increasing information transmission fidelity and outperform a distributed signal in this regard.
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Ng, Tony Ling Tin. "Elucidating cellular signaling mechanisms of anoikis resistance." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46545.
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Anoikis, which describes a physiologic apoptotic mechanism of non-hematopoietic cells that is triggered following detachment of cells from their native extracellular matrix, functions as a key process to prevent unwanted dissemination of cells from their intended organ site. Cancer cells, in contrast, develop mechanisms to suppress anoikis, allowing them to metastasize through the lymphovascular system to secondary organ sites. In this thesis, we utilized screening methodologies to identify novel signaling mechanisms of anoikis resistance in cancer cells. While a functional approach using an siRNA-based screen of Ewing sarcoma cells did not yield validatable hits, use of gene expression profiling demonstrated a remarkable resemblance of the cellular detachment process to various prototypical forms of cellular and bioenergetic stress, such as nutrient deprivation, hypoxia and endoplasmic reticulum stress. Correspondingly, activation of various cellular stress response pathways was demonstrated, which appear critical for mitigating this stress. In particular, two pathways were shown to play a role in anoikis resistance, mediated by TXNIP and AMPK. TXNIP, which has been shown to play a homeostatic role to modulate glucose metabolism, redox status and proliferation during stress states, was shown to be rapidly up-regulated following cellular detachment, and promotes anoikis in certain cell line models. AMPK is also rapidly activated, activating multiple downstream pathways to restore the bioenergetic status of detached cells, which show marked reduction in ATP levels following detachment. In particular, AMPK-mediated suppression of the mTORC1 pathway plays a particularly important role through the suppression of total protein synthesis levels, an otherwise energetically-costly anabolic process. Blockade of the AMPK pathway or restoration of mTORC1 activation in cancer cells help to restore anoikis, while direct inhibition of protein synthesis in AMPK-deficient cancer cells restores their ability to suppress anoikis. Overall, we show that activation of energy-conserving pathways, normally considered “tumor suppressive” in nature, in fact promotes survival of cancer cells in this early stage of metastasis. This highlights the ambiguous role of many such pathways, which can both promote and suppress tumor progression in a context-dependent manner.
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Rogers, Laura Ann. "Membranes as a hub for cellular signaling /." Access full-text from WCMC, 2007. http://proquest.umi.com/pqdweb?did=1481668281&sid=2&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Dudu, Veronica. "TGF-beta signaling at the cellular junctions." [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11878497.
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Roberts, Craig Dane. "cAMP Signaling in Chemosensory Transduction." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/161.
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cAMP is a second messenger in a variety of chemosensory receptors, including taste buds and glucose-sensitive pancreatic beta-cells. cAMP is modulated during taste transduction, yet the significance of cAMP changes and the taste cell types in which they occur (Type I glial-like; Type II Receptor; Type III Presynaptic) remain unclear. I developed techniques to image real-time changes in intracellular cAMP in taste cells using genetically-encoded cAMP reporters. This FRET-based reporter permits one to measure single-cell cAMP levels with excellent spatial and temporal resolution (Zaccolo & Pozzan 2002, Science 295:1711). Using a biolistic approach I have transfected rat fungiform taste buds with cAMP reporter plasmids. Focal application of bitter tastant to living fungiform tastebuds in situ produced a decrease in [cAMP]i within individual taste receptor cells. These results are qualitatively similar to previous biochemical measurements from homogenized taste tissue (Yan et al. 2001, Am J Physiol Cell Physiol 280:C742) but are now allowing us to examine the cAMP response in individual, identified cells. I next explored the effect of elevating cAMP on calcium levels, using Fura-2 imaging of isolated mouse vallate taste buds. Elevating [cAMP]i in taste buds evoked calcium responses in presynaptic/Type III taste cells, which do not express GAD1. cAMP induced responses were generated by calcium influx. Using pharmacological antagonists, I determined that the calcium influx triggered by cAMP is through L-type calcium channels, whereas influx following depolarization is primarily through P/Q-type calcium channels. Consistent with these data, single cell RT-PCR showed that the L-type subunit (alpha 1C) was expressed primarily in GAD-negative Presynaptic cells, while the P/Q-type (alpha 1A) was expressed in all Presynaptic cells. Thus, cAMP may modulate the function of synapses in some taste cells. Finally, we have developed a mouse strain expressing a cAMP reporter in a tissue-specific and tetracycline-inducible manner. We crossed this mouse with another strain expressing tet-activator in beta cells of the pancreas. Such islets responded to increasing concentrations of glucose (5.5 to 35mM) with an increase in cAMP levels. The half maximum of 9mM glucose for the cAMP response corresponds well with reported glucose concentrations that elicit insulin release from whole islets. Stimulating pancreatic islets with glucose is known to drive calcium influx into beta-cells. When we simultaneously imaged both second messengers, we found that cAMP changes precede and are independent of calcium changes. In conclusion, these studies have outlined novel potential functions for cAMP signaling in the transduction of both primary tastant and plasma glucose information. In addition, the flexibility of the tet-system will enable cAMP reporter expression in numerous cell types, including those which mediate gustatory transduction.
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Shekarabi, Seyed Masoud. "Netrin-1 signaling : cellular consequences and molecular mechanisms." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19457.
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During the embryonic development of the nervous System, groups of multipotent cells proliferate, migrate, and differentiate to become neurons. The new born neurons need to make precise connections with their targets. These may be a great distance away from their soma. To make these connections, neurons send their axon through a biochemically complex environment and their growth cones may make many guidance decisions on the ways to their targets. The existence of axon guidance molecules was inferred by the early classical neuroanatomists. We now know of multiple examples of secreted or membrane-bound proteins that either attract or repel axonal growth cônes by causing the growth cône to collapse or extend. The molecular mechanisms that regulate growth cone collapse or extension are closely linked to reorganization of the cytoskeleton. The small Rho GTPases, Cdc42, Rac, and Rho play key roles in neuronal growth cônes by regulating the organization of the cytoskeleton. Netrins are a small family of secreted guidance eues that are implicated in the attraction and repulsion of axons during the development of the nervous System. The netrin-1 receptor deleted in colorectal cancer (DCC) is highly expressed by commissural neurons in the developing spinal cord. The findings described here show that DCC is present at the tips of filopodia and the edges of lamellipodia of HEK293T, NG108-15 neuroblastoma-glioma cells, and the growth cones of embryonic rat spinal commissural neurons. Furthermore, netrin-1 protein causes an increase in filopodia number and surface area of embryonic rat commissural neuron growth cônes and the cell fines when transfected to express DCC. Further experiments indicated that netrin-1 activates the small GTPases Cdc42 and Racl in the cell lines and the embryonic rat commissural spinal cord neurons. The activation of Cdc42 and Racl by netrin-1 requires DCC. Furthermore, netrin-1 causes increased phosphorylation of Pakl, an effector for both Cdc42 and Racl. Expression of a dominant negative form of N-WASP, an effector for Cdc42, blocks the netrin-1 induced morphological changes in the growth cones of commissural neurons. Evidence is presented that netrin-1 induces the formation of a complex of proteins interacting with the intra-cellular domain of DCC that includes Nckl, Cdc42, Racl, Pakl, and N-WASP. The findings described lead to a model whereby netrin-1 binding to DCC triggers the activation of Cdc42 and Racl, which leads to actin based membrane extension and changes in growth cone morphology.
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Vaziri, Homayoun. "Telomeres, DNA damage signaling molecules and cellular aging." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0020/NQ45836.pdf.
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Groban, Eli S. "The study and engineering of cellular signaling pathways." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3339232.
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Thesis (Ph.D.)--University of California, San Francisco, 2008.<br>Source: Dissertation Abstracts International, Volume: 69-12, Section: B, page: 7352. Advisers: Matthew P. Jacobson; Christopher A. Voigt.
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Wilkinson, Patrick. "Functional Adenosine Receptor 2B Drives Profibrotic and Proinflammatory Signaling in Renal Fibroblasts Through Modulation of TGFbeta Receptor Signaling." Thesis, University of the Sciences in Philadelphia, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10629210.
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<p> Extracellular adenosine signaling via the adenosine receptor 2B (AR<sub> 2B</sub>) is a potent profibrotic and proinflammatory molecule that has been shown to contribute to tissue remodeling and excessive matrix protein production under chronic conditions in kidney disease. Investigation of the adenosine pathway on interstitial renal fibroblasts is lacking even though fibroblasts are a major source of ECM production and contribute to the pathogenesis of renal failure in late stage kidney disease. Analysis of mRNA from the interstitial renal fibroblast cell line NRK-49F revealed these cells express AR<sub>1</sub> and AR<sub>2B</sub>. Utilizing highly selective small molecule agonists and antagonists specific to each individual adenosine receptor, it was determined by mobilization of intracellular cAMP, both receptors were functional. AR<sub> 2B</sub> was observed to be the dominant receptor under high μM concentrations of agonism leading to increased pro-inflammatory and profibrotic mediators. Specifically, agonism of AR<sub>2B</sub> lead to increased levels of αSMA and other inflammatory and fibrotic mediators, indicating a transdifferentiation of fibroblasts to a more activated myofibroblasts stage under strong and sustained adenosine signaling. The key fibrotic mediator TGF-β1 was observed to be increased with adenosine signaling while antagonism of AR<sub>2B</sub> suppressed TGF-β1 mediated increases in αSMA and fibronectin, suggesting complementary signaling pathways with significant crosstalk. It was further observed that AR<sub>2B</sub> receptor antagonism suppressed TGF-β receptor mediated SMAD binding element associated transcriptional activity the suppression of TGF-β receptor signaling and transcriptional activity was associated with decreased SMAD4, a critical protein necessary for proper formation of the SMAD complex transcription factor. Taken together these data highlight the impact of adenosine signaling on proinflammatory and profibrotic endpoints in renal fibroblasts and describe for the first time direct inhibition of TGF-β receptor signaling by antagonism of the AR<sub>2B</sub> receptor.</p><p>
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Tukachinsky, Hanna. "Mechanistic Studies of Vertebrate Hedgehog Signaling." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10691.
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Metazoans use Hedgehog signaling to direct many stages of embryonic development, and deregulation of this pathway is implicated in many types of cancer. I investigated several steps of Hedgehog pathway transduction that were poorly understood in mechanistic terms. The mature Hedgehog ligand is produced by a self-proteolysis reaction that covalently attaches a cholesterol molecule to the signaling half of the protein. I showed that the catalytic cysteine forms a disulfide bridge that is essential for the folding and function of the C-terminal tail of Hedgehog, and identified two protein disulfide isomerases that remodel this bridge to free the catalytic thiol group after folding is complete. Using pulse chase assays to follow Hedgehog processing, I demonstrated that the self-proteolysis reaction takes place in the endoplasmic reticulum, that the cleaved C-terminal tail of Hedgehog is degraded before moving to the Golgi, and that Hedgehog mutants defective in processing get degraded in their entirety by the same route. Lipidated Hedgehog ligand requires the transmembrane protein Dispatched for secretion. I devised a system to test Dispatched function in cultured cells, and showed that some inactive Dispatched mutants fail to bind Hedgehog, while others bind more tightly than the wild type protein. Scube2 was implicated as a Hedgehog pathway component in zebrafish genetic studies. I showed that Scube2 is a secreted protein that binds Hedgehog via its cholesterol adduct and solubilizes it in aqueous media. Dispatched and Scube2 bind Hedgehog on opposing faces, and they function synergistically to release it from the membrane. Vertebrate Hedgehog signaling relies on intraflagellar transport through an antenna-like organelle called the primary cilium. The Hedgehog receptor Patched and transducer protein Smoothened localize to primary cilia in a mutually exclusive pattern, depending on Hedgehog ligand presence. I showed that cytoplasmic components of the pathway Suppressor of Fused (SuFu, a pathway inhibitor) and Glioma-associated oncogene transcription factors (the Gli family, the effectors of the pathway) localize to primary cilia and accumulate there when Smoothened is activated. SuFu and Gli form a complex that dissociates when the pathway is turned on, and this dissociation depends on trafficking through the cilium.
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Yu, Lu. "Multiple signaling pathways cooperate to activate skeletal muscle differentiation /." View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BICH%202005%20YU.
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De, Jong Dorine. "Characterization of the Signaling Pathways Involved in Cellular Cannibalism Elicited by Ionizing Radiation." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS101.
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Les stratégies thérapeutiques anticancer sont nombreuses et variées. Elles visent à déclencher la mort des cellules tumorales mais les processus de mort cellulaire diffèrent en fonction du traitement, du type de cellule ciblé et des caractéristiques du patient. A côté des mécanismes classiques tels que l’apoptose et la nécrose, on retrouve également du cannibalisme cellulaire dans les biopsies de tumeurs des patients. Ce phénomène dont les mécanismes sont encore peu caractérisés, correspond à l’internalisation d’une cellule vivante par une cellule vivante. Il est fréquemment suivi par la dégradation de la cellule internalisée. Cette modalité de mort atypique est intéressante car nous avons montré qu’elle pouvait être modulée par des traitements anticancéreux et des études ont également démontré qu’elle pouvait servir de biomarqueur pronostique dans certains types de cancer. Ces travaux de thèse ont permis d'identifier des voies de signalisation cellulaire activées lors du déclenchement du cannibalisme cellulaire par les radiations ionisantes<br>Many types of anticancer therapies are available to kill tumor cells. The tumoral cell death modalities may be different upon the treatment, the cell type and inter-individual sensitivity. Besides the typical cell death processes apoptosis and necrosis, cellular cannibalism has also been reported in patients’ tumoral biopsies. This cellular process is defined as the engulfment of one live cell by another live cell followed by the degradation of the inner cell. The mechanisms beyond cellular cannibalism are still partially understoof but it appears to be of clinical relevance. Indeed, we have shown that these events could be modulated by anticancer treatments and there are evidences of their utility as a potent prognostic biomarker in some cancers. This thesis presents the in vitro experiments which led to the identification of the signaling pathways involved in cellular cannibalism induced by ionizing radiation
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Bonham, Kevin Scott. "Cellular and Biochemical Events in Toll-like Receptor Signaling." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11379.
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In multicellular organisms, communication between cells relies on transmitting information across membrane barriers. Different cell types interrogate particular aspects of their surrounding environment through protein receptors that span membranes and upon ligand binding, trigger enzymatic signaling cascades that culminate in the activation of one or more transcription factors. Information transmission is bidirectional, as individual cells must be able to sense unique aspects of their surroundings, relay their specialized knowledge with others, and receive the collective knowledge of surrounding cells and tissues. This two-way communication is particularly important in the innate immune system, where potentially infectious organisms must be readily detected and identified, and their presence communicated to other cells in the vicinity. Because of the rapid generation time of microorganisms, delays between any of these steps - detection, information processing or information transmission - can make the difference between successful control of infection and pathogen outgrowth. For this reason, the receptors that identify potential pathogens must be able to detect pathogens wherever they are found, be exquisitely sensitive, and initiate a robust response. At the same time, the inflammatory response to infection is itself damaging. This requires that the same receptors are tightly controlled, both by modulating their sensitivity and by rapidly turning off responses through negative feedback pathways. Here, I show that the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) plays a critical role in controlling the sensitivity of toll-like receptor (TLR) signaling. First, TIRAP controls the assembly of the myddosome, a protein complex that activates signal transduction, from both the plasma membrane and within endosomes of macrophages. Though TIRAP's role at the cell surface was previously described, its endosomal function was previously unknown. Second, TIRAP is an important target for negative regulation. After stimulation with the TLR4 ligand lipopolysaccharide (LPS), macrophages induce a state known as endotoxin tolerance, in which they are refractory for additional LPS stimulation. Many mechanisms for endotoxin tolerance have been proposed, but here I show that TIRAP is degraded in endotoxin tolerance, and that the mechanism of TIRAP degradation also has implications for viral/bacterial superinfection.
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Zi, Zhike. "Mathematical modeling and kinetic analysis of cellular signaling pathways." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15838.
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Aufgrund des wachsenden Interesses an der Systembiologie werden zunehmend mathematische Modelle in Kombination mit Experimenten für die Analyse von Stoffwechselnetzwerken, Genregulationsnetzwerken und zellulären Signalweiterleitungswegen verwendet. Diese Dissertationsschrift benutzt die mathematische Modellierung und kinetische Untersuchungsmethoden zum Studium von zelluären Signalwegen, insbesondere des Netzwerkes zur Festlegung der Rezeptorlokalisation und des Tumorwachstumsfaktor-beta-Signalweges. Ergänzend wurde ein Computerwerkzeug (SBML-PET) entwickelt, das die Modellentwicklung unterstützt und der Parameterschätzung dient. Mit diesem Werkzeug kann man Modelle bearbeiten, die in der Systems Biology Markup Language (SBML) formuliert sind. In dieser Arbeit wird ein quantitatives mathematisches Modell benutzt, um die Signalantwort in unterschiedlichen Rezeptorlokalisationsnetzwerken in Abhängigkeit von der Ligandenanzahl und der Zelldichte zu untersuchen. Die rechnergestützte Analyse des Modells hat ergeben, dass der Zustand eines Rezeptorlokalisationsnetzwerkes potenziell eine sigmoide Abhängigkeit von dem Verhältnis zwischen Ligandenanzahl und Oberflächenrezeptoranzahl pro Zelle zeigen. Dieses Verhältnis ist die entscheidende Kontrollgröße der Signalantwort in Rezeptorlokalisationsnetzwerken. Mit Hilfe des SBML-PET Software-Paketes haben wir eine Modellierungsmethode mit Randbedingungen vorgeschlagen, um ein umfangreiches mathematisches Modell für den Smad-abh?ngigen TGF-beta Signalweg zu erstellen und dessen Parameter aus experimentellen Daten unter Berücksichtigung qualitativer Nebenbedingungen zu fitten. Die Ergebnisse der kinetischen Untersuchung dieses Modells legen nahe, dass die Signalantwort auf einen TGF-beta-Reiz durch die Balance zwischen clathrin-abhängier Endozytose und clathrin-unabhängiger Endozytose reguliert wird.<br>With growing interests in systems biology, mathematical models, paired with experiments, have been widely used for the studies on metabolic networks, gene regulatory networks and cellular signaling pathways. This dissertation employs the mathematical modeling and kinetic analysis method to study cellular signaling pathways, in particular, the receptor trafficking network and TGF-beta signaling pathway. On the other hand, a systems biology markup language (SBML) based parameter estimation tool (SBML-PET), was developed for facilitating the modeling process. A quantitative mathematical model is employed to investigate signal responses in different receptor trafficking networks by simultaneous perturbations of the ligand concentration and cell density. The computational analysis of the model revealed that receptor trafficking networks have potentially sigmoid responses to the ratio between ligand number and surface receptor number per cell, which is a key factor to control the signaling responses in receptor trafficking networks. Using the SBML-PET software package, we proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. Kinetic analysis results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis.
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Curran, Timothy Gordon. "Tools for investigating cellular signaling networks by mass spectrometry." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/89866.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2014.<br>This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.<br>Cataloged from student-submitted PDF version of thesis.<br>Includes bibliographical references.<br>Mass spectrometry has become the tool of choice for proteomics. Its unrivaled coverage and reproducibility has positioned it head and shoulders above competing techniques for analyzing protein expression post-translational modification. With the increased popularity comes a flood of new research applications, each with its own biological motivations and goals. To ensure that mass spectrometry-based proteomics can be useful to as many biological questions as possible, it is of utmost importance to ensure high data quality. This research focuses on two general stages of the typical proteomics workflow and introduces tools to facilitate effective target screening, follow-up analysis, as well as more precise measurements. This new pipeline is then demonstrated in a case study of Epidermal Growth Factor Receptor (EGFR) signaling and phenotype prediction. The quantity of proteomic mass spectrometry data available from a single analysis has increased exponentially as new generations of instruments become quicker and more sensitive. This deluge of data leaves many tempted to forego time-intensive manual validation of database identified targets in favor of global data set quality statistics. Particularly in the realm of post-translational modifications, long lists of putative matches are often reported with little or no scan-specific validation. Such practices no longer provide assurance that any single identified target is indeed correct, leaving researchers vulnerable to expending vast resources chasing false positives. The argument is that manual validation is too time-intensive to be carried out for each and every identification. To remedy this problem we have introduced the Computer Assisted Manual Validation (CAMV) software package to expedite the procedure by preprocessing the database results so as to remove the tedious steps associated with the validation task and only recruit human judgment for the final quality decision. This approach has drastically decreased the time required for manual validation; a task that used to take weeks now is completed in hours. Another focus of this research is the development of a multiplex, multisite absolute quantification method, which has improved the quality of quantitative proteomic mass spectrometry data. Absolute site-specific data allows many more biological hypotheses to be directly tested with a single mass spectrometry experiment, including phosphorylation stoichiometry. This technique has been applied to the EGFR system to better understand signaling downstream of three distinct ligands. These ligands all bind the same receptor yet elicit different phenotypes, suggesting differential information processing. The analysis showed unique patterns of receptor phosphorylation present following sub-saturating ligand treatment. However, at saturating doses the same pattern of phosphorylation is produced regardless of ligand, but the magnitude of that pattern is still ligand-dependent. In this regime, the adaptor proteins were still able to retain ligand-specific phosphorylation patterns presumably responsible for differential phenotypes. The data set also permitted the identification of signals important for the regulation of only one of the two phenotypes examined.<br>by Timothy Gordon Curran.<br>Ph. D.
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Sun, Jian, James B. Hoying, Pierre A. Deymier, Donna D. Zhang, and Pak Kin Wong. "Cellular Architecture Regulates Collective Calcium Signaling and Cell Contractility." Public Library of Science, 2016. http://hdl.handle.net/10150/618963.
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A key feature of multicellular systems is the ability of cells to function collectively in response to external stimuli. However, the mechanisms of intercellular cell signaling and their functional implications in diverse vascular structures are poorly understood. Using a combination of computational modeling and plasma lithography micropatterning, we investigate the roles of structural arrangement of endothelial cells in collective calcium signaling and cell contractility. Under histamine stimulation, endothelial cells in self-assembled and microengineered networks, but not individual cells and monolayers, exhibit calcium oscillations. Micropatterning, pharmacological inhibition, and computational modeling reveal that the calcium oscillation depends on the number of neighboring cells coupled via gap junctional intercellular communication, providing a mechanistic basis of the architecture-dependent calcium signaling. Furthermore, the calcium oscillation attenuates the histamine-induced cytoskeletal reorganization and cell contraction, resulting in differential cell responses in an architecture-dependent manner. Taken together, our results suggest that endothelial cells can sense and respond to chemical stimuli according to the vascular architecture via collective calcium signaling.
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Pasquali, Christian. "Minning cellular phosphoinositide-binding proteins by signaling pathway proteomics." Compiègne, 2004. http://www.theses.fr/2004COMP1500.
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Regroupée en trois thèmes, nos travaux ont été basés sur l'identification de cibles protéiques pouvant aboutir à des applications thérapeutiques dans l'inflammation et le système endocrinien. L'association de la protéomique avec les signaux de transmissions cellulaires a permis l'identification de nouveaux médiateurs protéiques impliqués dans le recrutement cellulaire, le système endocrinien et la biologie des lipides. Ainsi, PI3Ky est impliqué dans la migration des macrophages également induite par l'activation de Rac. Des phosphatases ont été identifiées comme étant spécifiques du récepteur, activé par l'hormone de croissance. Enfin, comme thème principal, notre stratégie globale utilisant la chromatographie d'affinité et un nouvel essai enzymatique a permis l'identification, la validation et la caractérisation fonctionnelle de nouvelles protéines interagissant avec les phosphoinostides cellulaires résultant de l'activation de PI3K<br>To identify relevant cellular proteins involved in human pathophysiological processes and thereby, improve our understanding in cell-signalling mechanisms; we merged signaling knowledge with proteomics-based approaches. Ln the resulting functional findings, we first provide evidence for the involvement of the phosphoinositide-3 kinase gamma (PI3Ky) in chemokine-induced Rac-signaling in macrophages, Second, we show the identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. Finally, and as main project, we describe a functional signalling-proteomics approach that allows the selective identification and characterization of navet cellular proteins that differentially recognize 3-phosphorylated phosphoinositides (PIPs). This study provides a three-way intersection of biological chemistry, lipid-mediated signaling, and proteomics to create a target oriented protein discovery platform for predefined subsets of the cellular proteome
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Bell, Andrea. "TSH signaling and cellular responses in preadipocytes and adipocytes." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/29077.
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Thyroid stimulating hormone (TSH) action in adipose tissue remains largely unknown. We demonstrate that TSH activates protein kinase B (PKB/Akt) and p70 S6 kinase (p70 S6K) in a phosphoinositide 3-kinase (PI3K)-dependent manner in 3T3-L1 preadipocytes. TSH had no effect on cAMP levels, suggesting adenylyl cyclase is not involved in TSH activation of the PI3K-PKB/Akt-p70 S6K pathway. 3T3-L1 preadipocyte cell death was reduced by 29 to 76%, in serum-deprived (6 h) preadipocytes treated with 1--20 muM TSH, respectively. In the presence of 20 muM TSH, an 88% reduction in TUNEL-positive cells was observed in serum-starved (3 h) 3T3-L1 preadipocytes, as well as a 93% reduction in the level of cleaved activated caspase 3. TSH acts as a survival factor for serum-deprived preadipocytes, reducing TUNEL-positive cells and caspase 3 activation. A role for TSH may exist in adipose tissue development and remodeling.
Interleukin-6 (IL-6), a pro-atherogenic cytokine, is expressed and secreted by adipocytes, but little is known about its regulation. Since an elevated TSH serum level is a cardiovascular disease (CVD) risk factor, and since thyroid stimulating hormone receptor (TSHR) is expressed in adipocytes, we investigated whether TSH modulates IL-6 secretion in cultured 3T3-L1 and 3T3-F442A mouse adipocytes, and in primary cultures of human abdominal adipocytes differentiated in culture. TSH increased the secretion of IL-6 by 5-fold in 3T3-F442A adipocytes, by 2-fold in 3T3-L1 adipocytes, and by 3.5-fold in human differentiated adipocytes. TSH is a novel regulator of adipocyte IL-6 secretion, providing a potential mechanism for epidemiological observations identifying an elevated serum TSH level as a CVD risk factor.
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Karunamuni, Ganga. "Lymphangiogenic Signaling in the Epicardium." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1291230892.
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Ma, Kewei. "Investigation of the phosphatidylinositol 3-kinase pathway in B cells." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/3818.
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There is hardly a cellular process that is not regulated in some way by phosphoinositides, which makes biochemical and physiological studies of these lipids extremely important. PI 3-kinases are key regulators of phosphoinositide metabolism and have been shown to affect a large variety of cellular responses. The key products of PI 3-kinases that have functional activity in higher eukaryotic cells are PI(3,4,5)P₃ and PI(3,4)P₂. PI(3,4,5)P₃ is universally accepted as one of the most important second messengers in signal transduction. However, our knowledge of the functions of PI(3,4)P₂ as a lipid second messenger is much less precise. In this dissertation, work was undertaken to elucidate the regulation of PI(3,4,5)P₃ and PI(3,4)P₂ production and downstream signaling in B cells. Cells with membrane targeted exogenous SHIP were utilized to manipulate phosphoinositide levels. The relationship of PI(3,4,5)P₃ and PI(3,4)P₂ levels to downstream PKB phosphorylation and activation was studied. PI(3,4,5)P₃ and PI(3,4)P₂ levels were found to closely correlate with PKB phosphorylation levels at Thr308 and Ser473, respectively. In addition, PI(3,4)P₂ levels determine the PKB activity in the cytosol; while PI(3,4,5)P₃ levels determine PKB activity at the plasma membrane. Different doses and different forms of B cell receptor (BCR) agonists were used for stimulation. PI 3-kinase activation was studied carefully following stimulation with low doses of anti-BCR antibody and F(ab')₂ fragments. Low concentrations of F(ab')₂ fragments produced higher levels of PI(3,4,5)P₃ than did a high concentration of F(ab')₂ fragments. Downstream PKB signaling was studied in these models. Similar conclusions were drawn from both SHIP over-expressing BJAB cells and dose-dependent BCR stimulations. We speculated that phosphoinositides’ regulation of the kinetics of PKB phosphorylation at Ser473 and Thr308 might be mediated by additional proteins. Investigation of plasma membrane-associated PKB showed that it formed a protein complex of around 400KD, which we attempted to characterize further with respect to PKB phosphorylation and association with lipids. In conclusion, phosphoinositide production is intricately regulated in vivo to control downstream signaling. The levels of PI(3,4)P₂ and PI(3,4,5)P₃ have precise and profound effects on PKB and other molecules such as TAPP and Bam32. This study has contributed new insight into the PI 3-kinase signaling pathway from the aspect of phosphoinositide lipid function.
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Rui, Hongliang. "Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by axin /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20RUI.
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Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004.<br>CD-ROM contains electronic versons of the thesis in pdf and word format. Includes bibliographical references (leaves 129-151). Also available in electronic version. Access restricted to campus users.
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Nikolaou, Elissavet. "Phylogenetic diversity of fungal stress signaling pathways." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=24849.
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Michael, James. "Regulation of Ras signaling and oncogenesis by plasma membrane microdomains." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/377230.
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Cell Biology<br>Ph.D.<br>In this study, we assessed the contributions of plasma membrane (PM) microdomain targeting to the functions of H-Ras and R-Ras. These paralogues have identical effector-binding regions, but variant C-terminal targeting domains (tDs) which are responsible for lateral microdomain distribution: activated H-Ras targets to lipid ordered/disordered (Lo/Ld) domain borders, and R-Ras to Lo domains (rafts). We hypothesized that PM distribution regulates Ras effector interactions and downstream signaling. We used tD swap mutants, and assessed effects on signal transduction, cell proliferation, transformation, and tumorigenesis. R-Ras harboring the H-Ras tD (R-Ras-tH) interacted with Raf, and induced Raf and ERK phosphorylation similar to H-Ras. R-Ras-tH stimulated proliferation and transformation in vitro, and these effects were blocked by both MEK and PI3K inhibition. Conversely, the R-Ras tD suppressed H-Ras-mediated Raf activation and ERK phosphorylation, proliferation, and transformation. Thus, Ras access to Raf at the PM is sufficient for MAPK activation and is a principal component of Ras mitogenesis and transformation. Fusion of the R-Ras extended N-terminal domain to H-Ras had no effect on proliferation, but inhibited transformation and tumor progression, indicating that the R-Ras N-terminus also contributes negative regulation to these Ras functions. PI3K activation was tD-independent; however, H-Ras was a stronger activator of PI3K than R-Ras, with either tD. PI3K inhibition nearly ablated transformation by R-Ras-tH, H-Ras, and H-Ras-tR, whereas MEK inhibition had a modest effect on Ras-tH-driven transformation but no effect on H-Ras-tR transformation. R-Ras-tH supported tumor initiation, but not tumor progression. Whereas H-Ras-tR-induced transformation was reduced relative to H-Ras, tumor progression was robust and similar to H-Ras. H-Ras tumor growth was moderately suppressed by MEK inhibition, which had no effect on H-Ras-tR tumor growth. In contrast, PI3K inhibition markedly suppressed tumor growth by H-Ras and H-Ras-tR, indicating that sustained PI3K signaling is a critical pathway for H-Ras-driven tumor progression, independent of microdomains. In the second phase of the study, we investigated the combinatorial use of two drugs currently either in active use as anti-cancer agents (Rapamycin) or in clinical trials (OTX008), as a novel strategy to inhibit H-Ras-driven tumor progression. H-Ras anchored to the plasma membrane shuttles from the lipid ordered (Lo) domain to the lipid ordered/lipid disordered border upon activation, and retention of H-Ras at these sites requires Galectin-1 (Gal-1). We have previously found that genetically-mediated Lo sequestration of H-Ras inhibited MAPK signaling but not PI3K activation. Here we show that inhibition of Gal-1 with OTX008 sequestered H-Ras in the Lo domain, blocked H-Ras-mediated MAPK signaling, and attenuated H-Ras-driven tumor progression in mice. H-Ras-driven tumor growth was also attenuated by treatment with mTOR inhibitor Rapamycin, and this effect was further enhanced in tumors driven by Lo-sequestered H-Ras. These drugs also revealed bidirectional cross-talk in H-Ras pathways. Moreover, dual pathway inhibition with OTX008 and Rapamycin resulted in nearly complete ablation of H-Ras-driven tumor growth. These findings indicate that membrane microdomain sequestration of H-Ras with OTX008, coupled with mTOR inhibition, may support a novel therapeutic approach to treat H-Ras mutant cancers.<br>Temple University--Theses
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Lao, Yuanzhi. "Calcium signaling in apoptotic mammalian cells /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202008%20LAO.
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Su, YuTing. "Functional Characterization of FLNB in VEGF signaling." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1371485215.
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Wen, Wenyu. "Structural characterization of proteins involved in cellular signaling and trafficking /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BICH%202008%20WEN.
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Borensztajn, Keren Sarah. "Action and function of coagulation Factor Xa on cellular signaling." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2009. http://irs.ub.rug.nl/ppn/317.
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Er, Ekrem Emrah. "Discovering Novel Feedback and Crosstalk Mechanisms in Cellular Signaling Pathways." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11011.
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Multiple signaling pathways control cellular response to environmental cues such as nutrients, growth factors and stress. Interpretation of these cues requires coordinated regulation of intracellular signaling pathways. Our attempt to understand how cells coordinate different signaling pathways led to the discovery of two crosstalk mechanisms between different signaling cascades. We found that PI3K-AKT signaling reduces EGFR signaling to the parallel ERK-MAPK pathway by enhancing EGF induced EGFR degradation. At the molecular level AKT activates PIKfyve to facilitate EGFR trafficking from early endosomes to the lysosomes. Using a mass spectrometry based approach we also found growth factor signaling by EGF inhibits stress response. In particular, inhibiting RSK signaling downstream of EGF increased the activity of stress activated kinases p38, MSK2 and ERK5. We propose that when growth factors are present active RSK phosphorylates and inhibits a master regulator of stress response MEKK3, which leads to termination of MEKK3 signaling to downstream kinases. Our unbiased phosphoproteomic approach also lead to identification of many ERK and RSK substrates that will help us explain how growth factor signaling regulates a wide variety of biological processes.
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Zhu, Chuan. "Src signaling in neuromuscular junction induction /." View abstract or full-text, 2010. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202010%20ZHU.
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Lopez, Lyle Villamater. "Regulation of Gli proteins by the Hedgehog Signaling Pathway." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11095.
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Ramanathan, Saumya. "Extracellular Regulation of Nitric Oxide Signaling via Soluble Guanylate Cyclase." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/223312.
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Nitric Oxide (NO) regulates cardiovascular homeostasis by binding to soluble guanylate cyclase (sGC), leading to cGMP production, reduced cytosolic calcium concentration ([Ca²⁺]ᵢ) and vasorelaxation. Thrombospondin-1 (TSP-1), a secreted matricellular protein, was recently discovered to inhibit NO signaling and sGC activity. Inhibition of sGC requires binding to cell-surface receptor CD47. Here, I show that a TSP-1 C-terminal fragment (E3CaG1) readily inhibits sGC in Jurkat T cells, and that inhibition requires an increase in [Ca²⁺]ᵢ. Using digital imaging microscopy on live cells, I further show that E3CaG1 binding results in a substantial increase in [Ca²⁺]ᵢ, up to 300 nM. Addition of angiotensin II, a potent vasoconstrictor known to increase [Ca²⁺]ᵢ, also strongly inhibits sGC activity. sGC isolated from calcium-treated cells or from cell-free lysates supplemented with Ca²⁺ remains inhibited, while addition of kinase inhibitors staurosporine, genistein, PP1 or PP2 reverse inhibition, indicating inhibition likely involves a tyrosine kinase, more specifically, a src family kinase. Rat sGC is also inhibited by lysates supplemented with Ca²⁺, suggesting that the site of modification is at an evolutionarily conserved residue. Inhibition is through an increase in K(m) for GTP, which rises to 834 μM for the NO-stimulated protein, a 13-fold increase over the uninhibited protein. Compounds YC-1 and BAY 41-2272, allosteric stimulators of sGC that are of interest for treating hypertension, overcome E3CaG1-mediated inhibition of NO-ligated sGC. Taken together, these data suggest that sGC not only lowers [Ca²⁺]ᵢ in response to NO, inducing vasodilation, but is also inhibited by high [Ca²⁺]ᵢ, providing a fine balance between signals for vasodilation and vasoconstriction.
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Hughes, Hallett James. "Systems Level Analysis of TORC1 Pathway Signaling in S. cerevisiae." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/556430.
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The target of rapamycin complex I (TORC1) regulates cell growth and metabolism in all eukaryotes. Previous studies have shown that nitrogen and amino acid signals activate TORC1 via three GTPases; Gtr1, Gtr2, and Rho1, and the SEA-associated Npr2/3 proteins. However, little is known about the way that other nutrient or stress signals are transmitted to TORC1. Here I present two studies identifying how, and at what level, glucose and other environmental stimuli act to tune TORC1 signaling. In the first study I show that the TORC1 pathway populates three additional stress/starvation states. First, in glucose starvation conditions, the AMP-activated protein kinase (AMPK/Snf1) and at least one other factor push the TORC1 pathway into an off state, in which Sch9-branch signaling and PP2A-branch signaling are both inhibited. The TORC1 pathway remains in the glucose starvation state even when cells are simultaneously starved for nitrogen and glucose or treated with rapamycin. Second, in osmotic stress, the MAPK Hog1/p38 drives the TORC1 pathway into a different state, in which Sch9 signaling and PP2A-branch signaling are inhibited, but PP2A-branch signaling can still be activated by nitrogen starvation. Third, in oxidative stress and heat stress, TORC1-Sch9 signaling is blocked while weak PP2A-branch signaling occurs. Together, the data show that the TORC1 pathway acts as an information-processing hub, activating different genes in different conditions to ensure that available energy is allocated to drive growth, amino acid synthesis, or a stress response, depending on the needs of the cell. In the second study I investigate further the observed hierarchy of TORC1 inputs. I show that glucose starvation triggers disassembly of TORC1, and movement of the key TORC1 component Kog1, to a single body near the edge of the vacuole. These events are driven by AMPK/Snf1-dependent phosphorylation of Kog1 at Serine 491/494 and two nearby prion-like motifs. Kog1-bodies then serve to increase the threshold for TORC1 activation in cells that have been starved for a significant period of time. Together, this data shows that Kog1-bodies create hysteresis (memory) in the TORC1 pathway and help ensure that cells remain committed to a quiescent state under suboptimal conditions.
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Taylor, Robert James. "Systems biology of cellular signaling : quantitative experimentation and systems genetics approaches." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/7101.
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Cellular regulation is governed by dense biomolecular networks consisting of proteins, nucleotides, lipids, and metabolites that dynamically coordinate cellular decision making in the face of complex and time-varying environmental stimuli. Obtaining predictive models of these complex networks is a central goal of systems biology and requires sophisticated technologies for the acquisition and integration of many disparate data types. Recent genomic, proteomic and cellular imaging developments have greatly enabled systems-level studies, but further technological advances are needed. For instance, current high-throughput biochemical and cellular measurement techniques are generally limited to the analysis of cell populations, and the development of single-cell technologies are needed to advance predictive models of cellular networks. Large-scale genetic analyses are highly informative of the complex architecture of cellular networks but further computational methods are required to manage data complexity. In this thesis I present the development of two technologies, a microfluidic single-cell experimental platform and a genetic-network computational analysis platform, to address these issues and apply them to the study of prototypical eukaryotic signaling systems in Saccharomyces cerevisiae.
First I describe microfluidic technology for the high-throughput analysis of single-cells subject to complex environmental conditions. Using this platform, I studied cellular response of the mating pathway in Saccharomyces cerevisiae under a series of genetic and time-varying environmental perturbations. This analysis revealed dynamic phenotypes that are not observable under static conditions and allowed for the stratification of system components into distinct functional roles. In addition, I describe advances to this technology that allow for the tracking of individual cells over long experimental time frames. These developments enabled the investigation of sources of cell-to-cell variability not detectable otherwise. Second I describe a computational platform for analyzing complex genetic interaction networks. These networks describe functional relationships between gene systems and can be used to delineate information flows through complex cellular circuits. Genetic interactions networks are dense and information rich, and require sophisticated computational methods for their analysis. In this work, I developed network algorithms to identify biologically informative patterns within a multi-mode genetic interaction network to reveal functional sub-networks and information-hubs of the filamentation pathway in Saccharomyces cerevisiae.
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Cichy, Annika [Verfasser]. "Molecular and cellular mechanisms of vomeronasal signaling in mammals / Annika Cichy." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2013. http://d-nb.info/1044490713/34.
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Mustafa, Elwaleed Ibrahim. "Experimental autoimmune sialadenitis : studies of immunopathogenesis, cellular signaling and MHC genetics /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4791-0/.
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Trotter, Justin Howard. "Molecular and Cellular Mechanisms of Reelin Signaling in the Adult Hippocampus." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4848.
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The Reelin signaling pathway is critical for neuronal migration during development and the function of excitatory synapses in the adult forebrain. Despite a growing body of evidence implicating impaired Reelin signaling in the pathogenesis of numerous neuropsychiatric and neurodegenerative disorders, including Schizophrenia and Alzheimer's disease, little is known still regarding the specific molecular and cellular mechanisms whereby Reelin signaling modulates the function of synapses to enable normal learning and memory. In this dissertation, we addressed these knowledge gaps by identifying mechanisms of Reelin proteolysis following synaptic potentiation (Chapter 2) and dissociated the synaptic function of Reelin signaling at excitatory (Chapter 3) and inhibitory synapses (Chapter 4). In the adult brain, Reelin is secreted by GABAergic interneurons into the extracellular space, after which it is cleaved by unknown proteases to generate active fragments that signal downstream. In Chapter 1, we demonstrate that tissue plasminogen activator (tPA) and its major in vivo substrate, plasminogen, cleave Reelin under cell-free conditions to generate major Reelin fragments found in vivo. Since manipulation of tPA levels under basal conditions had no effect on Reelin processing, we hypothesized that synaptic activity may be required to render Reelin susceptible to proteolysis by tPA. Indeed, the modulation of Reelin processing by synaptic potentiation of ex vivo hippocampal slices required the presence of tPA. These data are the first to demonstrate a specific context in which Reelin signaling may be initiated in the intact brain and further emphasize that extracellular proteolysis of Reelin by tPA and other yet-to-be identified proteases is important to consider when trying to understand how altered Reelin processing and/or expression contribute to cognitive impairments associated with disease states. In Chapters 2 and 3 of this dissertation, we describe recent attempts by our lab to elucidate cellular mechanisms of Reelin signaling in the adult brain. To do this, we generated two conditional knockout mutants that lack the obligate downstream adaptor protein, Disabled-1 (Dab1), specifically in postnatal excitatory neurons (eKO) or GABAergic interneurons (iKO). Despite some overlap of Reelin and Dab1 in a subset of GABAergic interneurons, we found that their expression was generally juxtaposed, with Dab1 being primarily expressed by principle neurons and a more widespread population of Reelin-negative GABAergic interneurons. While eKO mice exhibited normal forebrain lamination, dendritic architecture, and dendritic spine density, they did have reductions in spine volume and a loss of basal and activity-dependent Akt and MAPK activation. These changes culminated in impairments in short-term and long-term synaptic plasticity, as well as impairments in associative learning and spatial memory. Taken together, our observations in the eKO mice are the first to definitively establish a synaptic function of Reelin signaling in the adult hippocampus. While characterizing the eKO mice, we also observed that GABAergic interneurons expressed Dab1, which motivated us to explore the inhibitory synapse as a novel locus of Reelin signaling (Chapter 4). Although loss of Dab1 in GABAergic interneurons did not affect forebrain development or the overall patterning of inhibitory synapses, iKO mice presented with an ataxic gait, resting tremor and cerebellar hypoplasia. Interestingly, loss of Dab1 in interneurons led to altered expression of some major glutamatergic synapse proteins (i.e. NMDA receptor subunits NR1 and NR2B), while other excitatory and inhibitory synapse proteins were normal (e.g. NR2A, GAD67/65, and gephyrin). Hippocampal field recordings further demonstrated that even partial loss of Dab1 expression in iHET mice, led to enhanced presynaptic activation and impaired theta-burst induced LTP. These data establish the inhibitory synapse as a novel locus of Reelin signaling in the developing and adult brain. Taken together, data discussed herein should prove useful for understanding and treating disorders associated with Reelin signaling impairments (e.g. AD and Schizophrenia).
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Stucki, David [Verfasser]. "Implication of carbon monoxide signaling in cellular stress response / David Stucki." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1232490040/34.
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Moon, Junsang. "Design for selective remote control of cellular signaling using magnetic nanoparticles." Thesis, Massachusetts Institute of Technology, 2021. https://hdl.handle.net/1721.1/130676.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Materials Science and Engineering, February, 2021<br>Cataloged from the official PDF of thesis.<br>Includes bibliographical references (pages 137-147).<br>Understanding the structure and dynamics of the mammalian cellular signaling and the nervous system opens up the chances to induce tissues, organs, or organisms to function in a coordinated way. Consequently, extensive research and efforts have rapidly developed strategies for rationally manipulating cellular and neuronal signaling. In this thesis, I pursued to develop a wirelessly modulating system that can selectively control a targeted biological circuit. Heat dissipating properties of magnetic nanoparticles have garnered sustained research interest in biomedical applications, including drug release, cancer hyperthermia, and neural stimulations. However, research has been mainly focused on improving the magnetic nanomaterials' heat dissipation efficiency. To introduce selective heat dissipation of magnetic nanoparticles, I have designed a custom AC magnetometer that can capture dynamic magnetization of magnetic particles suspended in solution. The collected magnetic response data fed to an equation called multiplexing factor to find optimized alternative magnetic field conditions that can selectively trigger heat dissipation on each particle ensemble. This approach was confirmed by direct temperature change observation using a thermographic camera. The selective heating system was later combined with genetic engineering and a drug delivery system for selective cellular modulation. This work culminates in a demonstration of selective remote control of cellular signaling in vitro. The theoretical background, systematic design, and precisely executed demonstration can be transplanted to any system using magnetic nanoparticles as a heat transducer. Therefore, this study will set a strong foundation and suggest new approaches for researches utilizing magnetic nanoparticle's heat dissipation for any applications.<br>by Junsang Moon.<br>Ph. D.<br>Ph.D. Massachusetts Institute of Technology, Department of Materials Science and Engineering
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Krishnan, Kalaiselvan. "Studies on molecular mechanisms in calcium signaling and cellular energy consumption." Doctoral thesis, KTH, Tillämpad fysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-204418.
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Ion signaling plays fundamental role in cell survival. Na+ and Ca2+ are critical players in ion signaling. Cells spend the major amount of energy to maintain and regulate Na+ and Ca2+ gradients across the cell membrane. Any disruption in cellular energy consumption by plasma membrane ATPases affects ion signaling and vice versa. This thesis is a combination of four separate research studies. In the first study, We measured ATP consumption dynamics of Na+/K+-ATPase using a genetically encoded fluorescent indicator called Perceval HR. we demonstrate that PercevalHR is an excellent tool to visualize ATP:ADP in mammalian cells. In the second study, We studied the role of calcium signaling and TRP channels in angiotensin II type 1 receptor signaling cascade. We prove that low inhibition of CaV1.2 with physiological and therapeutically relevant concentration of Angiotensin II up regulate AT1R signaling. In the third study, We studied the role of the TRPM5 channel in regulating insulin secretion, and cytoplasmic free calcium concentration in the rat β-cells by usingtriphenyl phosphine oxide, a selective inhibitor of the channel. In the fourth study, We tested whether, the genetically engineered human β-cell line (EndoC-BH1) could be used as models for studying Ca2+signaling in the context of Type II Diabetes. We found that the EndoC-BH1 cells could be a relevant model to study stimulus-secretion coupling and Ca2+ signaling in the human β-cells.<br><p>QC 20170328</p>
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Cipriano, Rocky. "Unraveling The Signaling Network in Human Cell Transformation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270123159.
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Schwarcz, Leslie Esther. "Linking steroid hormone and Wnt signaling /." view abstract or download file of text, 2006. http://wwwlib.umi.com/cr/uoregon/fullcit?p3211226.
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Thesis (Ph. D.)--University of Oregon, 2006.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 71-82). Also available for download via the World Wide Web; free to University of Oregon users.
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Thomas, Gawain M. "The Role of Integrins in Cellular Response to Mechanical Stimuli." Digital WPI, 2017. https://digitalcommons.wpi.edu/etd-theses/114.
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Tissue cells exhibit varying responses according to the stiffness of their extracellular matrix (ECM). The mechanism of this stiffness sensing is not fully understood; however, it is known that cells probe stiffness by applying intracellular force to the ECM via integrin-mediated focal adhesions. The bonds between integrins and ECM have been described as “catch bonds�, and it is unclear how ECM viscoelasticity affects these bonds. We have observed the effects of ECM stiffness on the binding strength of integrins to ECM ligands by measuring the dissociation force of individual integrin-ligand bonds of 3T3 fibroblasts on collagen-coated polyacrylamide gels using atomic force microscopy. Results show that integrins exhibit higher rates of activation on stiff substrates. Furthermore, increased matrix stiffness results in the occurrence of larger, multi-bond dissociation events, which suggests that substrate stiffness may affect the cellular response by promoting integrin clustering as well as by modulating the maximum possible force between individual integrins and the ECM.
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Zhou, Liying. "Studying the mitochondria-dependent apoptotic signaling pathway in mammalian cells /." View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202005%20ZHOU.
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Menon, Harita. "Deciphering the Role of Kekkon5 in BMP signaling and Cell Junction Biology." Digital WPI, 2013. https://digitalcommons.wpi.edu/etd-dissertations/459.
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Precise spatial and temporal control of cellular adhesion and signal transduction events are necessary for accurate animal development. Given the necessity for cell communication in carrying out processes like cell fate specification, growth, cell migration and differentiation, it is not surprising that signaling transduction pathways, such as EGFR, BMP, Notch, Wingless and Hippo, are intimately involved. All these pathways encompass a cascade of molecular events over which there is exquisite spatial and temporal control. A wide array of mechanisms, involving a diverse set of molecules, acts to provide this regulatory control. One such molecule implicated in the BMP signaling pathway in Drosophila development is Kek5, a Leucine rich repeat and Immunoglobulin domain (LIG) family member. Here I show that Kek5 modulates both BMP signaling and adherens junctions. For these functions, I further demonstrate that structural elements in both extracellular and intracellular region of Kek5 are critical, providing new insight into the LIG family and their roles in signaling pathways.
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Singh, Harinder. "CAVEOLAE AS SPATIO-TEMPORAL COMPARTMENTS FOR ROS/RNS GENERATION AND NITROXIDATIVE STRESS SIGNALING." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/275561.
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Cell Biology<br>Ph.D.<br>During inflammatory conditions excessive production of reactive oxygen (ROS) and nitrogen species (RNS), peroxynitrite, is implicated in the development of vascular pathologies. Our previous studies showed that both NADPH oxidase enzyme complexes and eNOS localize to endothelial caveolae microdomains. Additionally, caveolae internalization has been shown as an activating mechanism for enzyme eNOS. However, roles of caveolae in ROS/RNS generation and downstream signaling roles in activating endothelial cells are not well known. Hypothesis: Caveolae act as, a) micro-environments in providing spatio-temporal reaction compartments for ROS/RNS generation, tyrosine nitration of proteins, b) platforms to propagate localized nitroxidative signaling in inducing endothelial cell activation and dysfunction (ICAM-1, VCAM-1 expression), and c) intracellular redox signaling endosomes to regulate adhesion molecule expression. Objectives: The aim of the study was to investigate whether, a) caveolae compartmentalize ROS, regulate localized tyrosine nitration of proteins, b) nitroxidative-signaling in the endothelium is compartmentalized in caveolae, c) dynamin-2-dependent internalization of caveoale is important for activating redox signaling, and d) caveolae compartments can be targeted to reduce endothelial ROS Methods and results: Cultured primary bovine aortic endothelial cells were stimulated with TNFα to generate ROS/RNS. Blockade of NADPH oxidase (gp91ds-tat) or scavenging of peroxynitrite (Uric acid) inhibited TNFα-induced protein tyrosine nitration, activation of the NFkB, and upregulation of ICAM-1/VCAM-1 expression. To test the role of caveolae in this process, cultured cells were depleted of caveolin-1 (siRNA). Similar to inhibitors, TNFα failed to induce protein-tyrosine nitration, activate NFkB or enhance adhesion molecule expression in cells lacking caveolin-1. These findings were corroborated in vivo using Cav1KO animals. Our results show that several caveolar residing proteins were nitrated on tyrosine in response to TNFα. Here, immunoprecipitation of cell lysates with an anti-nitrotyrosine antibody revealed Src-family kinases (SFK) in the precipitated fraction. Moreover, SFK nitration was lost in cells depleted of caveolin-1. Given that SFK nitration is associated with enzyme activation, cells were pretreated with PP2 to inhibit SFK activity. We found that PP2 attenuated the NFkB and adhesion molecule pathway activated by TNFα. Depletion of dynamin-2 (Dyn2siRNA) or inhibiting GTPase activity (Dynasore) also showed reductions in ROS generation, NFkB redox signaling and ICAM-1/VCAM-1 expression. Development of caveolae targeting peptide tagged with gp91ds-tat showed inhibitions in compartmentalized ROS production. Conclusions: Caveolae act as sites for ROS/RNS production where resident redox-sensitive second messengers are activated and propagate signals that regulate endothelial inflammatory phenotype. Targeting NADPH oxidase enzyme specifically in caveolae can be used a therapeutic strategy to limit vascular oxidative stress.<br>Temple University--Theses
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Zettervall, Carl-Johan. "Signaling pathways in the activation and proliferation of Drosophila melanogaster blood cells." Doctoral thesis, Umeå : Umeå centrum för molekylär patogenes (UCMP), 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-513.
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Bobbs, Alexander Sebastian. "FGF Signaling During Gastrulation and Cardiogenesis." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/265335.
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An early event in animal development is the formation of the three primary germ layers that define the body plan. During gastrulation, cells migrate through the primitive streak of the embryo and undergo changes in morphology and gene expression, thus creating the mesodermal and endodermal cell layers. Gastrulation requires expression of Fibroblast Growth Factor (FGF), Wnt, and Platelet-Derived Growth Factor (PDGF). Embryos treated with FGF inhibitors fail to gastrulate, as cell migration is completely halted. During gastrulation, 44 microRNAs are expressed in the primitive streak of G. gallus embryos, and six (microRNAs -let7b, -9, -19b, -107, -130b, and -218) are strongly upregulated when FGF signaling is blocked. The abundance of these six FGF-regulated microRNAs is controlled at various stages of processing: most are regulated transcriptionally, and three of them (let7b, 9, and 130b) are blocked by the presence of Lin28B, an RNA-binding protein upregulated by FGF signaling. These microRNAs target various serine/threonine and tyrosine kinase receptors. We propose a novel pathway by which FGF signaling downregulates several key microRNAs (partially through Lin28B), upregulating gene targets such as PDGFRA, which permits and directs cell migration during gastrulation. These findings add new layers of complexity to the role that FGF signaling plays during embryogenesis. FGF signaling is also required for the formation of the heartfields, and has an overlapping pattern of expression with BMP (Bone Morphogenetic Protein). A microarray experiment using inhibitors of FGF and BMP found that thousands of genes in pre-cardiac mesoderm are affected by FGF signaling, BMP signaling, or a cooperative effect of the two. The promoter regions of similarly regulated genes were queried for over-represented transcription factor binding sites or novel DNA motifs. Cluster analysis of over-represented sites determined candidate transcriptional modules that were tested in primary cardiac myocyte and fibroblast cultures. About 75% of predicted modules in FGF-upregulated genes proved to be functional enhancers or repressors. Functional enhancers among FGF-upregulated genes contained clusters of CdxA and NFY sites, and increased transcription in the presence of a constitutively active FGF receptor.
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Petrie, Ryan John. "Cellular organization of the netrin receptor DCC and its associated signaling pathways." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18667.
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The netrin-1 receptor Deleted in Colorectal Cancer (DCC) acts as a tyrosine kinase-associated receptor to mediate the attractive response of the growth cone towards the source of netrin-1. Fyn phosphorylates DCC on tyrosine 1418 to trigger neurite formation. DCC function requires lipid rafts, but it is not known how lipid rafts regulate DCC signaling. The activity of the Rho family GTPases Rac1 and Cdc42 are required to mediate DCC-dependent neurite formation. Determining how lipid rafts regulate DCC signaling and where Rac1 and Cdc42 activity is in a cell relative to DCC would aid in understanding the complex mechanism by which DCC connects netrin-1 binding to polarized cytoskeletal remodeling and axon growth to guide the growth cone towards the netrin-1 source. In the first part of this thesis, we have demonstrated that while netrin-1 binds to DCC in lipid rafts at the cell surface, DCC targeting to lipid rafts is insensitive to netrin-1 addition. DCC is phosphorylated both in rafts and non-lipid rafts and its association with Fyn and activation of FAK are all detected outside of lipid rafts. Thus, we show that while netrin-1 binds to DCC in lipid rafts, subsequent signals are propagated outside of this compartment independently of DCC translocation out of lipid rafts. In the second part, we developed a methodology and analysis regimen to image active Rac1 and Cdc42 by using sensitized emission fluorescence resonance energy transfer (FRET) in living cells and compared the utility of using intermolecular versus intramolecular FRET-based biosensors in visualizing Rho GTPase activity. In the last part we combined the FRET-biosensors with DCC in optimal imaging environment of Hela cells and determined that DCC localized to an F-actin enriched compartment on the cell surface, along with Rac1 and Cdc42, that did not correspond to early, late, or recycling endosomes. ICY-Cdc42 revealed that DCC colocalized with active Cdc42 and induced a gradient of Cdc42 activity, wh<br>Le récepteur transmembranaire Deleted in Colorectal Cancer (DCC) agit comme un récepteur à activité tyrosine kinase pour arbitrer l'attraction du cône de croissance vers une source de protéines chémotropiques, les nétrines. Fyn phosphoryle DCC sur le résidu tyrosine en position 1418 et cette action est nécessaire pour déclencher la formation de neurites. Les domaines membranaires appelés « lipid rafts » sont requis pour la fonction de DCC mais la façon dont ces « rafts » régulent la signalisation de DCC est jusqu'à ce jour inconnue. L'activité des GTPases Rho, en particulier celles de Rac1 et Cdc42, est cruciale pour la croissance de neurites induite par DCC. Démontrer la manière dont les rafts régulent la signalisation de DCC ainsi que positionner les activités de Rac1 et Cdc42 dans la cellule par rapport à DCC pourrait aider à comprendre le mécanisme complexe par lequel la nétrine-1 agit via DCC afin de provoquer la réorganisation du cytoskelette et la croissance axonale qui permet de guider le cône de croissance vers une source de nétrine-1. Dans la première partie de cette thèse, nous avons démontré que la nétrine-1 se lie à DCC à la surface cellulaire dans les rafts mais que la relocalisation de DCC dans ces domaines membranaires était insensible à l'ajout additionnel de nétrine-1. La phosphorylation de DCC survient aussi bien à l'intérieur ou à l'extérieur des rafts mais son association avec Fyn et l'activation de Fak sont des événements qui ont été seulement observés à l'extérieur des rafts. Par conséquent, nous montrons que lorsque la nétrine-1 se lie à DCC dans les rafts, des signaux subséquents se propagent à l'extérieur de ces domaines, indépendamment de la translocation de DCC à l'extérieur de ces derniers. Dans la deuxième partie, nous avons développé une méthodologie et une façon analytique servant à imager les activités de Rac1 et Cdc42 dans les cellules vivantes en utilisant la te
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Chibaya, Loretah. "Akt Regulation of Mdm2-p53 Signaling in Cellular Stress Responses and Tumorigenesis." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1028.
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In cells undergoing stress, the p53 transcription factor is stabilized and activates the expression of numerous genes contributing to p53-mediated tumor suppression. One p53 target gene is Mdm2, which encodes an oncoprotein that binds and ubiquitinates p53 for proteasomal degradation, thus limiting the amplitude and duration of the p53-mediated stress response. Our lab recently discovered that Mdm2 phosphorylation by ATM and c-Abl regulates the DNA damage response and tumorigenesis in mice. AKT has also been found in transfection studies to phosphorylate Mdm2 at serine residues 166 and 186 (mouse S163 and S183) to alter p53 activity. However, the physiological significance of Mdm2 phosphorylation by Akt remains unknown. Therefore, I generated Mdm2S163A or Mdm2S183A mice expressing mutant Mdm2 incapable of being phosphorylated by Akt.
In contrast with our previous studies, Akt phosphorylation of Mdm2 does not alter spontaneous tumorigenesis or the DNA damage response to ionizing radiation. However, Akt phosphorylation of Mdm2-S183 (but not -S163) upregulates nuclear localization of Mdm2, destabilizes p53, and reduces p53-mediated senescence in response to elevated levels of reactive oxygen species (ROS). To examine the effects of Mdm2-S183 phosphorylation on p53 tumor suppression, I utilized three different mouse models of ROS-induced cancer. Increased levels of p53 and senescence in Mdm2S183A mice yielded reduced tumorigenesis in an activated Ras model of lung cancer, a phorbal ester-induced skin cancer model, and a diethylnitrosamine-induced model of hepatocellular carcinoma. Since AKT is also important regulator of cell metabolism, I explored the impact of the Mdm2-S183 allele on metabolic functions. Mdm2 phosphorylation by Akt reduced glucose metabolism via glycolysis in vitro, and reduced insulin tolerance in mice, without altering glucose tolerance and glucose-stimulated insulin secretion. Collectively, these findings document a unique physiologic role for the AKT-Mdm2-p53 signaling axis in regulating cell growth and tumorigenesis.
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Huang, Shao-shan Carol. "A constraint optimization framework for discovery of cellular signaling and regulatory networks." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65772.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2011.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>Cellular signaling and regulatory networks underlie fundamental biological processes such as growth, differentiation, and response to the environment. Although there are now various high-throughput methods for studying these processes, knowledge of them remains fragmentary. Typically, the majority of hits identified by transcriptional, proteomic, and genetic assays lie outside of the expected pathways. In addition, not all components in the regulatory networks can be exposed in one experiment because of systematic biases in the assays. These unexpected and hidden components of the cellular response are often the most interesting, because they can provide new insights into biological processes and potentially reveal new therapeutic approaches. However, they are also the most difficult to interpret. We present a technique, based on the Steiner tree problem, that uses a probabilistic protein-protein interaction network and high confidence measurement and prediction of protein-DNA interactions, to determine how these hits are organized into functionally coherent pathways, revealing many components of the cellular response that are not readily apparent in the original data. We report the results of applying this method to (1) phosphoproteomic and transcriptional data from the pheromone response in yeast, and (2) phosphoproteomic, DNaseI hypersensitivity sequencing and mRNA profiling data from the U87MG glioblastoma cell lines over-expressing the variant III mutant of the epidermal growth factor receptor (EGFRvIII). In both cases the method identifies changes in diverse cellular processes that extend far beyond the expected pathways. Analysis of the EGFRVIII network connectivity property and transcriptional regulators that link observed changes in protein phosphorylation and differential expression suggest a few intriguing hypotheses that may lead to improved therapeutic strategy for glioblastoma.<br>by Shao-shan Carol Huang.<br>Ph.D.