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Claverie, Justine. "Identification du xyloglucane comme nouvel éliciteur oligosaccharidique stimulant l’immunité de Vitis vinifera et d’Arabidopsis thaliana et caractérisation de deux récepteurs aux chito-oligosaccharides chez la vigne (VvLYK1-1 et VvLYK1-2)." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCK076/document.
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L’activation des réponses immunitaires des plantes repose sur la reconnaissance de motifs moléculaires associés aux pathogènes (aussi appelés PAMP) par des récepteurs de l’immunité, également nommés PRR (pattern recognition receptors). La chitine, principal composant de la paroi des champignons, est un PAMP bien caractérisé qui induit des réponses de défense aussi bien chez les mammifères que chez les plantes.La première partie de cette étude met en évidence que deux chito-oligosaccharides, la chitine et le chitosan, agissent comme des PAMP chez la vigne (Vitis vinifera) puisqu’ils induisent des évènements précoces de signalisation, l’expression de gènes de défense et une résistance contre des agents pathogènes. Ces résultats suggèrent que des systèmes de perception existent chez la vigne. Une analyse phylogénétique a permis d’identifier trois récepteurs kinases à domaine LysM (LysM-RK ou LYK) chez V. vinifera (VvLYK1-1, -2, -3) appartenant au même clade que le récepteur à la chitine chez Arabidopsis et nommé AtCERK1 (Arabidopsis thaliana Chitin Elicitor Receptor Kinase 1). Leur analyse fonctionnelle a été réalisée par complémentation du mutant d’Arabidopsis Atcerk1, affecté dans la perception de la chitine. Nos résultats montrent que VvLYK1-1 et VvLYK1-2, mais pas VvLYK1-3, complémentent fonctionnellement le mutant Atcerk1 en restaurant l’activation des MAPK (Mitogen-Activated Protein Kinases) et l’expression de gènes de défense induits par les chito-oligosaccharides. De plus, l’expression de VvLYK1-1 chez Atcerk1 restaure la résistance basale à l’agent de l’oïdium de la vigne (Erysiphe necator).La seconde partie du projet s’est focalisée sur les éliciteurs oligosaccharidiques de type « damage-associated molecular patterns (DAMP) ». Ces molécules endogènes peuvent provenir de la dégradation de la paroi lors d’une attaque et sont capables d’activer les réponses immunitaires de la plante. Les DAMP les mieux caractérisés actuellement sont les oligogalacturonates (OG), des fragments de pectine qui induisent des réponses immunitaires chez de nombreuses espèces végétales dont l’activation de MAPK, la production d’H2O2, l’expression de gènes de défense et le dépôt de callose. Nous avons montré dans cette étude que les xyloglucanes (Xh), des fragments d’hémicellulose pariétale purifiés, induisaient l’activation de MAPK et l’expression de gènes de défense chez la vigne et Arabidopsis, afin d’induire une résistance contre le champignon nécrotrophe Botrytis cinerea. Les Xh induisent également la production de resvératrol, une phytoalexine majoritaire chez la vigne, et un dépôt de callose chez Arabidopsis. Par une approche génétique, nous avons identifié certains composants de la signalisation induite par les Xh chez Arabidopsis. L’utilisation de mutants suggère que la résistance induite par les Xh contre B. cinerea est dépendante des voies de la camalexine, de l’acide salicylique, de l’acide jasmonique et de l’éthylène chez Arabidopsis. De manière globale, nos résultats mettent en lumière que les xyloglucanes peuvent être considérés comme de nouveaux éliciteurs de l’immunité chez la vigne et ArabidopsisActivation of the plant immune responses requires recognition of common pathogen-associated molecular pattern (PAMP) by their cognate pattern recognition receptors (PRR). Chitin, a major component of fungal cell walls, is a well-known PAMP that triggers defense responses in several mammal and plant species.In the first part of this study, we show that two chitooligosaccharides, chitin and chitosan, act as PAMPs in grapevine (Vitis vinifera) as they elicit immune signaling events, defense gene expression, and resistance against pathogens. These two PAMPs are active in grapevine suggesting that at least one perception system exists. Phylogenetic analysis clearly distinguished three V. vinifera LysM Receptor Kinases (VvLYK1-1, -2, -3) located in the same clade as the Arabidopsis Chitin Elicitor Receptor Kinase 1 (AtCERK1), which mediates chitin-induced immune responses. Their functional characterization was achieved by complementation assays in the Atcerk1 mutant, impaired in chitin perception. Our results provide evidence that VvLYK1-1 and VvLYK1-2, but not VvLYK1-3, functionally complement the loss of AtCERK1 function by restoring chitooligosaccharide-induced MAPK activation and immune gene expression. Moreover, expression of VvLYK1-1 in Atcerk1 restored penetration resistance to the non-adapted grapevine powdery mildew (Erysiphe necator).The second part of this study focused on damaged-associated molecular patterns (DAMP), endogenous molecules that can be released from the plant cell wall during an attack and activate the plant innate immunity. Until now, the best characterized DAMPs are oligogalacturonides (OG) coming from pectin fragments that induce innate immune responses in various plant species, including MAPK activation, H2O2 production, defense gene expression and callose deposition. In this study, we showed that purified xyloglucans (Xh), derived from the plant cell wall hemicellulose, elicit MAPK activation and immune gene expression in grapevine (V. vinifera) and Arabidopsis to trigger induced resistance against the necrotrophic fungus Botrytis cinerea. Xh also elicit the production of resveratrol, the main grapevine phytoalexin, and callose deposition in Arabidopsis. Using a genetic approach, we identified some signaling components of Xh-induced immunity. The use of Arabidopsis mutants suggests that Xh-induced resistance against B. cinerea is dependent on the camalexin, salicylate, jasmonate and ethylene pathways. Taken together, our data highlight that Xh can be considered as new elicitors of grapevine and Arabidopsis immunity
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Czechowski, Tomasz. "Nitrogen signalling in Arabidopsis thaliana." Phd thesis, [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975976095.
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McDonald, Sarah E. "Steroid pre-receptor signalling in human endometrium." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/24938.
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This work has shown that 11βHSD-1 mRNA is present at highest levels in the menstrual phase of the cycle and in first trimester deciduas, the times when an inflammatory response is evident. 11βHSD-2 mRNA and protein are present at all stages of the cycle, and also in first trimester deciduas. GR mRNA and protein are highly expressed throughout the cycle. MR mRNA expression varies across the cycle in a pattern similar to progesterone expression. 11βHSD-1 mRNA expression is increased in response to IL-1α and cortisol, and GR mRNA shows a similar trend. 11βHSD-1 and MR expression are not altered by IL-1α or cortisol.3βHSD-1 mRNA has been shown to be present only in first trimester deciduas; 3βHSD-1 is not detectable by these methods. Immunohistochemistry using an antibody which detects both 3βHSD-1 and -2 has shown low levels of protein in the tissues studied. AKR1C1-3 mRNAs are expressed throughout the menstrual cycle; all three enzymes are predominantly expressed in the secretory phase. AKR1C3 is localised to the glandular and surface epithelial cells, and vascular endothelium. AKR1C4 mRNA is not detectable in the endometrium at any stage of the menstrual cycle. Expression of steroid-metabolising enzymes is perturbed in the endometrium of users of a Levonorgestrel intra-uterine system, and also the following GnRH antagonist treatment for sub-fertility. These studies have shown that the endometrium has the ability to precisely regulate its balance of steroid hormone availability at a local level, and that this balance may be altered following administration of exogenous steroids. Further functional studies such as knockout or knockdown of these enzymes would expand this knowledge and fully elucidate steroid hormone metabolism and pre-receptor signalling.
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McKenzie, Maxine. "Akt signalling in the human parasite 'Schistosoma mansoni'." Thesis, Kingston University, 2017. http://eprints.kingston.ac.uk/41116/.
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The study of cell signalling in schistosomes is crucial in deepening our knowledge of the biology of these blood flukes, which affect hundreds of millions of people worldwide. Here, Akt/protein kinase B (PKB) signalling has been functionally characterised and mapped in Schistosoma mansoni; an Akt variant of approximately 52 kDa has been characterised and RNA interference of the S. mansoni Akt gene, resulted in an 84% reduction in Akt expression. The phosphorylation (activation) status of the characterised Akt protein was increased by host molecules, including insulin and L-arginine in somules and adult worms, and L-arginine and linoleic acid in cercariae. Akt phosphorylation (activation) was also attenuated by Akt Inhibitor X and herbimycin A treatment. Immunohistochemistry/confocal laser scanning microscopy revealed phosphorylated Akt in all S. mansoni human infective/resident life stages. Somules and adult worms displayed activated Akt primarily in the tegument, particularly the tubercles and gynaecophoric canal of adult males. Cercariae exhibited activated Akt in the nervous system and punctate regions along the length of the tail prompting investigation into the role of Akt in cercarial motility. Behavioural studies demonstrated a significant increase in cercarial swimming in response to host factors, which was attenuated following exposure to Akt inhibitor X. The striking activation of Akt observed in the tegument of adult worms stimulated research into its possible role in glucose uptake in this host-interactive layer. RNAi of Akt resulted in a 59% and 47% reduction in SGTP4 glucose transporter expression in male and female adult worms respectively with a concomitant reduction in glucose uptake by the parasite. In somules, the expression of SGTP4 and its evolution at the apical tegument membrane during transformation were significantly attenuated by Akt Inhibitor X; a 74% reduction in glucose uptake was also demonstrated following Akt inhibition. Bioinformatic analysis of S. mansoni Akt interacting proteins uncovered a putative connection between Akt and Rab vesicle trafficking proteins and a mechanistic model illuminating the possible role of Akt in the translocation of SGTP4 to the parasite surface was proposed. Collectively, this research highlights the significance of Akt in schistosome homeostasis and host-parasite interactions and thus demonstrates that Akt may be a suitable target for anti-schistosome drug development strategies.
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Groves, Tim C. "Pre-TCR and TCR-Ãß signaling during T cell development." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ27657.pdf.
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Wang, Fang. "The Role of Acinus in Retinoic Acid Signaling Pathway." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/277479.
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BiochemistryPh.D.
Retinoic acid receptor (RAR), a member of the steroid/thyroid hormone nuclear receptor superfamily, functions as a RA-dependent transcription activator bound to the RA response element (RARE) within the promoter or enhancer region of target genes. The transcriptional activity of RAR is modulated by a large number of coregulators including coactivators and corepressors. Acinus is a nuclear protein with three isoforms (Acinus-L, Acinus-S and Acinus-S'). Acinus-S' interacts with the A/B domain of RAR and represses RAR-regulated genes expression. Acinus (without isoform definition) has been identified as a component of nuclear speckles, the spliceosome and the exon junction complex (EJC), suggesting its localization in nuclear speckles and involvement in RNA processing. Acinus-S has been shown to localize in nuclear speckles. However, it is unclear whether the other two isoforms also localize in nuclear speckles. In addition, the role of Acinus in regulating pre-mRNA splicing is unclear. The goal of these studies was to examine the nuclear localization of Acinus-L and Acinus-S' and to determine the role of Acinus isoforms in RAR-dependent splicing. The sub-nuclear localization of Acinus-L and Acinus-S' was determined using fluorescence microscopy. Acinus-S' colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S'. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S' were identified. The speckled sub-nuclear localization of Acinus-S' is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. The role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S', with the activity of Acinus-L higher than that of Acinus-S', increase the splicing of a RA-responsive minigene containing a weak 5' splice site but not a RA-responsive minigene containing a strong 5' splice site. RA treatment further enhances the splicing activity of Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus on the splicing of pre-mRNAs containing the weak 5' splice site occurs to varying degrees using minigene constructs containing several different promoters while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by the RARE-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The ligand-dependent splicing activity of Acinus was further shown to be promoter-specific, depending on the ligand-dependent transcription activator. The RRM domain was identified to be necessary for the RA-dependent splicing activity of Acinus. The RA-independent splicing activity of Acinus is repressed by RNPS1. Unexpectedly, the C-terminal RS- and RD/E rich region is dispensable for the splicing activity of Acinus in regulating the minigene containing a weak 5' splice site. Importantly, measurement of the splicing of endogenous human RARâ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5' splice site of these two genes in a RA-dependent manner for RARâ and in a RA-independent manner for Bcl-x. Taken together, these studies demonstrate the distinct sub-nuclear localization of Acinus-L and Acinus-S', and identified the domains that are responsible for their sub-nuclear localization, which shed light on possible distinct functions between Acinus isoforms. In addition, both Acinus-L and Acinus-S' have been shown to be splicing cofactors (with the activity of Acinus-L higher than that of Acinus-S') that facilitate constitutive splicing of pre-mRNAs containing a weak 5' splice site and regulate alternative splicing in favor of the isoform generated from the weaker alternative 5' splice site. Both Acinus-L and Acinus-S' have a RA-dependent splicing activity specific for RA-responsive genes, which suggests that Acinus functions in RAR-dependent splicing.
Temple University--Theses
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Bhangu, P. S. "Vesicular 'pre-synaptic' glutamatergic signalling mechanisms in bone." Thesis, University of York, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288814.
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Krjukova, Jelena. "Investigation on Pre- and Postsynaptic Ca2+ Signaling in Neuronal Model Systems." Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4300.
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Communication between neuronal and non-neuronal is called volume transmission when the released neurotransmitter (NT) acts via diffusion and affects several target cells. Both the neurosecretory and postsynaptic cell responses are linked to [Ca2+]i elevations. In the present thesis the role of pre-and postsynaptic Ca2+ elevations has been investigated in the reconstituted "synapse" model comprised of NGF-differentiated PC12 and HEL cells as well as in SH-SY5Y neuroblastoma cells. In PC12 cells, both 70mM K+ and nicotine triggered NT release, which could be detected as a secondary [Ca2+]i increase in surrounding HEL cells. Both secretagogues shared the same voltage-dependent Ca2+ influx pathway as judged from the pharmacological profile blockers of voltage-gated Ca2+ channels. The coupling of electrical responses to the activation of Ca2+ signaling via muscarinic receptors in SH-SY5Y cells was also studied. These data revealed that depolarization caused a considerable potentiation of the muscarinic Ca2+ response. The potentiated Ca2+ increase was mainly dependent on the enhanced Ca2+ influx and to a lesser extent on [Ca2+]i release from intracellular stores. A phospholipase C (PLC) activator, m-3M3FBS was used to further study the role of G-protein coupled receptor (GPCR)-coupled Ca2+ signaling. However, it was found that m-3M3FBS instead triggered [Ca2+]i elevations independently of PLC activation. In conclusion, the results indicate that the magnitude of NT release from PC12 cells is sufficient to cause a robust activation of neighboring target cells. Postsynaptic muscarinic signaling is amplified due to integration of electrical excitation and GPCR signaling. The PLC activator, m-3M3FBS is not suitable for studies of PLC-mediated signals in intact cells.
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Simón, Moya Miguel. "Unveiling the role of Phytochrome Interacting Factor 1 (PIF1) homologs in tomato." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670860.
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La llum és un dels senyals ambientals més importants que influeixen en el cicle de vida de la planta. Les plantes han desenvolupat un conjunt de complexos mecanismes moleculars que detecten canvis en la qualitat i quantitat de la llum. Els PHYTOCHROME INTERACTING FACTORS (PIFs) són factors de transcripció que interactuen amb els fotoreceptors fitocroms (phy) i intervenen les respostes a llum vermella / vermella llunyana. Els PIF estan involucrats en la regulació d'una àmplia gamma de processos de desenvolupament. S'han estudiat àmpliament en Arabidopsis thaliana, però se sap molt poc sobre el seu paper en altres espècies. En aquesta tesi, vam investigar el paper dels dos homòlegs de PIF1 presents en tomàquet (Solanum lycopersicum): PIF1a i PIF1b.
L'anàlisi de l'expressió de PIF1a i PIF1b va mostrar patrons molt diferents, el que indica una possible divergència evolutiva en els seus rols. Els experiments d'estabilitat de les corresponents proteïnes en llum vermella i vermella llunyana van revelar que PIF1b ha perdut la seva capacitat d'interactuar amb PhyB, mentre que PIF1a encara pot fer-ho, confirmant la hipòtesi de divergència evolutiva.
D'altra banda, l'edició del genoma de plantes de tomàquet per CRISPR-CAS9 va generar línies de pèrdua de funció pif1a i pif1b, així com mutants dobles pif1a pif1b. La caracterització fenotípica d'aquests mutants va mostrar que tots dos factors de transcripció estan involucrats en la regulació de la germinació de les llavors, la síntesi de pigments en les fulles durant la des-etiolació i la producció de fruits. Altres processos estan regulats només per PIF1a, com l'allargament de pèls radiculars, la síntesi de glicoalcaloides esteroides en fulles, el temps de floració i el creixement i estovament del fruit. No identifiquem cap procés que estigui regulat específicament per PIF1b.
A causa del paper central de PIF1a, vam decidir realitzar experiments de RNA-seq en línies induïbles. Els resultats van mostrar que la inducció de PIF1a té un impacte relativament menor en el perfil transcriptòmic, i que els possibles gens diana de PIF1a en tomàquet són diferents dels identificats prèviament en Arabidopsis.
Totes aquestes dades en conjunt suggereixen que PIF1a i, en molt menor grau, PIF1b comparteixen algunes funcions amb el seu homòleg PIF1 d'Arabidopsis, però també il·lustren que s'han produït esdeveniments de neofuncionalització en tomàquet. Al fer això, l'evolució ha pogut utilitzar el potencial d'aquests factors de transcripció per regular nous processos específics en aquest cultiu d'interès agronòmic.La luz es una de las señales ambientales más importantes que influyen en el ciclo de vida de la planta. Las plantas han desarrollado un conjunto de complejos mecanismos moleculares que detectan cambios en la calidad y cantidad de la luz. Los PHYTOCHROME INTERACTING FACTORs (PIFs) son factores de transcripción que interactúan con los fotorreceptores fitocromos (phy) y median las respuestas a luz roja/roja lejana. Los PIF están involucrados en la regulación de una amplia gama de procesos del desarrollo. Se han estudiado ampliamente en Arabidopsis thaliana, pero se sabe muy poco sobre su papel en otras especies. En esta tesis, investigamos el papel de los dos homólogos de PIF1 presentes en tomate (Solanum lycopersicum): PIF1a y PIF1b. El análisis de la expresión de PIF1a y PIF1b mostró patrones muy diferentes, lo que indica una posible divergencia evolutiva en sus roles. Los experimentos de estabilidad de las correspondientes proteínas en luz roja y roja lejana revelaron que PIF1b ha perdido su capacidad de interactuar con PhyB, mientras que PIF1a todavía puede hacerlo, confirmando la hipótesis de divergencia evolutiva. Por otro lado, la edición del genoma de plantas de tomate por CRISPR-Cas9 generó líneas de pérdida de función pif1a y pif1b, así como mutantes dobles pif1a pif1b. La caracterización fenotípica de estos mutantes mostró que ambos factores de transcripción están involucrados en la regulación de la germinación de las semillas, la síntesis de pigmentos en las hojas durante la des-etiolación y la producción de frutos. Otros procesos están regulados solo por PIF1a, como el alargamiento de pelos radiculares, la síntesis de glicoalcaloides esteroideos en hojas, el tiempo de floración y el crecimiento y ablandamiento del fruto. No identificamos ningún proceso que esté regulado específicamente por PIF1b. Debido al papel central de PIF1a, decidimos realizar experimentos de RNA-seq en líneas inducibles. Los resultados mostraron que la inducción de PIF1a tiene un impacto relativamente menor en el perfil transcriptómico, y que los posibles genes diana de PIF1a en tomate son distintos a los identificados previamente en Arabidopsis. Todos estos datos en conjunto sugieren que PIF1a y, en mucho menor grado, PIF1b comparten algunas funciones con su homólogo PIF1 de Arabidopsis, pero también ilustran que se han producido eventos de neofuncionalización en tomate. Al hacer esto, la evolución ha podido utilizar el potencial de estos factores de transcripción para regular nuevos procesos específicos en este cultivo de interés agronómico.
Light is one of the most important environmental cues influencing the plant life cycle. Plants have developed a set of complex molecular mechanisms that sense changes in light quality and quantity. PHYTOCHROME INTERACTING FACTORs (PIFs) are transcription factors that interact with the photoreceptors phytochromes (phy) and mediate the responses to red/far-red light. PIFs are involved in the regulation of a broad range of developmental processes. They have been extensively studied in Arabidopsis thaliana, but very little is known about their roles in other species. In this thesis, we investigate the role of the two homologs of PIF1 found in tomato (Solanum lycopersicum): PIF1a and PIF1b. The analysis of PIF1a and PIF1b expression showed very different patterns, indicating a potential evolutionary divergence in their roles. Protein stability experiments in red and far-red light unveiled that PIF1b has lost its ability to interact with PhyB, while PIF1a is still able to do it, confirming the evolutionary divergence hypothesis. On the other hand, tomato genome editing by CRISPR-Cas9 generated pif1a and pif1b loss-of-function lines, as well as double mutants pif1a pif1b. The phenotypic characterization of these mutants showed that both transcription factors are involved in the regulation of seed germination, synthesis of leaf pigments during de-etiolation and fruit production. Other processes are regulated just by PIF1a, such as root hair elongation, synthesis of steroidal glycoalkaloids in leaves, flowering time and fruit growth and softening. We did not identify any process regulated specifically by PIF1b alone. Due to the central role of PIF1a, we decided to perform RNA-seq experiments in PIF1a-inducible lines. The results showed that the induction of PIF1a had a relatively minor impact in the transcriptomic profile, and that the putative gene targets of PIF1a in tomato were different from those previously identified in Arabidopsis. All this data together suggests that PIF1a and, to a much lower extent, PIF1b share some roles with Arabidopsis PIF1, but also illustrate that neofunctionalization has taken place in tomato. Doing this, evolution managed to use the potential of these transcription factors to regulate new specific processes in this crop of agronomic interest.
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Macfarlane, Scott Robert. "Proteinase-activated receptor-2 mediated signalling in a human keratinocyte cell line." Thesis, University of Strathclyde, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366849.
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Thomas, Mélissa. "Etude de la voie non-apoptotique de CD95 et de l’implication du facteur d’initiation de la traduction eIF4A1." Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B048.
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Depuis sa découverte en 1991, l’implication du récepteur CD95 dans l’induction de l’apoptose a été plus que largement décrite. Mais bien qu'ayant été identifié comme étant un récepteur de mort, CD95 est aussi capable d'induire un signal pro-oncogénique lorsqu'il est fixé au CD95L clivé. L’activation de cette voie de signalisation non-apoptotique par le s-CD95L contribue au processus inflammatoire dans le lupus et à la dissémination métastatique dans les cancers du sein triples négatifs. Cependant aucun traitement thérapeutique satisfaisant n’est à ce jour disponible. De par son implication dans des pathologies cancéreuses et inflammatoires, mieux comprendre les mécanismes à l’origine de la double signalisation de CD95 n’est plus un enjeu mais une nécessité. Afin de développer des molécules pour bloquer la signalisation non apoptotique de CD95, il est essentiel d’en identifier tous les protagonistes et de définir leur fonction biologique. C’est avec cet objectif que notre équipe a mené deux études protéomiques dont les résultats ont permis d’identifier eIF4A1 comme un nouveau partenaire direct de CD95. Nous montrons que eIF4A1 est indispensable à la mise en place de la signalisation pro-motile de CD95 dépendante de la voie PI3K. De plus eIF4A1 est recruté à la membrane ainsi que les autres protéines du complexe eIF4F. Nos données de séquençage ont montré que de par cette interaction, CD95 recrute à la membrane un ensemble d’ARNm impliqués dans la réponse immunitaire et l’adhésion cellulaire. En outre, une perte de CD95 dans certaines cellules cancéreuses conduit à la perte d’expression de ces ARNm. Ainsi CD95 pourrait protéger certains ARNm de la dégradation et favoriser la traduction des ARNm pro-inflammatoires de manière indépendante du ligand. Cibler spécifiquement cette interaction pourrait être une piste thérapeutique prometteuse dans la lutte contre les cancers du sein triples négatifs mais aussi contre le lupusSince its discovery in 1991, the involvement of the CD95 receptor in the induction of apoptosis has been more than widely described. But although identified as a death receptor, CD95 is also capable of inducing a pro-oncogenic signal when attached to the cleaved CD95L. Activation of this non-apoptotic signaling pathway by s-CD95L contributes to the inflammatory process in lupus and metastatic spread in triple negative breast cancers. However, no satisfactory therapeutic treatment is currently available. By its implication in cancerous and inflammatory pathologies, better understanding the mechanisms at the origin of the double signaling of CD95 is no longer an issue but a necessity. In order to develop molecules to block the non-apoptotic CD95 signaling, it is essential to identify all the protagonists and define their biological function. Our team conducted two proteomic studies, the results of which identified eIF4A1 as a new direct partner of CD95. We show that eIF4A1 is essential for the implementation of PI3K pathway-dependent CD95 signaling. In addition eIF4A1 is recruited to the membrane as well as the other eIF4F complex proteins. Our sequencing data showed that by this interaction, CD95 recruits a set of mRNAs involved in the immune response and cell adhesion. In addition, a loss of CD95 in some cancer cells leads to the loss of expression of these mRNAs. Thus CD95 could protect certain mRNA from degradation and promote the translation of pro-inflammatory mRNAs independently of the ligand. Specific targeting of this interaction could be a promising therapeutic avenue in the fight against triple negative breast cancers but also against lupus
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Bragdon, Beth Christie. "Membrane Regulation of Bone Morphogenetic Protein 2 Signaling in Pre-Osteoblastic Cells." Fogler Library, University of Maine, 2011. http://www.library.umaine.edu/theses/pdf/BragdonB2011.pdf.
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Ranganathan, Padhma. "Reciprocal regulation of Par-4 and caspase-8 in theTRAIL signaling pathway." Lexington, Ky. : [University of Kentucky Libraries], 2008. http://hdl.handle.net/10225/961.
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Thesis (Ph. D.)--University of Kentucky, 2008.Title from document title page (viewed on January 29, 2009). Document formatted into pages; contains: x, 118 p. : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 104-116).
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Hicks, Mellissa. "Signaling Networks as Possible Therapeutic Implications in Breast Cancer." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861.
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Leonardi, Anthony Joseph. "Cell to cell signaling via AKT causes T cell differentiation and collapse of tumour stroma." Thesis, Kingston University, 2018. http://eprints.kingston.ac.uk/41981/.
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Adoptive Cell Therapy of cancer using T cells is entering mainstream practice after years as a research method. Central to the efficacy of this “living therapy” is the function of the T cells transferred. T-cells, like other primary tissue cells, undergo differentiation and death. Clinical and preclinical data shows that lesser differentiated, less glycolytic, and more proliferative-capable cells used for the adoptive transfer yield superior tumor responses. This introductory section will describe discoveries which elucidate and control T-cell differentiation and function for the improvement of adoptive cell therapy. Namely by use of inhibition of the PI3k/AKT pathways, and through the discovery of a dual function of death and differentiation by the canonical death receptor Fas, which can be parsed apart with a mutation from valine to cysteine at the 194 position (C194V), differentiation can be withheld while leaving cell proliferation unhindered during T-cell stimulation and expansion. The data also reveals that the differentiation signal caused by extracellular Fas ligation passes through AKT, revealing both Fas and AKT as points of intervention for targeting differentiation along the same pathway. From further investigation, this introduction will describe the effect of AKT inhibition on T-cell differentiation on a transciptional and metabolic level. The data reveals AKT inhibition promoted FOXO1 intranuclear organization, which creates a more naive-like phenotype to the cells, and lower glycolytic status, another phenotype associated with persistent and long-lived cells. Furthermore, this control of AKT and Fas in T-cells yields benefits in several modalities of pre-clinical models of adoptive T-cell immunotherapy of cancer, in both use of a chimeric antigen receptor (CAR) and with use of Tumor Infiltrating Lymphocytes (TIL). Finally, the real-world applicability of the finding including the use of AKT inhibition in current approved Adoptive T-cell immunotherapies will be discussed.
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Ranganathan, Padhma. "RECIPROCAL REGULATION OF PAR-4 AND CASPASE-8 IN THE TRAIL SIGNALING PATHWAY." UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_diss/670.
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Par‐4 is a pro‐apoptotic tumor suppressor that is mutated, suppressed or inactivated in cancer. Par‐4 exploits components of the extrinsic pathway to cause apoptosis selectively of cancer cells. This study identified Par‐4 as an essential component of the apoptotic pathway induced by TRAIL, which selectively targets cancer cells. RNA interference‐mediated knockdown of Par‐4 rendered cancer cells unresponsive to TRAIL‐induced apoptosis. Cells with knocked‐down levels of Par‐4 were deficient in the activation of the apoptosis‐initiator caspase‐8 and the apoptosis‐effector caspase‐3 in response to TRAIL. Par‐4 was identified as a critical mediator of membrane translocation of caspase‐8 and the adapter protein FADD. Surprisingly, Par‐4 was also found to interact with caspase 8 in untreated cells, and was cleaved at the N‐terminus at aspartic acid residue 123 in response to TRAIL. This, along with another cleavage by caspase‐9 effectively generated a fragment containing the functional module of Par‐4, the SAC domain, which is sufficient for apoptosis of cancer cells. Moreover, TRAIL activated caspase‐8 was also found to be involved in nuclear translocation of Par‐4, a crucial step during apoptosis induction by Par‐4. Together, our findings suggest that Par‐ 4 is an essential downstream target of caspase‐8 that is activated by TRAIL signaling and that, in turn, activates caspase‐8 and the downstream apoptotic pathway in response to TRAIL.
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Payne, Laura Beth. "Differential Impact of VEGF and FGF2 Signaling Mechanisms on Flt1 Pre-mRNA Splicing." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/81133.
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The human proteome is exponentially derived from a limited number of genes via alternative splicing, where one gene gives rise to multiple proteins. Alternatively spliced gene products, although crucial for normal physiology, are also linked to an increasing number of pathologies. Consequently, a growing focus is currently being placed on elucidating the extrinsic cues and ensuing signaling mechanisms which direct changes in gene splicing to yield functionally distinct proteins. Of note is the dysregulation of the vascular endothelial growth factor (VEGF) receptor, Flt1 and its soluble splice variants, sFlt1_v1 and sFlt1_v2, in the pregnancy-related disorder, preeclampsia. Preeclampsia is characterized by proteinuria and hypertension and is responsible for almost 600,000 maternal and fetal yearly deaths, worldwide.
Here, we examined the impact of endothelial mitogens VEGF and FGF2 (fibroblast growth factor 2), both of which are upregulated in preeclampsia, on Flt1 transcript variants in umbilical vein endothelial cells. We tested the hypothesis that VEGF modulates the expression of Flt1 variants via the signaling kinase Akt and its impact on SR proteins. VEGF was observed to induce expression of overall Flt1 mRNA, principally as variants Flt1 and sFlt1_v1. Conversely, FGF2 induced a shift in splicing toward sFlt1_v2 without significant increase in overall Flt1. Based on inhibitor studies, the VEGF and FGF2 signals were transduced via ERK, but with the involvement of different upstream components. We mapped predicted SR protein binding to Flt1 pre-mRNA and identified two candidate proteins, SRSF2 and SRSF3, that may be involved in VEGF- or FGF2-induced Flt1 pre-mRNA splicing. Examination of SRSF2 and SRSF3 relative mRNA expression levels, following inhibition of VEGF- and FGF2-activated kinases, indicates that FGF2 significantly downregulates SRSF3 mRNA levels via PKC-independent activation of ERK. Additionally, our data suggest that FGF2 may impact Flt1 and sFlt1_v1 via SR protein kinases Akt and SRPK, while conversely regulating sFlt1_v2 levels via Clk. We did not find evidence of VEGF-induced Flt1 variant splicing via SR protein kinase activation or SRSF2 and SRSF3 mRNA levels. Thus, VEGF and FGF2 signals were tranduced via related but distinct mechanisms to differentially influence Flt1 pre-mRNA splicing. These findings implicate VEGF and FGF2 and their related intracellular signaling mechanisms in soluble Flt1 regulation.Ph. D.
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Benamar, Mehdi. "Modulation de la plasticité et des fonctions suppressives des lymphocytes T régulateurs par les molécules de signalisation Themis1 et Vav1." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30249.
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Les lymphocytes T régulateurs Foxp3+ jouent un rôle crucial dans l'établissement de la tolérance au soi, le contrôle des réponses inflammatoires et le maintien de l'homéostasie du système immunitaire. La compréhension des mécanismes moléculaires impliqués dans la fonction de ces cellules représente un défi important. Chez le rat, la déficience en Themis1, une nouvelle molécule de la signalisation du TCR, associée à un locus de 117kb d'origine BN induit un défaut fonctionnel des Tregs et le développement spontané d'une maladie inflammatoire des intestins. Au sein de ce locus, le rat BN présente deux polymorphismes non-synonymes, un au niveau du gène C3 et un au niveau du gène Vav1 (R63W). Ce dernier est un candidat potentiel du fait du rôle joué par Vav1 dans l'activation des lymphocytes T et de sa régulation par Themis1. Dans ce travail de thèse, j'ai étudié l'effet de la déficience en Themis1 associé au polymorphisme R63W de Vav1 chez la souris de fond génétique C57BL/6 sur les fonctions des lymphocytes T régulateurs. J'ai montré que la déficience en Themis1 associé au polymorphisme R63W induit un défaut fonctionnel des Tregs in vitro et in vivo dans un modèle de colite. Ce défaut est associé à une production accrue de cytokines pro-inflammatoires par ces Tregs. J'ai également mis en évidence que l'association de ces deux mutations induit une sensibilité accrue à la colite induite par le DSS. Au niveau moléculaire, j'ai mis en evidence que ce défaut fonctionnel est associé à une réduction de la signalisation du TCR impliquant les vois Erk et NF-ĸB. De plus, j'ai montré que l'inhibition d'une phosphatase de la signalisation du TCR, SHP-1, permet de restaurer les fonctions suppressives des Tregs Vav1R63W-Themis1-/-. Cette étude souligne l'importance de l'intégrité du hub de la signalisation impliquant Vav1, Themis1 et SHP-1 dans la plasticité des lymphocytes T régulateurs et dans le maintien de leur fonction suppressive. Ainsi ce hub de signalisation représente une cible thérapeutique pour augmenter les fonctions des Tregs dans le cadre des maladies inflammatoires ou réduire leurs fonctions suppressives pour favoriser les réponses immunes anti-tumorales dans le cadre du cancerRegulatory T cells (Treg) are of paramount importance for restraining excessive immune responses and their manipulation holds enormous therapeutic potential. Our recent results using a congenic rat model suggested that the integrity of Vav1/Themis1 T-cell receptor signaling hub plays a crucial role in Treg suppressive function. Indeed, Themis1 deficiency in BN, but not in LEW rats, led to the development of inflammatory bowel disease (IBD), linked to a defect in Treg suppressive function. Genetic studies revealed that this phenotype depended on a 117 Kb genomic locus, containing the R63W polymorphism on Vav1 that impacted its expression and functions. To test the importance of the Vav1/Themis1 TCR signaling hub in Treg function, we generated Themis1-T-/- mice expressing conditionally Themis1 in thymocytes, but not in peripheral T cells. In contrast to regular germline Themis1 knockout mice, these mice were not lymphopenic and exhibited normal proportions of CD4+ T cells in the thymus and in peripheral lymphoid organs. Next, Themis1-T-/- mice were crossed with Vav1R63W mice to assess the impact of these combined mutations on Treg suppressive functions. Using in vitro approaches, together with in vivo analyses of IBD, we showed that suppressive activity of Treg was impaired in Themis1-deficient mice harboring the mutated Vav1; this defect is linked to higher production of IL-17 and IFNg. Functional studies showed that Themis1-deficient associated with the mutated Vav1 induced a defect in Erk and P65 phosphorylation after TCR engagement. Interestingly, the inhibition of the SHP-1 phosphatase restore the functional defect of Tregs. Together, these data showed that Themis1, Vav1 and SHP-1 cooperate in the signaling hub to regulate the suppressive function of regulatory T cells. Thus, this signaling hub represents a therapeutic target to enhance the suppressive functions of Tregs in the context of autoimmune and inflammatory diseases or to decrease their functions to favor anti-tumoral immune responses
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Salari, Samira. "Mechanisms of Recombinant Heat Shock Protein 27 Atheroprotection: NF-κB Signaling in Macrophages." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20725.
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The O’Brien lab has demonstrated that Heat shock protein 27 (HSP27)shows attenuated expression in human coronary arteries as the degree of atherosclerosis progresses. Moreover, over-expression of HSP27 reduces
atherogenesis in mice. The precise mechanism(s) for HSP27-mediated "atheroprotection" are incompletely understood. Nuclear Factor-kappaB (NF-κB)
is a key signaling modulator in atherogenesis. Hence, this project sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling to affect atheroprotection. Treatment of THP1 macrophages with rHSP27 resulted in degradation of IκBα, coincided with nuclear translocation of the p65 subunit and produced transcriptional evidence of activation of NF-κB signaling. When the transcriptional profile of THP1 macrophages treated with rHSP27 was analyzed using NF-κB-pathway-specific qRT-PCR arrays, among the regulated genes, IL-10 and GM-CSF mRNA levels were markedly increased, as were parallel translational effects observed. These data provide new mechanistic insights into the atheroprotective effects of HSP27.
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Ruez, Richard. "Mécanotransduction par les cavéoles : rôle dans l'activation de stat3 par l'interferon alpha." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112232.
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Hypothèse : Notre équipe étudie le rôle, mal connu, du trafic membranaire dans le contrôle de l’activation de la voie de signalisation JAK/STAT par les interférons (IFN), une voie clé du contrôle des processus cancéreux. La liaison de l’IFN-a à son récepteur IFNAR active les kinases JAK1 et TYK2 puis des transducteurs de signal comme STAT1, antiprolifératif, ou STAT3, qui a un pouvoir oncogénique. Le laboratoire a démontré récemment que le trafic membranaire d’IFNAR détermine la spécificité du signal des différents IFNs.L’objet de cette thèse est l’étude du rôle des cavéoles dans ce contrôle. Les cavéoles sont des invaginations membranaires enrichies en cholestérol et glycosphingolipides, formées par l’oligomérisation de la cavéoline1 (Cav1). Les cavéoles ou le gène CAV1 ont souvent été associés à la progression tumorale, notamment des cellules mammaires, mais ce rôle reste énigmatique et controversé. Le fait que IFNAR ait été détecté par biochimie dans des fractions de membrane enrichies en cholestérol et positives pour la cavéoline-1 chez la souris et le fait que l’expression du gène CAV1 ait été corrélée à l’action antitumorale de l’IFNa nous ont conduit à étudier le rôle des cavéoles dans l’action antitumorale des IFNs.Résultats: Le rôle putatif des cavéoles sur le contrôle de la voie JAK/STAT a été étudié dans des cellules murines MLEC n’exprimant pas Cav1 et dans des lignées humaines par interférence ARN contre Cav1. Nous avons pu démontrer que la présence de Cav1 régule de manière opposée deux étapes de la voie de signalisation de STAT3 activée par l’IFN-a. Par contre, ni l’activation de STAT1 par l’IFN-a ni celle de STAT3 par les autres IFNs ne nécessitent Cav1. Parallèlement, le laboratoire a montré que les cavéoles jouent un rôle capital dans la réponse cellulaire aux stress mécaniques en se dépliant lors d’un étirement membranaire, ce qui amortit la tension membranaire. Nous montrons qu’un tel stress mécanique par étirement module spécifiquement la signalisation de STAT3 par l’IFN-a d’une manière dépendante de Cav1 dans les cellules MLEC, suggérant pour la première fois un rôle de STAT3 et de l’IFN-a dans la mécanotransduction dépendante des cavéoles. Ce résultat permet aussi de relier les contraintes mécaniques présentes dans la masse tumorale et leur effet sur la progression tumorale. Perspectives : Les IFNs et la voie JAK/STAT sont bien caractérisés pour leur action antiproliférative, mais si l’IFN-a est utilisé en thérapeutique oncologique, les mécanismes de l’effet antitumoral sont mal connus. Nos résultats impliquent pour la première fois les cavéoles dans l’activation sélective du proto-oncogène STAT3 par l’IFN-a et proposent STAT3 comme un des nouveaux acteurs de la mécanotransduction par les cavéoles. Elucider les mécanismes moléculaires mis en jeu dans ces deux fonctions inédites des cavéoles devrait permettre d’identifier de nouvelles cibles thérapeutiques dans la progression tumoraleHypothesis: Our team studies the poorly investigated role of membrane trafficking in the control of the activation of the JAK / STAT signaling pathway by interferons (IFN), a key mechanism in the control of tumorigenesis. The binding of the IFN-a to its receptor IFNAR activates the kinases JAK1 and TYK2 and then, signal transducers and activators of transcription including the antiproliferative STAT1 or the oncogenic STAT3. The laboratory demonstrated recently that the trafficking of IFNAR at the plasma membrane determines the signal specificity of the various IFNs.The goal of this thesis was to study the role of caveolae in this control. Caveolae are specialized membrane invaginations enriched in cholesterol and glycosphingolipids, formed by the oligomerization of their main structural protein, caveolin-1 (Cav1). Caveolae or the CAV1 gene have often been associated with tumorigenesis, in particular in mammary cancer cells, but this role remains enigmatic and controversial. The fact that IFNAR was previously found in Cav1-positive lipid microdomains and the fact that the expression of the CAV1 gene had been functionally linked to the antitumoral function of IFN-a led us to investigate the role of caveolae in the antitumoral function of the IFNs.Results: The putative role of caveolae in the control of the JAK / STAT signaling pathway have been studied in murine lung endothelial MLEC cells that do not express Cav1 and in a human lineage by RNA interference against Cav1. We were able to demonstrate that the presence of Cav1 regulates in an opposite manner two stages of the signaling pathway of STAT3 activated by the IFN-a whereas the activation of STAT1 by IFN-a, or STAT3 by the other type I and II IFNs do not require Cav1.At the same time, the laboratory showed that caveolae play a major role in the cellular answer to mechanical stress by flattening during a membrane stretching, thus buffering the membrane tension. We show that mechanical stress by uniaxial cell stretching modulates specifically the signaling pathway of STAT3 activated by the IFN-a in a Cav1-dependant manner in MLEC cells. This result suggests for the first time a role of STAT3 and of IFN-a in caveolae-driven mechanotransduction. This result also allows us to link the mechanical constraints found in the tumoral mass to their effect on tumorigenesis.Prospects:The IFNs and the JAK / STAT signaling pathway protect the cells from tumorigenesis, but although IFN-a is used in oncology, the mechanisms of its antitumoral effect are poorly known. Our results involve for the first time caveolae in the selective activation of the proto-oncogenic STAT3 by the IFN-a and allow us to propose STAT3 and the IFN-a as new actors of the mechanotransduction by caveolae. Clarifying the molecular mechanisms involved in these two new functions of caveolae should allow us to identify new therapeutic targets in tumorigenesis
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Yoo, Ji Seung. "INVESTIGATIONS INTO THE ROLES OF PKR-INDUCED ANTIVIRAL STRESS GRANULE AND DHX36 IN RIG-I SIGNALING." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/189378.
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Krjukova, Jelena. "Investigation on Pre- and Postsynaptic Ca2+ Signaling in Neuronal Model Systems." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4300.
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Su, Ting-Cheng. "Regulation of pheromone response in saccharomyces by Ste12-PRE interaction and TOR-Cdc55 signaling." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43645.
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Ste12 is the key regulator in the yeast pheromone response pathway and works as an
important model for understanding gene regulation by MAP kinase cascades. In this
thesis I address how the binding strength of pheromone-response element (PRE)
sequences, their orientation, and intervening nucleotide distance between two PREs
govern the overall response to pheromone. I found that Ste12 binds as a monomer to a
single PRE in vitro, and that two PREs upstream of a minimal core promoter cause a
level of induction proportional to their relative affinity for Ste12 in vitro. Although
consensus PREs are arranged in a variety of configurations in the promoters of
pheromone responsive genes, I found there are severe constraints with respect to how
they can be positioned in an artificial promoter to cause induction of gene expression.
Two closely-spaced PREs can induce transcription in a directly-repeated or tail-to-tail
orientation, while PREs separated by at least 40 nucleotides are capable of inducing
transcription when oriented in a head-to-head or tail-to-tail configuration. By comparing
the constraints defined by analysis of artifical promoters, I found that a single PRE can
cause response to pheromone induction in combination with a properly oriented PRE-like
sequence.
By studying Ste12 multimerization, I found that this process might involve
dephosphorylation on Ste12 to regulate the expression of pheromone-regulated genes. I
discovered that Cdc55, a regulatory subunit of protein phosphatase IIA, can affect
pheromone response. In the cdc55 null mutant I observed decreased expression level of a
reporter gene and decreased mating efficiency. Cdc55 directly or indirectly alters the phosphorylation status of Ste12, as I observed hyperphosphorylated Ste12 in the cdc55
mutant compared to wild type. The effect of Cdc55 is independent of the pheromone
response MAP kinase pathway, but was found to be controlled downstream of TOR.
Analysis of artificial reporter genes and a candidate set of pheromone responsive
promoters demonstrated that TOR-Cdc55 signaling regulates a distinct subset of
pheromone-responsive genes. These results demonstrate a new regulatory circuit for the
pheromone response controlled by the TOR signal pathway, which operates to control
mating of yeast haploids in response to nutrients.
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Devignes, Claire-Sophie. "Hypoxia signaling in osteoblast lineage cells promotes Systemic breast cancer growth and metastasis." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC325.
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La formation de métastases osseuses implique de nombreuses interactions entre les cellules de cancer du sein et le microenvironnement osseux. Les gradients d’hypoxie et l’activation de HIF (hypoxia inducible factor) 1alpha sont essentiels au maintien de l’homéostasie osseuse. Le rôle de la signalisation HIF dans les ostéoblastes lors du processus métastatique n’a pourtant jamais été exploré. Dans cette étude, nous montrons que les cellules ostéoprogénitrices (OPC), se situent dans des niches hypoxique, et que l’activation de la signalisation HIF dans ces cellules augmente la masse osseuse et favorise les métastases osseuses du cancer sein. L’effet de la signalisation HIF dans les OPC n’est pas limité au squelette, en effet celle-ci stimule aussi la croissance des tumeurs mammaires et la dissémination tumorale dans les poumons et d’autres organes distants. Nous avons mis en évidence que la signalisation HIF dans les OPC induit l’augmentation de la concentration plasmatique de la chimiokine C-X-C motif ligand 12 (CXCL12), qui entraine une augmentation systémique de la prolifération et de la dissémination tumorale, via l’activation de son récepteur CXCR4 sur les cellules cancéreuses. Ainsi, nos résultats mettent en évidence le rôle protumorigénique de l’hypoxie dans le lignage ostéoblastique, lors de la formation de métastases osseuse, mais également par une action systémique sur les tumeurs mammaires et les métastases dans les tissus mous. Nous démontrons également que des altérations de l’anabolisme osseux peuvent affecter la progression du cancer du sein, révélant un nouveau rôle du squelette au sein du macroenvironnement tumoralBone metastasis involves dynamic interplay between tumor cells and thelocal stromal environment. In bones, local hypoxia and activation of the hypoxiainducible factor (HIF)-1alpha in osteoblasts are essential to maintain skeletalhomeostasis. However, the role of osteoblast-specific HIF signaling in cancermetastasis is unknown. Here we show that osteoprogenitor cells (OPC) are locatedin hypoxic niches in the bone marrow, and that activation of HIF signaling in thesecells increases bone mass and favors breast cancer metastasis to bone locally.Remarkably, HIF signaling in osteoblast lineage cells also promotes breast cancergrowth and dissemination remotely, in the lungs and in other tissues distant frombones. Mechanistically, we found that activation of HIF signaling in OPC increasesblood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to asystemic increase of breast cancer cell proliferation and dissemination, throughdirect activation of the CXCR4 receptor. Hence, our data reveal a previouslyunrecognized role of the hypoxic osteogenic niche in promoting tumorigenesisbeyond the local bone microenvironment. They also indicate that alterations inbone formation can affect breast cancer progression, and support the concept thatthe skeleton is an important regulator of the systemic tumor environment
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Minh, Vu Nhat. "Optimal Signaling Schemes and Capacities of Non-Coherent Correlated MISO Channels under Per-Antenna Power Constraints." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1533115867950851.
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Brown, Joanne Louise. "The role of the dsRNA dependent protein kinase (PKR) in cell signalling." Thesis, St George's, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391775.
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Sassonia, Rogerio Corte. "Caracterização termodinamica de reações de nitrosação e interações proteicas por titulação calorimetrica isotermica." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/248521.
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Orientador: Marcelo Ganzarolli de OliveiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
Made available in DSpace on 2018-08-15T02:21:46Z (GMT). No. of bitstreams: 1 Sassonia_RogerioCorte_D.pdf: 2947110 bytes, checksum: fc316c83bed9508d2e27063d89528d56 (MD5) Previous issue date: 2009
Resumo: Este trabalho apresenta os resultados da aplicação da titulação calorimétrica isotérmica na caracterização termodinâmica de reações de S-nitrosação de tióis e de interações proteínaproteína e proteína-íon. Foram estudadas as reações de S-nitrosação da N-acetil-L-cisteína (NAC), L-cisteína (CYS), L-glutationa (GLU) e do ácido mercaptosuccínico. Também foram avaliadas as interações entre a proteína sinalizadora Shc (Src homology collagen-like) e as proteínas glutationa S-transferase (GST) e a ciclofilina A (CypA) e a interação entre a região Cterminal da proteína humana EFHC1 (EFHC1-C) com íons Ca e Mg. Os valores da variação de entalpia revelaram que a S-nitrosação é um fenômeno exotérmico e ocorre com diminuição de entropia. Estes dados termodinâmicos revelam que as reações de S-nitrosação investigadas são entalpicamente dirigidas a 25 °C (1 atm) e possuem valores semelhantes de variações de entalpia, entropia e energia livre, apesar das diferenças entre as estruturas químicas dos tióis. Verificou-se que a proteína EFHC1C liga-se tanto a íons Ca quanto Mg numa estequiometria de 1:1, com afinidades definidas por diferentes contribuições entálpicas e entrópicas. Este dado confirmou a existência de um suposto domínio EF-hand ligante de Ca na porção C-terminal previsto pela seqüência primária da EFHC1C. Por outro lado, a EFHC1C perde sua capacidade de interação com íons Ca e Mg em solução sem 1,4-ditiotreitol (DTT), provavelmente, devido à formação de dímeros. A ausência de sinais térmicos de ITC mostrou que nem a proteína GST, nem a proteína CypA interagem com a proteína Shc nas condições experimentais usadas.
Abstract: This work presents the results of isothermal titration calorimetry application in the thermodynamic characterization of thiol nitrosation reactions, protein-protein and protein-ion interactions. The S-nitrosation reactions of N-acetyl-L-cysteine (NAC), L-cysteine (CYS), Lglutathione (GLU) and acid mercaptosuccinic were studied. The interactions of the signaling protein Shc (Src homology collagen-like) with glutathione S-transferase (GST) and ciclofilina A (CypA) and of the EF-hand motif from human EFHC1C with Caand Mg ions were also evaluated. Enthalpy change values revealed that the S-nitrosation reaction is an exothermic phenomenum associated to a decrease in entropy. These thermodynamic data show that the S-nitrosation reactions investigated are enthalpically driven at 25 °C (1 atm) and have similar enthalpic, entropic and free energy change values, despite the differences among the chemical structures of the thiols. It was verified that the EFHC1C protein binds to both Ca and Mg ions in a 1:1 stoichiometry with affinities defined by different enthalpic and entropic contributions. These data confirmed the presence of a putative EF-hand Ca-binding motif at the C-terminal portion as expected by the primary sequence of EFHC1C. On the other hand, EFHC1C losses its ability to interact with Ca and Mgions in solution without 1,4-ditiotreitol (DTT) likely due to protein dimerization. The absence of ITC thermal signals showed that neither GST nor CypA interact with the Shc protein in the experimental conditions used.
Doutorado
Físico-Química
Doutor em Ciências
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Cheng, Jin [Verfasser]. "Precise somatotopic thalamocortical axon guidance depends on LPA-mediated PRG-2/Radixin signaling / Jin Cheng." Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1124104542/34.
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Mariotti, J. "MODULAZIONE DEL SIGNALING DI STAT PER PREVENIRE IL RIGETTO DEL TRAPIANTO DI MIDOLLO OSSEO ALLOGENICO." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217168.
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Janus Kinase (JAK)/ Signal Transducer of Activated Transcription (STAT) signaling represents the main molecular pathway dictating T cell differentiation both in humans and in mice. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative strategy for patients with hematologic malignancies and its outcome depends on the interplay between host and donor immune system resulting in graft rejection (GR) or graft versus host disease (GVHD), respectively. We therefore proposed to investigate the role of JAK/STAT signaling in these two phenomena that are biologically considered as mirror images. First, we found that host-mediated graft rejection requires JAK3 expression and that a broad inhibitor of STAT3 signaling prevents GR in a mouse model of rejection. Second, we moved to assess the role of STAT3 signaling in acute GVHD that represents the major cause of mortality in allogeneic HSCT, for which administration of FoxP3+ Treg cells has been proposed as a therapy. However, the phenotypic stability of Treg cells is controversial and cytokines that signal through STAT3 can inhibit FoxP3 expression. In a mouse model of acute GVHD, we assessed whether the elimination of STAT3 in T cells could limit the severity of GVHD, and if so, what mechanisms were involved. We found STAT3 limited the numbers of FoxP3+ Tregs following allogeneic bone marrow transplant by two pathways: instability of natural Tregs and inhibition of inducible Treg polarization from naïve CD4+ T cells. Third, we found that the infusion in vivo of a potent inhibitor of STAT3 could prevent the onset of acute GVHD, both by reducing Th1 alloreactivity and maintaining the Treg subset in vivo. These data strongly support the potential use of JAK/STAT inhibitors in vivo in order to prevent GR and GVHD in patients receiving allogeneic HSCT.
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Branco, Diana Santos 1983. "Sinalização por carboidratos em cana-de-açucar e divergencia evolutiva." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317165.
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Orientadores: Michel Georges Albert Vincentz, Juliana de Maria FelixDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo:Além de fonte primária de carbono e energia para os principais tipos celulares, os açúcares produzidos pela fotossíntese adquiriram importantes funções ao longo da evolução das plantas, no controle do crescimento e desenvolvimento, do metabolismo e na resistência a estresses abióticos (osmótico, energético) e bióticos (potógenos). Os açúcares atuam como sinalizadores ativando cascatas de transdução e, desta forma, promovendo mudanças na programação da expressão gênica. Com o objetivo de entendermos como a sinalização por açúcares diversificou-se em angiospermas, iniciamos uma análise comparativa dos perfis de expressão gênica em resposta aos açúcares sacarose e glicose em plântulas da monocotiledônea Saccharum spp e da eudicotiledônea Arabidopsis thaliana. Para tanto, duas abordagens foram utilizadas. O primeiro aspecto do trabalho estabeleceu relações entre elementos de resposta rápida (resposta primária) a açúcar e acúmulo de sacarose em genótipos de cana contrastantes para teor de sacarose. Outra abordagem, mais abrangente, procurou identificar genes diferencialmente expressos em resposta à sacarose. Na primeira parte do trabalho, a análises por qRT-PCR revelaram uma clara relação entre genes envolvidos em acúmulo de sacarose em cana-de-açúcar e sinalização primária por carboidratos. A partir de 34 SAS (Sugarcane Assembled Sequence) testados envolvidos em acúmulo de sacarose em cana, 24 deles também foram responsivos à glicose e/ou sacarose, sendo que 9 deles responderam em um mesmo sentido em genótipos de cana-de-açúcar que acumulam maior quantidade de sacarose (alto Brix). Dos 24 SAS responsivos à sacarose e/ou glicose, apenas 6 deles apresentaram genes ortólogos em Arabidopsis thaliana cuja regulação por estes açúcares ocorreu de maneira similar. Dentre eles, temos o fator de transcrição IAA16, que se mostrou reprimido por sacarose e glicose, constituindo um possível gene de interação entre sinalização por açúcares e auxina. Duas SNFs quinases parálogas de cana-de-açúcar tem como ortólogo um único gene de Arabidopsis thaliana. Os três genes foram reprimidos por sacarose e glicose, sendo outra parte conservada, na via de sinalização a açúcares entre as duas espécies. Outro gene de particular interesse corresponde a uma deidrina, reprimida por sacarose e glicose em cana, assim como seu ortólogo em Arabidopsis e genótipos alto Brix, sugerindo importante papel deste gene em processos relacionados a sinalização/acúmulo de sacarose. Na segunda parte do trabalho, utilizando-se a técnica de microarranjos de cDNA a partir do chip SUCAST, encontramos 55 genes diferencialmente expressos em resposta à sacarose. Destes, apenas 3 apresentaram genes ortólogos de Arabidopsis regulados por açúcar num mesmo sentido que em cana, correspondentes a duas proteínas quinases e a um gene pseudo-response-regulator. Este estudo preliminar identificou genes conservados da sinalização por açúcares em angiospermas que representam possíveis nós importantes das redes de controle relacionadas a carboidratos. O estabelecimento de um possível envolvimento de alguns destes genes no controle da capacidade de acumular mais sacarose no colmo da cana, abriu novas perspectivas na análise molecular desta importante característica. Estudos mais abrangentes são necessários para melhorar os conhecimentos sobre o grau de diversificação da sinalização por açúcares em angiospermas e os valores adaptativos associados.
Abstract: Besides act as carbon primary source in the major types of cells, sugars produced by photosynthesis acquired important functions in the course of plant's evolution like controlling growth, development, and metabolism and acting in resistance to abiotic and biotic stresses like osmotic, energetic and response to pathogens. Sugars can be signals that active signal transduction pathways to change genes expression programs. In order to access the diversification of sugar pathway signaling in angiosperms we conduct comparative analysis of the gene expression in response to sucrose and glucose in seedlings of the monocot Saccharum sp. and the eudicot Arabidopsis thaliana. We also aimed to access the possible correlation between genes related to sucrose storage in sugar-cane and genes related to primary sugar responses. Another aim was to identify deferentially expressed genes in sucrose response. A clearly relation between genes related to sucrose storage in sugar-cane and quickly primary response to sugars was obtained by qRT-PCR analysis. We tested 34 SAS (Sugar Assembled Sequence) related to sucrose storage in sugar-cane and we found that 24 of them were responsive to glucose and/or sucrose. Nine genes showed the same expression pattern (induction or repression) in response to sugar as seen in high Brix genotypes. Six, of this 24 genes, have Arabidopsis orthologues regulated in the same direction (induced or repressed). One is an IAA16 transcription factor that is repressed by both, glucose and sucrose, and may play a role in an integrative pathway of sugar and auxin responses. We also find two SNFs kinases (paralogues) related to a single Arabidopsis ortholog showing the repression response. Another interesting gene is a dehydrin that was repressed in response to sucrose and glucose in sugar-cane and Arabidopsis (its ortholog) and in the high Brix sugar-cane genotypes. It suggests an important role for this dehydrin in processes related to sucrose signaling and storage. In the second part of this work, the sugar-cane cDNA microarray chip, called SUCAST, allow us to identify 55 deferentially expressed in response to sucrose. Only three of these genes have orthologues regulated in same way in sugar-cane and Arabidopsis. These genes correspond to two protein-kinase and a pseudo-response regulator. This preliminary approach leads us to identify conserved genes in sugar signaling among angiosperms that possibly represents important nodes in the regulatory networks in response to sugars. Establishing the involvement of some of these genes in the ability of sucrose storage in sugar-cane's culm will lead us to new perspectives in the molecular basis of this characteristic. More specific works are also needed to improve the knowledge about the real degree of evolutive diversification in sugar signaling among angiosperms and associated genetic fitness.
Mestrado
Genetica Vegetal e Melhoramento
Mestre em Genética e Biologia Molecular
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St-Pierre, David. "Mécanismes de signalisation d’AT1R médiés par des analogues cycliques de l’angiotensine II." Mémoire, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11091.
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L'angiotensine II (Ang II) joue un rôle important dans la régulation du système cardiovasculaire par l’activation de plusieurs voies de signalisation. L’activation de ces voies passe par le récepteur de l'angiotensine II de type 1 (AT1R). Ce récepteur fait partie de la famille des récepteurs couplés aux protéines G (GPCRs). De plus, il est maintenant connu que certains ligands peuvent lier le récepteur et induire une conformation qui permet d'activer certaines voies de signalisation tout en n’étant pas favorable à l'activation d'autres voies. Il est alors question de sélectivité fonctionnelle, aussi appelée signalisation biaisée. Ainsi, avec cette approche, il est possible de cibler les voies qui produiront les effets thérapeutiques désirés sans toutefois activer les voies qui seraient responsables des effets indésirables. Nous avons émis l’hypothèse que de cycliser des ligands va restreindre les conformations possibles lors du couplage avec AT1R et induire un agonisme biaisé. Ainsi, des analogues cycliques de l’AngII substitués aux positions 3 et 5 par des cystéines et des homocystéines ont été synthétisés: [Sar1Hcy3,5]AngII, [Sar1Cys3Hcy5]AngII et [Sar1Cys3,5]AngII. D’abord, la capacité de ces analogues cycliques à activer la voie Gq a été évaluée par la mesure de la production des inositol phosphates. Puis, la capacité à activer les voies G12, le recrutement des β-arrestines (1 et 2) ainsi que l’activation de ERK1/2 a également été évaluée. Nos travaux ont montré que l’analogue cyclique [Sar1Hcy3,5]AngII a une puissance et une efficacité maximales sur toutes les voies testées à l'exception de la voie Gq. Des simulations de dynamique moléculaire ont été effectuées pour nous permettre de comprendre comment la conformation du ligand influence la structure d’AT1R et donc l’activation des différentes voies de signalisation. Les simulations en dynamique moléculaire ont montré que la barrière énergétique associée à l'insertion du résidu Phe8 de l’AngII dans le coeur hydrophobe d'AT1R est augmentée avec [Sar1Hcy3,5]AngII, pouvant expliquer que cet analogue active moins bien la voie Gq. D’autres analogues cyclisés aux positions 3 et 5 de l’AngII ont été synthétisés; [Sar1Hcy3Ile4Hcy5]AngII, [Sar1Hcy3,5Ile8]AngII et [Sar1Hcy3Cys5]AngII. Leur capacité à activer les voies Gq, ERK1/2 et le recrutement des β-arrestines (1 et 2) a été évaluée. L’analogue [Sar1Hcy3Cys5]AngII semblait bien activer la voie ERK1/2, mais pas les voies G12 et β-arrestines. Ces résultats suggèrent que le fait de contraindre les mouvements des déterminants moléculaires d’un ligand en introduisant des structures cycliques peut entraîner un biais dans la signalisation en stabilisant différentes structures du récepteur.Abstract: Angiotensin II (Ang II) has an important role in the regulation of the cardiovascular system by its ability to activate several signaling pathways. The activation of these pathways occurs via the angiotensin II receptor type 1 (AT1R). This receptor belongs to the family of G protein-coupled receptors (GPCRs). Moreover, it is now known that certain ligands can bind to the receptor and induce a conformation that allow the activation of certain signaling pathways while not promoting the activation of other pathways. This concept is known as functional selectivity or biased signaling. With this approach, it is possible to target the signaling pathways that produce the desired therapeutic effects rather than activating the pathways responsible for adverse effects. We hypothesized that cyclizing ligands would restrict possible conformations when coupled with AT1R and induce biased agonism. Thus, cyclic AngII analogs substituted at positions 3 and 5 by cysteines and homocysteines were synthesized: [Sar1Hcy3,5]AngII, [Sar1Cys3Hcy5]AngII and [Sar1Cys3,5]AngII. First, the ability of these cyclic analogs to activate the Gq pathway was measured by the inositol phosphates production. Then, the G12 pathway activation, β-arrestin (1 and 2) recruitment and the ability of these analogs to activate the ERK1/2 pathway was evaluated. Our work has shown that [Sar1Hcy3,5]AngII has maximum potency and efficacy on all of the evaluated pathways, except for the Gq pathway. Molecular dynamic simulations were used to understand how a distinct ligand conformation influences the AT1R structure and the activation of signaling pathways. These studies have shown that the energy barrier associated with the insertion of the Phe8residue of AngII within the hydrophobic core of AT1R is increased with [Sar1Hcy3,5]AngII, possibly explaining why this analog is less potent in activating the Gq pathway. Other analogues cyclized at positions 3 and 5 of AngII were synthesized; [Sar1Hcy3Ile4Hcy5]AngII, [Sar1Hcy3,5Ile8]AngII and [Sar1Hcy3Cys5]AngII. Their ability to activate Gq, ERK1/2 and recruitment of β-arrestins (1 and 2) was evaluated. The analog [Sar1Hcy3Cys5]AngII appeared to activate the ERK1/2 pathway but not the G12 and β-arrestin pathways. These results suggest that constraining the movements of molecular determinants of a ligand by introducing cyclic structures can lead to a signaling bias by stabilizing different structures of the receptor.
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Kupittayanant, Sajeera. "The role of calcium and signalling pathways in the control and modulation of uterine contraction : with emphasis on human myometrium." Thesis, University of Liverpool, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269569.
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Farabaugh, Kenneth Thomas kt. "Insights into a Novel Signaling Pathway that Determines Cell Fate in Response to Hyperosmotic Stress." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1571692276973131.
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Schwob, Aurélien. "Rôle des récepteurs de l'autophagie sélective dans la modulation de la signalisation NF- κB par l'oncoprotéine Tax du virus HTLV-1." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSEN027/document.
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L’activation constitutive de la voie NF-κB est une étape cruciale dans le processus de transformation des lymphocytes T par le virus humain T-lymphotrope de type 1 (HTLV-1). La protéine virale Tax y joue un rôle majeur en recrutant la protéine régulatrice IKKγ. De précédents travaux effectués par notre équipe ont montré que l’activation de la voie NF-κB parTax est promue par le recrutement des facteurs celluaires Optineurine (OPTN) et Tax1-binding protein 1 (TAX1BP1), deux protéines récemment décrites comme des membres de la famille de récepteurs autophagiques Sequestosome-Like Receptors (SLR), posant la question des liens fonctionnels entre la signalisation NF-κB et la machinerie autophagique.Notre étude décrit l’interaction de Tax avec le récepteur p62, autre membre de la famille des SLR. L’interaction est directe et indépendante de l’ubiquitination de Tax. Les facteurs Tax, p62 et IKKγ forment des complexes localisés au niveau de membranes autophagiques. Le facteur p62 promeut spécifiquement l’activation de la voie NF-κB médiée par Tax. Étonnamment, la sur-expression de p62 limite la capacité de Tax à activer la voie NF-κB, en induisant la déplétion cytosolique de Tax. Ces résultats indiquent que p62 peut exercer des effets antagonistes sur Tax selon son taux d’expression. Des données préliminaires suggèrent que Tax lie également d’autres membres de la famille des SLR, avec des conséquences variables sur l’activation de la voie NF-κB.Ce travail apporte des connaissances nouvelles concernant les relations entre Tax, la signalisation NF-κB et la machinerie autophagique, suggérant l’utilisation des membranes autophagiques comme plateformes de signalisation viraleNF-κB constitutive activation is a key step in the HTLV-1-mediated T lymphocytes transformation process. This activation is mainly driven by the viral protein Tax, which recruits the IKKγ regulator factor. Previous work performed in our lab showed that Tax-induced NF-κB activation is promoted by the interaction with several cellular factors such as Optineurin (OPTN) and Tax1-binding protein 1 (TAX1BP1), two members of the Sequestosome-Like Receptors (SLR) family, rising the hypothesis of functional interplay vetween NFκB signaling and the autophagic pathway.Our study demonstrates that Tax interacts with the p62 receptor, which is another SLR member, in a direct, ubiquitin independent manner. Tax and p62 form complexes located at autophagic membranes, together with IKKγ. P62 potentiates the Tax-mediated NF-κB activation. Unexpectedly, p62 over-expression inhibits Tax-mediated NF-κB activation by inducing Tax cytoplasmic depletion. These results show that p62 plays a dual role on Tax in a dose-dependent manner. Preliminary data suggest that Tax is also able to interact with other SLR, with various consequences on activation of the NF-κB pathway.This work contributes to the further caracterization of the complex interplay between Tax, NF-κB signaling and the autophagic pathway, suggesting the use of autophagic membranes as viral signaling platforms
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Ortet, Cortada Laura. "Signalling of ciclyn o complexes through EIF2alpha phosphorylation." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/7259.
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We have identified a novel Cyclin, called Cyclin O, which is able to bind and activate Cdk2 in response to intrinsic apoptotic stimuli. We have focused on the study of Cyclin Oα and Cyclin Oβ, alternatively spliced products of the gene. Upon treatment with different stress stimuli, transfected Cyclin Oα accumulates in dense aggregations in the cytoplasm compatible with being Stress Granules (SGs). Furthermore, we have seen that Cyclin Oβ and a point mutant of the N-terminal part of the protein constitutively localize to the SGs. Although both alpha and beta isoforms are proapoptotic, only Cyclin Oα can bind and activate Cdk2. On the other hand, we have demonstrated that Cyclin O is upregulated by Endoplasmic Reticulum (ER) stress and is necessary for ER stress-induced apoptosis. Cyclin O activates specifically the PERK pathway and interacts with the PERK inhibitor protein p58IPK. Moreover, Cyclin O participates in the activation of other eIF2α kinases. We have also observed that a pool of Cyclin O is located in active mitochondria, suggesting a function of the protein linked to oxidative metabolism.Hemos identificado una nueva Ciclina, llamada Ciclina O, que es capaz de unirse y activar Cdk2 en respuesta a estímulos apoptóticos intrínsecos. Nos hemos centrado en el estudio de la Ciclina Oα y la Ciclina Oβ, productos de splicing alternativo del gen. En respuesta a diferentes tipos de estrés, la Ciclina Oα se acumula en agregaciones citoplásmicas densas que podrían corresponder a Gránulos de Estrés (SGs). Además, hemos visto que la Ciclina Oβ y un mutante puntual de la parte N-terminal de la proteína se localizan constitutivamente en los SGs. Aunque las dos isoformas alfa y beta son proapoptóticas, solo la Ciclina Oα es capaz de unirse y activar Cdk2. Por otro lado, hemos demostrado que los niveles de Ciclina O se incrementan en respuesta al estrés de Retículo Endoplásmico (RE) y que esta proteína es necesaria para la inducción de apoptosis dependiente de estrés de RE. La Ciclina O activa específicamente la vía de PERK e interacciona con la proteína inhibidora de PERK p58IPK. Además, la Ciclina O participa en la activación de otras quinasas de eIF2α. La Ciclina O se localiza en mitocondrias activas, lo que sugiere una función de la proteína ligada al metabolismo oxidativo.
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Thakuri, Bal Krishna Chand. "SIP-428, a SIR2 Deacetylase Enzyme and Its Role in Biotic Stress Signaling Pathway." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3505.
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SABP2 (Salicylic Acid Binding Protein 2) plays a vital role in the salicylic acid signaling pathway of plants both regarding basal resistance and systemic acquired resistance against pathogen infection. SIP-428 (SABP2 Interacting Protein-428) is a Silent information regulator 2 (SIR2) like deacetylase enzyme that physically interacts with SABP2 in a yeast two-hybrid interaction and confirmed independently by a GST pull-down assay. We demonstrated that SIP- 428 is an NAD+ dependent SIR2 deacetylase enzyme. Transgenic tobacco plants silenced in SIP- 428 expression via RNAi showed enhanced basal resistance to microbial pathogens. Moreover, these SIP-428-silenced lines also exhibited a robust induction of systemic acquired resistance. In contrast, the transgenic tobacco lines overexpressing SIP-428 showed compromised basal resistance and failed to induce systemic acquired resistance. These results indicate that SIP-428 is likely a negative regulator of SA-mediated plant immunity. Experiments using a SABP2 inhibitor showed that SIP-428 likely functions upstream of SABP2 in the salicylic acid signaling pathway. It also indicates that SABP2 is dependent on SIP-428 for its role in the SA signaling pathway. Subcellular localization studies using confocal microscopy and subcellular fractionation showed that SIP-428 localized in the mitochondria. These results clearly show a role for SIP-428 in plant immunity.
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Porchet, Nicolas. "Role of signaling pathays in cell-fate specification in the early mouse embryo." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7096.
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Lors du développement précoce de l’embryon de souris, divers évènements de spécification des destins cellulaires induisent la formation du blastocyste pré-implantatoire. Ces évènements sont majoritairement contrôlés par l’action de voies de signalisation activées via la fixation de molécules signal à la membrane de la cellule. L’activité de ces voies de signalisation permet la régulation de la transcription de gènes cible responsable de l’acquisition d’une identité cellulaire et de son arrangement sous forme de tissu. Ici je m’intéresse aux rôles des voies ACTIVINE/NODAL et βCATENIN dans la spécification de ces identités cellulaires lors de la formation du blastocyste de sourisDuring the early mouse embryogenesis, cell-fate specification events result in the formation of the pre-implantation blastocyst. Those events are mainly regulated by the action of signaling cascades activated upon fixation of the signaling molecules at the cell membrane. The activity of these signaling pathways allow the transcriptional regulation of a specific pool of genes responsible for cell-fate decisions and the formation of tissues. Here, I am interested in the roles of both ACTIVIN/NODAL and βCATENIN signaling pathways in the specification of cell identities during the maturation of the mouse blastocyst
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Naik, Shambhavi. "Characterisation of TRAIL receptor signalling to apoptosis in pre-clinical models of breast cancer." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9913.
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TNF-Related Apoptosis-Inducing Ligand (TRAIL) belongs to the TNF cytokine family and can signal to apoptosis by binding to either of two membrane-bound death receptors, TRAIL-R1 or TRAIL-R2. Using ligands specific for TRAIL-R1 (R1L) or TRAIL-R2 (R2L), our laboratory has previously shown that combining a histone deacetylase inhibitor with R1L, but not R2L, induces apoptosis in primary chronic lymphocytic leukaemia cells. The aim of this project was to extend the profiling of TRAIL-Receptor signalling to breast cancer, using breast cancer cell lines and importantly primary breast tumours as model systems. A 3-dimensional explant culturing technique was employed to maintain the primary tumour architecture and mimic the breast tumour microenvironment. In addition, tumour-initiating cells from advanced metastatic breast cancer patients were also tested for their sensitivity to TRAIL. The results obtained from breast cancer cell lines, primary mucinous carcinomas and advanced metastatic breast cancer cells suggest that in breast cancer, TRAIL-R1 is the predominant functional TRAIL death receptor independent of oestrogen receptor status. In contrast, invasive ductal/lobular carcinomas (IDC/ILC) were resistant to TRAIL-induced apoptosis and required the breast cancer chemotherapeutic, doxorubicin as a sensitising agent. Studies using the TRAIL-resistant cell line, T47D, demonstrated that doxorubicin sensitised tumour cells to TRAIL-induced apoptosis via enhanced TRAIL DISC formation. Importantly, in primary tumour explants, the combination of doxorubicin and TRAIL signalled to apoptosis exclusively in the tumour cells, but not in normal cells. Significantly, in four IDC/ILC tumours, doxorubicin sensitised breast tumour cells to R1L more efficiently than R2L. Therefore, using R1L in combination with sub-lethal doses of chemotherapeutic agents could improve the benefit of conventional therapy whilst reducing drug-associated side-effects and potential TRAIL-mediated cell proliferation/survival in apoptosis-resistant tumour cells. My data suggest that using a TRAIL-R1-selective agonist with an appropriate sensitising agent (example, doxorubicin), offers a promising therapeutic approach for treatment of breast cancer.
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Santos, Geisa Aparecida dos. "Análise comparativa de perfis de sinalização do receptor AT1 ativado por agonistas seletivos para a via de -arrestinas." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-31102013-150124/.
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Os receptores acoplados à proteína G (GPCRs), também chamados de receptores 7TM, são conhecidos por regular virtualmente todos os processos fisiológicos em mamíferos e cerca de 40% de todas as drogas comerciais agem através destes receptores. A sinalização mediada por eles é classicamente atribuída à proteína G, que é ativada pela troca de GDP por GTP, promovendo a separação das subunidades G e G, e leva à produção de mensageiros secundários como cAMP, Ca2+ e DAG. Após a resposta os GPCRs são fosforilados pelas quinases de GPCRs (GRKs), sinalizando para recrutamento das -arrestinas citoplasmáticas, que por sua vez desencadeiam a formação de endossomos internalizando e dessensibilizando o receptor. Entretanto, estudos mostram que este endossomo, contendo o complexo ligante-receptor--arrestina, pode interagir com proteínas sinalizadoras no citoplasma desencadeando vias de sinalização independentes de proteína G. Recentemente foram descritos para diferentes receptores, ligantes capazes de ativar seletivamente uma das duas vias, proteína G ou -arrestina, chamados agonistas seletivos. O receptor AT1 é um GPCR particularmente interessante no estudo do agonismo seletivo, tanto por sua vasta expressão em tecidos quanto pelo conhecimento de agonistas seletivos já estabelecidos, tais como os ligantes SII e TRV120027. O objetivo deste trabalho foi analisar comparativamente os perfis de sinalização decorrente da ativação de AT1 por SII ou TRV120027 através do uso de arranjos de quinases e da modulação de genes relacionados a sinalização de GPCRs. Ang II que é ligante natural e total (ativa via dependente de proteína G e de -arrestina) neste receptor foi usada como controle para fins de comparação. Nossos dados mostraram que o perfil da sinalização mediada pelo receptor AT1 varia não só entre AngII e os agonistas seletivos, mas também entre os dois ligantes seletivos SII e TRV120027, mostrando que a interação receptor-ligante pode influenciar a sinalização em um grau mais refinado, além da ativação dependente de -arrestina ou proteína G. Estes dados mostram que existem perspectivas para o desenvolvimento futuro de ligantes com ainda maior grau de seletividade.G protein coupled receptors (GPCRs), also known as 7TM receptors, are known to regulate virtually all physiological processes in mammals and approximately 40% of all current clinical drugs act by modulating such receptors. The signaling mediated by them is classically by coupling to G protein, which is activated by exchanging bound GDP for GTP, dissociation of G and G subunits, then leading to production of second messengers such as cAMP, Ca2+, and DAG. After the signal transduction, GPCR are phosphorylated by GPCR kinases (GRKs), followed by recruitment of cytoplasmic -arrestins, which initiate the endosome formation with consequent internalization and desensitization of the receptor. However, is has been demonstrated that the endosome assembling the ligand-receptor--arrestin complex can interact with cytoplasmic signaling proteins, therefore activating signaling pathways independently of G protein coupling. Recently, for different receptors, it has been described ligands capable of selectively activating one of these signaling pathways, G protein or -arrestin, called biased agonists. The AT1 receptor is a particularly interesting GPCR for the study of biased agonism, either due to its wide tissue expression as well as also due the existence of known and established biased ligands, such as SII and TRV120027. The aim of our study was to comparatively analyze the AT1 receptor signaling pathways profiles after activation by SII or TRV120027, using kinases arrays, and expression modulation of genes related to GPCRs signaling. AngII is the natural and full agonist of this receptor (activates both G protein and -arrestin signaling pathways) was used for comparison. Our data show that the signaling profile mediated by AT1 receptor can be distinct not only when comparing the profiles from AngII and the biased agonists, but also when comparing the profiles from the two biased ligands SII and TRv120027; revealing that the complex ligand-receptor can influence the downstream signaling pathways in a fine-tune way, further to the activation of -arrestin or G-protein. This data show that there are perspectives for the future development of ligands with even higher degree of selectivity.
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Bajaj, Garima. "A Pre and Post 9-11 Analysis of SS7 Outages in the Public Switched Telephone Network." Ohio University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1171294573.
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Rolim, Natale Pinheiro Lage. "Efeito do treinamento físico em modelo genético de insuficiência cardíaca induzida por hiperatividade simpática." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/39/39132/tde-12112007-170402/.
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A atividade nervosa simpática está aumentada na insuficiência cardíaca (IC) e relacionada com a gravidade e o prognóstico da doença. Camundongos com deleção dos receptores adrenérgicos α2A e α2C (α2A/α2CARKO) desenvolvem IC induzida pela hiperestimulação simpática e apresentam 50% de mortalidade aos sete meses de idade. A diminuição na contratilidade cardíaca, a perda de cardiomiócitos e a intolerância à realização de esforço físico sugerem esse modelo genético para o estudo de possíveis terapias farmacológicas e não-farmacológicas para o tratamento da IC. O presente estudo avalia o possível efeito terapêutico do treinamento físico (TF) na cardiomiopatia induzida pela hiperatividade simpática. Os benefícios sobre a tolerância ao esforço e a função sistólica observados nos camundongos α2A/α2CARKO com o TF foram acompanhados pelo aumento do pico do transiente de Ca2+ intracelular e da expressão de proteínas cardíacas que regulam o transiente de Ca2+ SERCA2 (20 %), fosfo-PLB-Ser16 (92 %), fosfo-PLB-Tre17 (285 %), bem como pela redução na expressão do NCX e da PP1. Portanto, esse estudo fornece evidências de alterações na sinalização intracelular de Ca2+ nos camundongos α2A/α2CARKO que contribuem para o agravamento da IC nesse modelo, e que o TF melhora a função ventricular associada ao aumento no transiente de Ca2+ intracelular no cardiomiócito.The sympathetic nervous activity is increased in heart failure (HF) and is associated with the severity and prognosis of disease. Mice lacking both α2A and α2C adrenergic receptors (α2A/α2CARKO) develop sympathetic hyperactivity- induced HF and present 50% mortality rate by seven mo of age. The decreased cardiac contractility, cardiomyocytes degradation and exercise intolerance suggest that these mice are a good genetic model to unravel molecular mechanisms involved in the improvements of ventricular function by different pharmacological and non-pharmacological therapies for HF. The present study was underlined to test the possible therapeutic effect of exercise training in sympathetic hyperactivity- induced HF. The improved exercise tolerance and systolic function after exercise training in α2A/α2CARKO was accompanied by increased intracellular Ca2+ transient and the expression of cardiac proteins which regulate Ca2+ transients, such as expression SERCA2 (20%), phospho-PLB-Ser16 (92%), phospho-PLB-Tre17 (285%), paralleled by reduction in NCX and PP1 expression. Therefore, this study provide direct evidence for the altered intracellular Ca2+ signaling in α2A/α2CARKO mice and that exercise training improves the ventricular function associated with an increase in intracellular Ca2+ transient in cardiomyocyte.
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Koetz, Clara Isabel. "A influência do afeto e do gênero do consumidor no processamento das informações de qualidade sinalizadas por meio da propaganda." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/31967.
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O objetivo desta tese consiste em analisar a influência do afeto e do gênero do consumidor na percepção da qualidade do produto nos processos de sinalização da qualidade por meio da propaganda. Para tal, dois estudos experimentais foram conduzidos. O primeiro estudo foi aplicado no Brasil, em uma amostra de 144 estudantes, no qual buscou-se analisar a influência do investimento em propaganda (abaixo da média, na média e acima da média praticada no mercado), do afetivo (positivo e negativo) e do gênero (masculino e feminino) na percepção da qualidade do produto. Na análise dos dados, foram conduzidos dois modelos ANOVA, nos quais foram utilizadas como variáveis dependentes, primeiramente, a variável “Q ualidade Geral”, que se refere a uma avaliação geral, e a variável “Qualidade Percebida”, que considera apenas a percepção subjetiva do respondente acerca da qualidade do produto. O segundo estudo foi aplicado na França, em uma amostra de 401 estudantes, cujo objetivo foi examinar a influência do afeto (positivo e negativo), do investimento em propaganda (abaixo da média, na média e acima da média praticada no mercado), da presença de informações sobre o produto (com informações e sem informações) e do gênero do sujeito (masculino e feminino) na percepção da qualidade do produto em processos de sinalização da qualidade por meio da propaganda. A análise dos dados foi desenvolvida em quatro etapas. Primeiramente, foi conduzida uma ANOVA que teve como variáveis independentes o “Afeto”, a “I nformação” e o “Investimento em Propaganda” e como variáveis dependentes as mesmas variáveis de percepção da qualidade utilizadas na análise dos dados do estudo anterior (em dois modelos distintos). A seguir, foi desenvolvido um novo modelo de ANOVA, no qual foram definidas como variáveis independentes o “Investimento em Propaganda”, o “Gênero” e a “Informação”, e como variáveis independentes as mesmas variáveis de percepção da qualidade. Os resultados demonstraram que houve uma interação entre a presença de informações e o estado afetivo do consumidor na percepção da qualidade do produto. Assim, nas situações em que os pesquisados tiveram acesso a informações sobre o produto, estas foram consideradas na avaliação do produto. Nesses casos, o estado afetivo do consumidor demonstrou não influenciar a percepção da qualidade do produto. Porém, quando não foram fornecidas informações, o julgamento foi influenciado pelo estado afetivo dos respondentes, sendo que aqueles que vivenciavam estado afetivos positivos avaliaram melhor o produto do que aqueles que vivenciavam estados afetivos negativos. Além disso, os resultados evidenciaram a interação entre o gênero e o montante investido em propaganda no julgamento da qualidade do produto. Nos contextos de baixo investimento em propaganda, em que o sinal de qualidade não foi emitido, as mulheres avaliaram melhor o produto do que os homens. Porém, nos contextos de investimento na média e acima da média de mercado, em que o sinal de qualidade foi emitido, homens e mulheres apresentaram médias similares de percepção da qualidade do produto, apenas quando a variável de avaliação da qualidade subjetiva foi utilizada. Assim, pode-se considerar que a sinalização da qualidade estabeleceu um sinal heurístico, o qual foi mais considerado pelos homens do que pelas mulheres na avaliação da qualidade do produto.The objective of this thesis is to examine the influence of affect and gender on consumer perceptions of product quality in the signaling quality processes through advertising. In order to do that, two experimental studies were conducted. The first study was implemented in Brazil, in a sample of 144 students, whose objective was to examine the influence of the amount invested in advertising (below the average, on the average and above the average invested by the main competitors), the affect (positive and negative) and the gender (male and female) in the perception of product quality. In the data analysis, two ANOVA models were conducted. In the first one, the dependent variable "Overall Quality” was applied, which refers to a more objective assessment of the product. In the second model, the dependent variable "Perceived Quality" was used, which considers a more subjective evaluation of the product. The second study was developed in France, in a sample of 401 students, whose goal was to examine the influence of affect (positive and negative), the amount invested in advertising (below average, on the average and above the average invested by the main competitors), product information (with and without product information) and the subject's gender (male and female) in the perception of product quality in the signaling quality processes through advertising. The data analysis was developed in four steps. First, an ANOVA was conducted with the independent variables "Affect", "Information" and "Advertising Budget", and the same dependent variables that were used to evaluate the product quality perception in the previous study (in two different models). Next, it was developed another ANOVA model, in which it was defined as independent variables the "Advertising Budget ", "Gender" and "Information", and as dependent variables the same variables of quality perception used before (again in two distinct models). The results showed an interaction between the presence of information and the consumer affective state in the product quality perception. Thus, in situations where the respondents had access to product information, they considered this information in the evaluation of the product. In such cases, the affective state did not influence the consumer perceptions of product quality. However, when information was not provided, the product evalua tion was influenced by the affective state of the respondents. Thus, those who were experiencing positive affective states evaluated better the product than those who were experiencing negative emotional states. Moreover, the results showed an interaction between the gender and the amount invested in advertising in the product quality judgment. In the contexts of low investment in advertising, where the signal quality has not been used, women evaluated the product better than men. However, in the contexts where investments in the market’s average and above the market’s average were applied, in which the quality signal was transmitted, men and women showed similar mean values of quality perception only when the subjective dependent variable of perceived qua lity was used. Thus, it can be considered that the quality signal established a heuristic signal, which was considered more by men than by women in the evaluation of the product quality.
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Castellanos, jankiewicz Ashley. "Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0218.
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Introduction : Les acides biliaires (AB) sont des molécules connues pour digérer les lipides. En activant le récepteur couplé à la protéine G Takeda 5 (TGR5) dans les tissus périphériques, ils peuvent également servir de molécules de signalisation pour réduire le poids corporel et améliorer le profil glycémique. L'activation de TGR5 peut aussi augmenter la dépense énergétique dans le tissu adipeux, mais les voies métaboliques impliquées dans ces effets sont encore mal connues. Ces observations impliquent une action anti-obésité du TGR5. Cependant, toutes les études sur les AB dans la balance énergétique se sont concentrées exclusivement sur des tissus périphériques. Comme le principal centre de convergence des signaux nutritifs, hormonaux et environnementaux se trouve dans le cerveau, et en particulier dans l'hypothalamus, nous avons émis l'hypothèse que l'activité hypothalamique du TGR5 pourrait moduler la balance énergétique, en particulier dans un contexte d’obésité. Objectif : Démontrer la fonction du système AB – TGR5 dans des populations de cellules hypothalamiques connues pour contrôler l’homéostasie énergétique et étudier sa pertinence pour le traitement de l’obésité. Méthodes : Des canules intra-cérébro-ventriculaires (ICV) ont été implantées sur des souris mâles C57Bl6/J minces (sous régime standard) ou obèses (sous régime riche en graisses) pour permettre l'administration pharmacologique aiguë ou chronique des agonistes du TGR5. Des souris TGR5flox/flox ont été utilisées pour provoquer la délétion du récepteur dans l'hypothalamus médio-basal (HMB), par l’injection in situ d’un AAV-Cre. Nous avons mesuré le poids corporel, prise alimentaire, composition corporelle, sensibilité à l'insuline, niveaux des AB hypothalamiques et plasmatiques et dépense énergétique. Pour bloquer la signalisation sympathique, nous avons exposé les souris à un environnement de thermoneutralité (30°C) ou à une sympathectomie chimique. Des marqueurs de la lipolyse, de la thermogenèse ou du métabolisme thyroïdien ont été mesurés dans le foie, le tissu adipeux et l’hypothalamus par qPCR ou western blot. Toutes les études ont été approuvées par le comité d'éthique en expérimentation animale de l'Université de Bordeaux. Résultats : Nous montrons que les transporteurs du TGR5 et des AB s’expriment dans l’HMB et que les souris obèses ont une diminution des AB dans la circulation et l’hypothalamus. L'administration aiguë d'agonistes du TGR5 (ICV ou intra-HMB) réduit la prise alimentaire et le poids corporel chez les souris obèses, tout en améliorant leur sensibilité à l'insuline. De plus, l'administration chronique ICV de l’agoniste réduit le poids corporel et l'adiposité, tout en augmentant la dépense énergétique et les marqueurs de l'activité sympathique dans le tissus adipeux. La thermo-neutralité ainsi que la sympathectomie chimique atténuent ces effets, démontrant que l’activité du récepteur TGR5 nécessite un tonus sympathique accru. La délétion de TGR5 dans le HMB (souris TGR5flox/flox) n'a aucun effet chez les souris minces. Cependant, l’exposition à une nourriture riche en graisse augmente rapidement leur poids, prise alimentaire et adiposité. Lors de l’exposition au froid (4 heures à 4°C), l’expression des marqueurs de lipolyse et thermogenèse dans le tissu adipeux était atténuée, suggérant une interruption de la signalisation sympathique. Enfin, la suppression du TGR5 dans le HMB de souris déjà obèses augmente l'adiposité en induisant une hyperphagie, aggravant l’obésité. Conclusions : Nos résultats prouvent l’existence d’un système fonctionnel du TGR5 hypothalamique, un récepteur des AB. Nous montrons pour la première fois que l'activation du TGR5 dans le HMB induit une myriade d'effets qui améliorent des paramètres métaboliques, et que cela dépend de l'activation du système nerveux sympathique. Ainsi, nous dévoilons un nouveau mécanisme d'action pour des potentiels traitements contre l'obésitéIntroduction: Bile acids (BA) are cholesterol-derived molecules mostly known for their role in digesting lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, they can also act as signaling molecules to reduce body weight and improve glucose homeostasis. Notably, TGR5 activation can increase energy expenditure in brown adipocytes, although the metabolic pathways involved in these effects are not yet clear. These outcomes imply an anti-obesity function for TGR5. However, all studies investigating BA in energy balance have exclusively focused on peripheral tissues. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, suggesting that hypothalamic TGR5 activity may participate in energy balance, specifically under dietinduced obesity. Objective: To demonstrate the function of the BA – TGR5 system in hypothalamic populations known to control energy homeostasis, and disentangle its relevance for the treatment of diet-induced obesity. Methods: C57Bl6/J male mice that were either lean (standard chow) or diet-induced obese (60% high-fat diet; HFD) were implanted with an intra-cerebroventricular (ICV) cannula for the pharmacological delivery of TGR5 agonists. TGR5flox/flox mice were used to target the sitespecific deletion of the receptor within the mediobasal hypothalamus (MBH), through the stereotaxic delivery of AAV-Cre. The following metabolic outputs were measured: body weight, food intake, body composition (EchoMRI analyzer), insulin sensitivity, serum and hypothalamic BA (liquid mass spectrometry), and energy expenditure (TSE Phenomaster system). To block sympathetic signaling, we exposed mice to thermoneutrality (30°C) or performed chemical sympathectomy (6-hydroxydopamine; 80mg/kg i.p.). Markers of lipolysis, thermogenesis, and thyroid metabolism were measured in the liver, adipose and hypothalamic tissues by qPCR or western blots. All studies received the approval from the animal ethical committee of the University of Bordeaux. Results: We demonstrate that TGR5 and BA transporters are expressed in the MBH and that diet-induced obese mice have decreased circulating and hypothalamic BA. Acute ICV or intra-MBH administration of TGR5 agonists reduced food intake and body weight in dietinduced obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and mRNA markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require an enhanced sympathetic tone. By using TGR5flox/flox mice coupled with the delivery of an AAVCre, we observed that the deletion of TGR5 in the MBH had no effect in chow-fed mice. However, a HFD switch rapidly increased their body weight, food intake and adiposity. When exposed to the cold (4 h at 4°C), protein levels of lipolysis and thermogenesis markers in the adipose tissue were blunted, implying an interruption in sympathetic signaling to the periphery due to hypothalamic downregulation of TGR5. Lastly, Cre-dependent deletion of TGR5 in the MBH of already obese mice rapidly increased adiposity by inducing hyperphagia, worsening their obese phenotype. Conclusions: Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. Taken together, these results expose a new mechanism of action for potential anti-obesity therapies
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McKenna, Mary Kathryn. "NOVEL ROLE OF PROSTATE APOPTOSIS RESPONSE-4 TUMOR SUPPRESSOR IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA." UKnowledge, 2017. https://uknowledge.uky.edu/microbio_etds/17.
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Chronic Lymphocytic Leukemia (CLL) is defined by the accumulation of clonally expanded CD5+ and CD19+ B lymphocytes in blood and secondary lymphoid organs with impaired apoptotic mechanisms. CLL represents one third of all leukemia cases with an average age of 72 years at diagnosis making it the most common adult leukemia. The Eµ-Tcl1 mouse serves as an excellent model to study the development of CLL as they progress to a CLL like disease by 9-14 months of age, due to overexpression of an oncogene, T cell Leukemia 1(Tcl1), specifically in B cells through the Ig VH promoter and Eµ enhancer (Bichi et al. PNAS. 2002). In an adoptive transfer model, intravenous or intraperitoneal injection of primary CD5+CD19+ CLL cells from the Eµ-Tcl1 CLL mouse into recipient syngeneic mice leads to the development of a CLL like disease within 3-8 weeks of transfer. We have characterized the growth of CLL cells in these mice by periodic submandibular bleeding, spleen ultrasonography and flow cytometry. We find that Eµ-Tcl1 CLL cells express more Prostate apoptosis response-4 protein (Par-4), a known pro-apoptotic tumor suppressor protein, than normal B-1 or B-2 cells in mice. Par-4 is silenced by promoter methylation in more than 30% of all cancers and has been shown to be secreted and to induce apoptosis selectively in various types of cancer cells but not in normal cells. We found that CLL cells have constitutively active B-cell receptor signaling (BCR) and that inhibition of BCR signaling with FDA approved drugs causes a decrease in Par-4 protein, mRNA levels, and an increase in apoptosis. In particular, activities of Src family kinases, spleen tyrosine kinase and Bruton’s tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling in both Eµ-Tcl1 CLL cells and primary human CLL samples. Consistent with this, lenti-viral shRNA mediated knockdown of Lyn kinase leads to a decrease in Par-4 expression in MEC-1 cells, a human CLL derived cell line. Igα (CD79a) silencing in primary human CLL cells also results in down regulation of Par-4 expression. Additionally, we knocked down expression of Par-4 in MEC-1 cells which resulted in a decrease in cell growth that could be attributed to an increase in p21 expression and a reduction in the G1/S cell cycle transition. We have also observed this phenomenon by crossing mice deficient in Par-4 with the Eµ-Tcl1 mouse where lack of Par-4 delays CLL growth in the mouse significantly (time to euthanization due to poor body condition - Eµ-Tcl1: 8.9mo vs Par4-/-EµTcl1: 11.97 mo, p = 0.0472) and splenic B-CLL cells from these mice also have increased expression of p21. Since mice in this cohort are whole body knockout for Par-4, the difference in survival times between the Par-4 +ve and Par-4 –ve EµTcl1 mice could be due to the influence of Par-4 on CLL cells as well as the effect of Par-4 secreted by the CLL cells on the microenvironment. There could be other potential roles for Par-4 in the context of CLL which are under further investigation. We have also investigated the site of CLL growth in mouse models to determine that the spleen is the primary organ to accumulate the CLL tumor burden. We have found that splenectomy significantly delays the development of CLL in the primary Eμ-Tcl1 mouse model and prevents growth and development in the adoptive transfer model. Interestingly, splenectomy did not delay CLL development as significantly in animals deficient for Par-4 compared to C57BL/6 wild type mice. Par-4 appears to regulate a specific microenvironment required for CLL growth. Current studies are investigating the role of Par-4 in the microenvironment and the cell types that are critical for CLL growth within the splenic niche.
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Deng, Xiaoling. "Identification of PAR₁-G protein signalling pathways involved in thrombin-induced CCL2/MCP-1 production." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444265/.
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Uncontrolled activation of the coagulation cascade following lung injury has been implicated in both lung inflammation and fibrosis. In addition to its role in coagulation, thrombin exerts pluripotent cellular effects via the activation of its high-affinity receptor, proteinase activated receptor-1 (PAR_1). PAR_1 is a seven transmembrane domain G protein-coupled receptor that exhibits the ability to couple to multiple G protein family subunits, including G\alpha_{i/o}, G\alpha_q and G\alpha_{12/13} within the same cell type. Activation of PAR_1 on fibroblasts, a key effector cell in lung fibrosis, results in the induction of several mediators, including the potent monocyte and fibrocyte chemoattractant CCL2. In this thesis, the G-protein and downstream signalling pathways involved in PAR_1-mediated CCL2 production and release were examined. Using a novel PAR_1 antagonist which blocks the interaction between PAR_1 and G\alpha_q, this thesis shows for the first time that PAR_1 coupling to G\alpha_q is essential for thrombin (10nM)-induced CCL2 gene expression and protein release in murine lung fibroblasts (MLFs). The work presented here further demonstrates that these effects are mediated via the cooperation between ERK1/2 and Rho kinase signalling pathways: a calcium-independent PKC, c-Raf and ERK1/2 pathway was found to mediate PAR_1-induced CCL2 gene transcription; whereas PLC, calcium, calcium-dependent PKC and Rho kinase pathway influences CCL2 protein release. This thesis represents the first demonstration of the cooperation between two pathways in mediating the stimulatory effects of thrombin, or indeed any other extra cellular stimulus, on the induction and release of the potent chemoattractant, CCL2. This thesis also examined the signalling receptor and downstream effectors involved in thrombin-induced CCL2 production in primary human lung fibroblasts (pHALFs). The results demonstrate that PAR_1 coupling to G\alpha_q is also both necessary and sufficient in mediating thrombin-induced CCL2 production at low concentration of the proteinase, whereas at high concentrations, these effects may be partially PAR-independent. This discrepancy between MLFs and pHALFs may be explained by differences of PAR receptor expression between species. Taken together, this thesis proposes that targeting the interaction between PAR_1 and specific G proteins may allow more selective blockade of PAR_1 pro-inflammatory and pro-fibrotic signalling, whilst preserving the essential role of other PAR_1-mediated cellular responses.
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McIntosh, Kathryn Ann. "Proteinase-activated receptor-2( PAR-2) and tumour necrosis factor-alpha ( TNFα) signalling in inflammation." Thesis, University of the West of England, Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489251.
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Proteinase activated receptor-2 (PAR-2) is a novel G-protein coupled receptor, that is activated by means of proteolytic cleavage (Macfarlane et al, 2001) and has both pro and anti-inflammatory actions depending upon the system examined. PAR-2 have been linked to the stress-activated protein kinases (SAPKs), JNK and p38 MAP kinase and NFK13 signalling (Kanke et al, 2001; Sabri et al, 2000), pathways known to be involved in proinflammatory responses in several cell types. TNFa has been demonstrated to up-regulate PAR-2 expression in a variety of cell types (Nystedt et al, 1996; Ritchie et al, 2007). Since both TNFa and PAR-2 are implicated in inflammation, we examined the possibility of altered PAR-2 trafficking under inflammatory conditions and possible crosstalk between PAR-2 and TNFa at the level of intracellular signalling. Previous studies have characterised P AR-2 trafficking in transfected cell lines, however the effects of inflammatory stimuli on the kinetics of PAR-2 trafficking has not been investigated. The study sought to re-characterise PAR-2 trafficking in the presence of inflammatory stimuli. NCTC2544 cells transfected with YFP epitope tagged PAR-2, demonstrated clear PAR-2 expression and trafficking of the receptor was successfully characterised, however no significant differences in the kinetics of P AR-2 trafficking under inflammatory conditions compared to control was observed. The latter part of the study examined PAR-2 and TNFa mediated activation of the MAPK and NFK13 pathways. In a keratinocyte cell line stably expressing PAR-2 (CloneG), trypsin, SLIGKV-OH, and TNFa, caused a time and concentration-dependent increase in p38 MAPK and JNK phosphorylation however, preliminary results failed to show evidence of synergy between the receptors. Surprisingly however, pre-activation of P AR-2 substantially reduced the ability of TNFa to activate JNK. The inhibitory effect of P AR-2 was mimicked by the protein kinase C activator PMA, partially reversed by the PKC inhibitor GF109203X, and completely reversed by the novel Gaqlll inhibitor YM-254890, consistent with a role for both Ca2+ -dependent and independent PKC isoforms and for P AR-2 coupling to Gaq/11 to mediate this agonist driven inhibitory response. These results indicate a potential mechanistic explanation for both the anti and pro-inflammatory actions of P AR- 2, and highlight a possible novel therapeutic avenue for the development ofPAR-2 agonists as anti-inflammatory drugs.
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Yamashita, Felipe Oliveira. "Memória fisiológica e comunicação radicular induzida por metil jasmonato." Botucatu, 2019. http://hdl.handle.net/11449/181889.
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Orientador: Luiz Fernando Rolim de AlmeidaResumo: Apesar de serem organismos sésseis, as plantas movimentam ativamente estruturas vegetativas e reprodutivas, levando a interação com o ambiente ao redor. As plantas mantêm comunicação com plantas vizinhas, herbívoros e predadores através da emissão de compostos químicos exsudados pela raiz e esses eventos modificam o ambiente ocupado pelos vegetais. Esses exsudatos podem induzir a alteração de padrões morfológicos e fisiológicos além da expressão gênica de plantas vizinhas. Utilizamos o metil jasmonato, um regulador vegetal, para desencadear dois ciclos indutivos em plantas e comunicação com plantas vizinhas. Durante o estímulo, analisamos assimilação líquida de CO2 (A), condutância estomática (gs), taxa de transpiração (E), eficiência do uso da água (EUA), taxa de transporte de elétrons (ETR), fluorescência máxima (FM) e basal (F0), dissipação fotoquímica (qP) e rendimento quântico efetivo do PSII (PSII), além da expressão do gene SHR, padrão de metilação de histonas e parâmetros anatômicos em plantas com aplicação e plantas vizinhas. Plantas com aplicação de metil jasmonato apresentaram queda nos parâmetros fisiológicos horas após o contato com o elicitor, porém em segundo contato, tais parâmetros não diferiram do controle, indicando possível efeito de memória (imprint). Plantas induzidas pelo metil jasmonato podem ter emitido sinais às plantas vizinhas, proporcionando maiores taxas de A, gs, FM e F0 das plantas vizinhas em relação às induzidas. Portanto a comunicação entre... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Although they are sessile organisms, plants actively move their vegetative and reproductive structures, leading to interaction with the surrounding environment. Plants maintain communication with neighboring plants, herbivores and predators through emission of chemical compounds by root and these events modify the environment occupied by plants. These exudates may induce changes in morphological and physiological patterns beyond the gene expression of neighboring plants. We used methyl jasmonate, a plant regulator, to trigger two inductive cycles in plants and communication with neighboring plants. During the stimulus, we analyzed CO2 net assimilation (A), stomatal conductance (gs), transpiration rate (E), water use efficiency (WUE), electron transport rate (ETR), maximum fluorescence (FM), basal fluorescence (F0), photochemical dissipation (qP) and quantum yield of PSII (FPSII), as well as SHR gene expression, histone methylation pattern and anatomical parameters in plants with application and neighboring plants. Plants with methyl jasmonate application showed minor physiological parameters hours after the elicitor contact, but in the second contact, these parameters did not differ from the control group, indicating a possible memory effect (imprint). Plants induced by methyl jasmonate may have emitted signals to neighboring plants, providing higher rates of A, gs, FM and F0 of the neighboring plants in relation to the induced ones. Therefore the communication between plants... (Complete abstract click electronic access below)
Mestre
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Franco, Danilo Miralha. "Comunicação radicular induzida por diferentes tipos de substâncias químicas." Botucatu, 2017. http://hdl.handle.net/11449/151529.
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Orientador: Luiz Fernando Rolim de AlmeidaResumo: Devido à natureza séssil, os vegetais estão sujeitos a modificações no ambiente que podem levar a deficiência hídrica, atividade alelopática e herbicida, e necessitam de respostas especificas para responder a elas. As respostas são induzidas pelas modificações, e demandam tempo e energia para serem ativadas. A comunicação vegetal pode ter importante função de processamento de informação, sinalizando sobre um evento estressante de uma planta para outra. Essa sinalização pode otimizar a aptidão de aclimatação ao estresse ambiental. Portanto, investigamos se diferentes tipos de substâncias podem induzir comunicação radicular em plantas de Sorghum bicolor (sorgo). Observando como a sinalização recebida por plantas vizinhas reflete alterações nos parâmetros avaliados, como o crescimento de raiz e parte aérea, trocas gasosas, fluorescência da clorofila a, atividade de enzimas antioxidantes e expressão de genes do desenvolvimento de raiz. Para isso submetemos plantas de sorgo com 25 dias após semeadura aos tratamentos com manitol, glifosato, extrato de Copaifera langsdorffii (copaíba), ácido indol-3-butírico (IBA) e rutina por 168 horas. Apenas a planta do primeiro vaso teve contato direto com as substâncias, caracterizando-a como planta tratada e a planta sem tratamento como planta vizinha. Os resultados indicam que as plantas vizinhas ao receberem comunicação apresentam redução do desenvolvimento de raiz. Com exceção do tratamento com extrato de copaíba, todos as plantas apresenta... (Resumo completo, clicar acesso eletrônico abaixo)
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Jancenelle, Vivien E. "Signaling Normative and Economic Orientations during Earnings Conference Calls: Market Performance Antecedents and Consequences." Cleveland State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=csu1488814095926987.
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Balsiger, Alexander 1975. "The Role of cyclin O in ER stress signalling." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/565441.
Full textAbstract:
We recently identified a novel cyclin called Cyclin O which is able to bind and activate Cdk1 and Cdk2 in response to intrinsic apoptotic stimuli like DNA damage or ER stress. Cyclin O has been shown to be involved in the unfolded protein response (UPR) as an activator of PERK signalling. The aim of this thesis has been to study the molecular role of Cyclin O in response to ER stress. We have found that expression of Cyclin O is upregulated upon ER stress by pathways of the UPR that signal through eIF2α phosphorylation and CHOP expression. Furthermore, we have observed that Cyclin O activates the MAPK pathways independently of IRE1α signalling. This effect is most likely mediated by Cdk1 and Cdk2-dependent phosphorylation and consequent activation of MEKK4, which leads to the activation of JNK and p38. We have also found employing phosphoproteomics technology that many proteins involved in protein folding and translation depend on Cyclin O.En nuestro laboratorio hemos identificado recientemente un nuevo miembro de la familia de las ciclinas, la Ciclina O, la cuál puede unirse y activar a Cdk1 y Cdk2 en respuesta a estímulos apoptóticos tales como el daño genético o el estrés del retículo endoplásmico. También hemos demostrado que la Ciclina O participa en la respuesta celular desencadenada por el acúmulo de proteínas mal plegadas (UPR) actuando a través de la activación de la señalización de la ruta de PERK. El objetivo de esta tesis ha sido el estudio molecular de la participación de la Ciclina O en la respuesta al estrés del retículo. Nuestros resultados indican que los niveles de expresión de la Ciclina O incrementan en respuesta al estrés del retículo a través de rutas de la UPR que señalizan a través de la fosforilación de eIF2α y de la expresión de CHOP. Además hemos observado que en respuesta al estrés reticular la Ciclina O activa la ruta de las MAPK de manera independiente de la señalización a través de IRE1α. Este efecto posiblemente tiene lugar a través de la fosforilación y consecuente activación de MEKK4 dependiente de Cdk1 y Cdk2. Esto conlleva la activación de las kinasas de stress JNK y p38. Asimismo, mediante experimentos de fosfoproteómica hemos demostrado que un gran número de proteínas involucradas en los procesos bioquímicos de traducción y plegado dependen de la expresión de la Ciclina O.