To see the other types of publications on this topic, follow the link: Mitogen-Activated Protein Kinase 3.
Dissertations / Theses on the topic 'Mitogen-Activated Protein Kinase 3'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Mitogen-Activated Protein Kinase 3.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Rojnuckarin, Ponlapat. "Mitogen-activated protein kinase pathways in megakaryocyte development /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/9200.
Full text
2
Ing, Y. Lynn. "MLK-3, identification and characterization of a protein kinase involved in mitogen-activated protein kinase signal transduction pathways." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0020/NQ45812.pdf.
Full text
3
Botton, Stéphane de. "Etapes terminales de la mégacaryopoïèse : mécanismes régulateurs de la formation des proplaquettes." Lille 2, 2006. http://www.theses.fr/2006LIL2S053.
Full textAbstract:
Les plaquettes naissent par fragmentation d'une cellule géante, le mégacaryocyte, par un processus dynamique très particulier appelé formation de proplaquettes. À la fin de la différenciation, le mégacaryocyte forme des allongements cytoplasmiques par déroulement des membranes de démarcation sous l'action du cytosquelette (microtubules et actine). Ces allongements cytoplasmiques contenant toutes les organelles, y compris les granules α et les mitochondries, se font habituellement à travers la barrière endothéliale \; plus rarement, le mégacaryocyte en entier migre à travers la barrière endothéliale. Les plaquettes sont formées soit à l'extrémité distale des proplaquettes, soit par rupture des proplaquettes au niveau de constrictions. Les mécanismes qui régulent ce phénomène sont mal connus mais ne semblent pas sous la dépendance du principal facteur de croissance de la lignée mégacaryocyto‐plaquettaire, la thrombopoïétine. Il existe certaines similitudes morphologiques entre formation des plaquettes et apoptose, ce d'autant que le corps résiduel du mégacaryocyte (noyau entouré d'une collerette cytoplasmique), appelé mégacaryocyte sénescent, meurt par apoptose. Le lien entre machinerie de l'apoptose et formation des plaquettes a été renforcé par le phénotype des souris transgéniques pour Bcl‐2 et Bcl‐xL (deux gènes anti‐apoptotiques) et des souris invalidées pour Bim (gène pro‐apoptotique), qui présentent toutes une thrombopénie modérée associée à un nombre de mégacaryocytes normal ou augmenté. In vitro chez l'homme, la surexpression de Bcl‐2 ou l'addition d'inhibiteurs des caspases, en particulier de la caspase 3 et de la caspase 9, inhibent la formation des plaquettes. Dans les mégacaryocytes matures, on retrouve une activation de la caspase 3 ainsi que le clivage de certains de ses substrats. Cette activation de la caspase 3 est très particulière car elle est compartimentalisée dans le cytoplasme du mégacaryocyte \; en revanche, quand le mégacaryocyte est apoptotique, cette activation est diffuse dans le cytosol. Ces résultats indiquent que le clivage de certains substrats des caspases est absolument nécessaire à la formation des plaquettesPlatelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extension called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34+ cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet bearing megakaryocytes and senescent MKs. Cleavage of caspase substrates such as gelsolin or PARP was also detected. Interestingly, activated forms of caspase-3 were detected in maturing megakaryocytes, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen, these MKs had signs of DNA fragmentation and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD. Fmk as well as more specific inhibitors of caspase-3 and 9 blocked proplatelet formation whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing megakaryocytes. Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited only to some cellular compartments
4
Chen, Xi. "The role of PI3K and ERK/MAPK signal transduction cascades in long-term memory formation /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/6248.
Full text
5
Thérier, Julien. "Régulation de la voie des Mitogen-Activated Protein Kinase ERK1/2 par la phospholipase C gamma dans le signal du Macrophage-Colony Stimulating Factor." Lyon 1, 2005. http://www.theses.fr/2005LYO10121.
Full textAbstract:
Le M-CSF régule l'établissement du lignage monocytaire/macrophagique en assurant la survie, la prolifération mais aussi la différenciation des progéniteurs myéloïdes en cellules très spécialisées : les macrophages. Ce contrôle nécessite la transduction d'un signal intracellulaire impliquant de nombreuses molécules. Parmi celles-ci, les MAPK ERK1/2 présentent une cinétique d'activation caractéristique : une première vague de phosphorylation rapide et transitoire puis une seconde vague tardive et soutenue essentielle à la différenciation macrophagique. J'ai montré au cours de cette étude que la phospholipase C régule spécifiquement cette seconde vague d'activation des kinases ERK1/2 par l'intermédiaire de Ras. Ce processus, indépendant du diacylglycérol, fait intervenir de façon prépondérante l'augmentation du taux de calcium intracellulaire. Ces résultats constituent un mécanisme d'activation original faisant potentiellement intervenir les kinases Src ou les complexes Gab2/SHP2
6
Poser, Steven Walter. "Coincident signaling of cAMP with phosphatidylinositol 3' kinase and mitogen activated protein kinase signal transduction cascades : a role in regulating gene exression during development and synaptic plasticity /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/10633.
Full text
7
Dikic, Inga. "Signal Transduction by Proline-Rich Tyrosine Kinase Pyk2." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5316-3/.
Full text
8
Zer, Cindy. "The genomic targets of p38 mitogen activated protein kinase mediating tumor necrosis factor alpha signaling in fribroblast-like synoviocytes." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1692114531&sid=3&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Full text
9
Chiri, Sandrine. "Rôles de MAP kinase et de PI 3-kinase dans le contrôle des premières divisions de l'œuf d'oursin." Paris 6, 2002. http://www.theses.fr/2002PA066077.
Full text
10
Eriksson, Therese. "Organelle movement in melanophores: Effects of Panax ginseng, ginsenosides and quercetin." Licentiate thesis, Linköpings universitet, Farmakologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19973.
Full textAbstract:
Panax ginseng is a traditional herb that has been used for over 2000 years to promote health and longevity. Active components of ginseng include ginsenosides, polysaccharides, flavonoids, polyacetylenes, peptides, vitamins, phenols and enzymes, of which the ginsenosides are considered to be the major bioactive constituents. Although widely used, the exact mechanisms of ginseng and its compounds remain unclear. In this thesis we use melanophores from Xenopus laevis to investigate the effects of Panax ginseng extract G115 and its constituents on organelle transport and signalling. Due to coordinated bidirectional movement of their pigmented granules (melanosomes), in response to defined chemical signals, melanophores are capable of fast colour changes and provide a great model for the study of intracellular transport. The movement is regulated by alterations in cyclic adenosine 3’:5’-monophosphate (cAMP) concentration, where a high or low level induce anterograde (dispersion) or retrograde (aggregation) transport respectively, resulting in a dark or light cell. Here we demonstrate that Panax ginseng and its constituents ginsenoside Rc and Rd and flavonoid quercetin induce a concentration-dependent anterograde transport of melanosomes. The effect of ginseng is shown to be independent of cAMP changes and protein kinase A activation. Upon incubation of melanophores with a combination of Rc or Rd and quercetin, a synergistic increase in anterograde movement was seen, indicating cooperation between the ginsenoside and flavonoid parts of ginseng. Protein kinase C (PKC) inhibitor Myristoylated EGF-R Fragment 651-658 decreased the anterograde movement stimulated by ginseng and ginsenoside Rc and Rd. Moreover, ginseng, but not ginsenosides or quercetin, stimulated an activation of 44/42-mitogen activated protein kinase (MAPK), previously shown to be involved in both aggregation and dispersion of melanosomes. PKC-inhibition did not affect the MAPK-activation, suggesting a role for PKC in the ginseng- and ginsenoside-induced dispersion but not as an upstream activator of MAPK.Panax ginseng är ett av de vanligaste naturläkemedlen i världen och används traditionellt för att öka kroppens uthållighet, motståndskraft och styrka. Ginseng är ett komplext ämne bestående av ett antal olika substanser, inklusive ginsenosider, flavonoider, vitaminer och enzymer, av vilka de steroidlika ginsenosiderna anses vara de mest aktiva beståndsdelarna. Flavonoider (som finns i till exempel frukt och grönsaker) och ginseng har genom forskning visat sig motverka bland annat hjärt-och kärlsjukdomar, diabetes, cancer och demens. Trots den omfattande användningen är dock mekanismen för hur ginseng verkar fortfarande oklar. I den här studien har vi använt pigmentinnehållande celler, melanoforer, från afrikansk klogroda för att undersöka effekterna av Panax ginseng på pigment-transport och dess maskineri. Melanoforer har förmågan att snabbt ändra färg genom samordnad förflyttning av pigmentkorn fram och tillbaka i cellen, och utgör en utmärkt modell för studier av intracellulär transport. Förflyttningen regleras av förändringar i halten av cykliskt adenosin-monofosfat (cAMP) i cellen, där en hög eller låg koncentration medför spridning av pigment över hela cellen (dispergering) eller en ansamling i mitten (aggregering), vilket resulterar i mörka respektive ljusa celler. Här visar vi att Panax ginseng, ginsenosiderna Rc och Rd samt flavonoiden quercetin stimulerar en dispergering av pigmentkornen. När melanoforerna inkuberades med en kombination av ginsenosid Rc eller Rd och quercetin, kunde en synergistisk ökning av dispergeringen ses, vilket tyder på en samverkan mellan ginsenosid- och flavonoid-delarna av ginseng. Ett protein som tidigare visats vara viktigt för pigmenttransporten är mitogen-aktiverat protein kinas (MAPK), och här visar vi att också melanoforer stimulerade med ginseng, men dock inte med ginsenosider eller quercetin, innehåller aktiverat MAPK. Genom att blockera enzymet protein kinas C (PKC) (känd aktivator av dispergering), minskade den ginseng- och ginsenosid-inducerade dispergeringen, medan aktiveringen av MAPK inte påverkades alls. Detta pekar på en roll för PKC i pigment-transporten men inte som en aktivator av MAPK.
11
Sii, Felice Karine. "Régulation par phosphorylation du facteur de transcription MafA." Paris 7, 2005. http://www.theses.fr/2005PA077081.
Full text
12
Krugmann, Sonja. "Structural and functional analysis of a novel, G protein-activated phosphoinositide 3-OH kinase." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624451.
Full text
13
Kotova, Olga. "Signaling to and from the sodium pump : effects of insulin and cardiotonic steroids /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-977-7/.
Full text
14
Machado, Aline Zamboni. "Estudo do gene MAP3K1 em pacientes portadores de distúrbios do desenvolvimento sexual 46,XY por anormalidades no desenvolvimento gonadal." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5166/tde-06062017-113840/.
Full textAbstract:
Introdução: Pearlman e colaboradores relacionou a presença de mutações ativadoras no gene MAP3K1 com o desenvolvimento testicular anormal em pacientes com disgenesia gonadal 46,XY familial, embora os estudos em camundongos tenham demonstrado que o gene Map3k1 não é essencial para a determinação testicular. No desenvolvimento gonadal masculino, a ligação do MAP3K1 à proteína RHOA promove uma fosforilação normal de p38 e ERK1/2, o que determina um bloqueio da via da beta-catenina pela MAP3K4. Já no desenvolvimento feminino, ocorre uma hiper fosforilação de p38 e ERK1/2, o que determina a ativação da via da beta-catenina e o bloqueio da via de retroalimentação positiva do SOX9 e o desenvolvimento testicular. Objetivos: Pesquisar a presença de variantes alélicas do gene MAP3K1 em pacientes portadores de distúrbios do desenvolvimento sexual (1) 46,XY por anormalidades do desenvolvimento gonadal e avaliar a repercussão funcional das variantes identificadas. Casuística e Métodos: Quarenta e sete pacientes com disgenesia gonadal 46,XY (17 com a forma completa e 29 com a forma parcial) e uma paciente com DDS 46,XY de causa etiológica não conhecida foram estudados. As regiões codificadoras do gene MAP3K1 foram amplificadas e sequenciadas pelo método de Sanger ou painel customizado de genes-alvo associados ao DDS. Estudo in vitro utilizando o método de detecção colorimétrica In-Cell ELISA com anticorpos específicos para detecção de ERK1/2 e AKT, fosforilado e não fosforilado foi realizado em fibroblastos obtidos por biópsia de pele e mantidos em cultura celular de 3 indivíduos portadores de variantes no MAP3K1. A quantificação da fosforilação de p38 e ERK por ensaio de citometria em células linfoblastóides mutadas foram realizados em amostras de 4 indivíduos portadores de variantes no MAP3K1 em estudo realizado em colaboração. Imunohistoquímica com anticorpos anti Caspase-3 foram realizadas em tecidos gonadais parafinados das pacientes portadoras de variantes alélicas nos genes MAP3K1 e FGFR2. Resultados: Vinte e uma variantes alélicas, sete das quais ainda não descritas na literatura, foram identificadas no gene MAP3K1. Quatro novas variantes alélicas exônicas e não sinônimas (p.Leu639Pro, p.Leu447Trp, p.Thr657Arg e p.Cys691Arg) foram identificadas em heterozigose; todas foram classificadas como deletérias para a proteína nos estudos de predição \"in silico\", não foram identificadas em indivíduos controles brasileiros estudados e não estão descritas nos bancos de dados populacionais. A variante p.Leu639Pro foi identificada em duas irmãs com disgenesia gonadal 46,XY portadoras da variante p.Ser453Leu no gene FGFR2 identificada previamente. A variante intrônica c.834+1G >T identificada em heterozigose foi classificada como deletéria à proteína na análise no site de predição para alteração de \"splicing\". Os ensaios colorimétricos para detecção de ERK1/2 e AKT, fosforilado e não fosforilado foram inconclusivos. Os estudos in vitro de avaliação dos níveis de fosforilação de p38 e ERK evidenciaram uma maior fosforilação nas culturas celulares mutantes para o MAP3K1 quando comparado com a linhagem celular selvagem, resultado estatisticamente significativo ( p < 0,001) e que corrobora com os dados publicados previamente. A imunohistoquímica com anticorpos anti Caspase-3 mostrou uma maior marcação em células germinativas nos tecidos gonadais das pacientes portadoras das variantes no MAP3K1 e FGFR2 do que no tecido testicular normal, porém marcações foram identificadas também em células germinativas de tecidos testiculares de indivíduos com DDS 46,XY de outras etiologias. Conclusões: Os achados sugerem fortemente a participação das mutações identificadas no MAP3K1 na etiologia dos distúrbios do desenvolvimento sexual dos pacientes estudados. Porém, uma melhor compreensão dos mecanismos de participação da via MAPK nas redes gênicas de regulação do processo de determinação testicular humano ainda é necessárioIntroduction: Pearlman et al. associated the presence of activating mutations in MAP3K1 gene with abnormal testicular development in patients with familial 46,XY gonadal dysgenesis, although studies in mice have shown that the Map3k1 gene is not essential for testicular determination. In male gonadal development, the binding of MAP3K1 to the RHOA protein promotes a normal phosphorylation of p38 and ERK1/2, and a blockade of the beta- catenin pathway is determined by MAP3K4. In the female development, hyperphosphorylation of p38 and ERK1/2 occurs. p38 and ERK1/2 hyperphosphorylated determine the activation of the beta-catenin pathway, the blockade of the positive feedback pathway of SOX9 and the testicular development. Objectives: To investigate the presence of allelic variants of the MAP3K1 gene in patients with 46,XY disorders of sex development (DSD) due to abnormalities of gonadal development and to evaluate the functional repercussion of the identified variants. Patients and Methods: Forty-seven patients with 46,XY gonadal dysgenesis (17 patients with complete form and 29 with partial form) and one patient with 46,XY DSD of unknown cause were studied. The MAP3K1 coding regions were amplified and sequenced by Sanger method or by custom panel of target genes associated with DSD. In-Cell ELISA assay with specific antibodies for the detection of phosphorylated and non-phosphorylated ERK1/2 and AKT was performed on fibroblasts obtained by skin biopsy and kept in cell culture of 3 individuals with MAP3K1 variants. Quantification of p38 and ERK phosphorylation by cytometric assay on mutated lymphoblastoid cells were performed on samples from 4 subjects with MAP3K1 variants in a collaborative study. Immunohistochemistry with anti-Caspase-3 antibodies were performed on paraffinembedded gonadal tissues of patients with MAP3K1 and FGFR2 allelic variants. Results: Twenty-one allelic variants, seven of them have not yet been described in the literature, were identified in the MAP3K1. Four novel exonic and non-synonymous allelic variants (p.Leu639Pro, p.Leu447Trp, p.Thr657Arg and p.Cys691Arg) were identified in heterozygous state; all of them were classified as deleterious in silico prediction sites; they were not identified in Brazilian control subjects and they were not described in the human genetic variation databases. The p.Leu639Pro variant was identified in two sisters with 46,XY gonadal dysgenesis carrying the previously identified FGFR2 variant (p Ser453Leu). The intronic c.834+1G > T variant identified in heterozygous state was classified as deleterious in the prediction sites. Colorimetric assays for the detection of phosphorylated and nonphosphorylated ERK1/2 and AKT were not significant. In vitro studies to evaluate p38 and ERK phosphorylation levels evidenced increased phosphorylation in the MAP3K1 mutant cells when compared to the wild type cells line; a statistically significant result (p < 0.001) that confirmed previously published data. The immunohistochemistry study with anti-Caspase-3 antibodies showed that the gonadal tissues of patients with MAP3K1 and FGFR2 variants exhibited more apoptotic germ ceIls than normal testicular tissue, but stained germ cells were also identified in the testicular tissues of the 46,XY DSD controls.Conclusions: These findings strongly suggest the participation of MAP3K1 mutations in the etiology of the testicular abnormalities of the 46,XY DSD patients of this study. However, a better understanding of the mechanisms of MAPK pathway in the gene regulatory networks of the human testicular determination process is still necessary
15
Court, Naomi Wynne. "The subcellular localisation, tissue expression, substrate specificity and binding partners of stress-activated protein kinase-3." University of Western Australia. School of Biomedical and Chemical Sciences, 2004. http://theses.library.uwa.edu.au/adt-WU2004.0084.
Full textAbstract:
[Truncated abstract] Cells need to be able to detect changes in their surrounding environment and transduce these signals into the appropriate cellular compartments. One of the major ways that the cell achieves this signal transduction is through the process of phosphorylation. Protein kinases are the enzymes responsible for catalysing this transfer of phosphate groups from ATP to amino acid residues of their specific substrates. A subfamily of serine/threonine kinases known as the Mitogen-Activated Protein Kinases (MAPKs) is essential in a diverse range of cell processes including growth, metabolism, differentiation and death. The first identified MAPKs, the Extracellular Signal-Regulated Kinases (ERKs), were found to be activated in response to mitogenic stimuli such as growth factors. However, since the discovery of the ERKs, other pathways leading to the activation of related kinases have been recognised. These kinases are preferentially activated in response to stress, and are thus termed “Stress-Activated Protein Kinases” or SAPKs. They consist of the c-Jun N-terminal kinase isoforms 1, 2 and 3 (also called SAPK1γ, SAPK1α and SAPKβ respectively) and the p38 MAPKs, p38α, p38β, p38γ and p38δ (also called SAPK2a, SAPK2b, SAPK3 and SAPK4 respectively). A major challenge in this field has been to identify the substrates and functions of the SAPKs. This has been partly achieved by the development of inhibitors for the JNK MAPKs and SAPK2a/b. However, no inhibitors currently exist that specifically inhibit SAPK3 and SAPK4. Therefore, elucidating the function of these SAPKs has proved more difficult. Recent studies suggest that SAPK3 may play a unique role in the cell compared to other members of the p38 MAPK family. For example, several signalling proteins appear to specifically activate SAPK3 in certain circumstances while not activating other members of the p38 MAPK family. In addition, SAPK3 contains a unique sequence motif that allows it to bind to specialised domains known as PDZ domains. The interaction of SAPK3 with proteins containing these domains may regulate its subcellular localisation and interactions with other proteins in the cell. This project was undertaken to expand the knowledge on the expression, localisation, substrate specificity and binding partners of SAPK3. In Chapter 3 of this thesis, a SAPK3 monoclonal antibody was evaluated for its ability to specifically recognise endogenous SAPK3 protein. SAPK3 was found to be expressed in immortalised cell lines and primary cultures of neonatal rat myocytes, and to be colocalised with the mitochondria of these cells. This co-localisation remained unaltered in response to treatment with the nuclear export inhibitor Leptomycin B, and with exposure to osmotic shock, suggesting that SAPK3 substrates may be localised at the mitochondria
16
Magne, Sandrine. "L'acide arachidonique : second messager des effets cardiaques des agonistes β2 adrénergiques." Paris 6, 2002. http://www.theses.fr/2002PA066435.
Full text
17
Chalmers, Laura Marie. "The roles of the mitogen-activated protein kinases in the electric field-induced elongation and reorientation of human umbilical vein endothelial cells." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25490.
Full text
18
Ellingson, William J. "The effects of 3-phosphoglycerate and other metabolites on the activation of AMP-activated protein kinase by LKB1/STRAD/MO25 /." Diss., CLICK HERE for online access, 2006. http://contentdm.lib.byu.edu/ETD/image/etd1406.pdf.
Full text
19
Boukhiar, Mohand-Akli. "Rôle du récepteur à l’antigène des cellules B (BCR) dans la survie des cellules du lymphome du manteau : Implication des facteurs de transcription STAT3 et EGR1." Paris 13, 2011. http://www.theses.fr/2011PA132045.
Full textAbstract:
Le lymphome à cellules du manteau (MCL) est un lymphome agressif caractérisé par une prolifération; de lymphocytes B matures CD5+ issus de la zone du manteau folliculaire des ganglions. Le MCL est défini pai' la translocation chromosomique t(11 ; 14) (q13 ; q32) qui entraine une surexpression de la cycline Dl. Cependant cette translocation ne suffit pas par elle-même pour induire la lymphomagénèse et des études récentes suggèrent un rôle de la sélection antigénique et de la signalisation du récepteur B (BCR) dans l'émergence du clone malin. Sur cette base, nous avons cherché à identifier dans des cellules primaires de patients MCL, des voies de signalisation dérégulées en aval du BCR et aboutissant à l'activation de facteurs de transcription impliqués dans les processus de survie des cellules tumorales. Nous avons tout d'abord montré que le facteur de transcription STAT3 est constitutivement phosphorylé dans les cellules de MCL et que cette phosphorylation est fortement augmentée en réponse à la stimulation du BCR. Les phosphorylations constitutive et induite par la stimulation du BCR de STAT3 sont le résultat d'une boucle autocrine de sécrétion d'IL6 et/ou d'IL10 dépendante du facteur de transcription NF-kB. L'inhibition de la voie Jak/STAT3 induit l'apoptose des cellules de MCL et supprime le signal de survie cellulaire induit par la stimulation antigénique. De plus, le traitement des cellules par le bortezomib, un inhibiteur du protéasome utilisé en clinique dans le traitement du MCL, supprime la phosphorylation de STAT3 ainsi que le signal de survie cellulaire induit par le BCR. Nous avons ensuite cherché à identifier d'autres facteurs de transcription, induits plus précocement en réponse à la stimulation du BCR et qui pourraient également être impliqués dans la dérégulation de la prolifération des cellules de MCL. Nous avons montré que la stimulation du BCR entraîne une augmentation importante et rapide (dès 30' avec maximum à 1h) du facteur de transcription EGR1 suivi de celle de c-MYC. De plus, l'inhibition spécifique de la kinase JNK constitutivement activée dans les cellules de MCL, entraîne une diminution de l'expression d'EGR1 associée à une augmentation de l'apoptose et à une inhibition du signal de survie cellulaire induit par le BCR. Par ailleurs, nous avons mis en évidence une activation constitutive des kinases de la famille Src (SFK) et plus précisément de Lyn, activation renforcée en réponse à la stimulation du BCR. Sur cette base, nous avons évalué l'efficacité du dasatinib (BMS-354825), une drogue qui cible les kinases SFK. Nous avons montré que le dasatinib à de très faibles doses (100nM) inhibe in vitro la phosphorylation constitutive et induite par le BCR de Lyn et de JNK, supprime l'expression d'EGR-1 et induit l'apoptose des cellules de patients leucémiques. En conclusion, nos résultats ont permis de mettre en évidence une dérégulation de voies de signalisation (SFK, JNK) et de facteurs de transcription (STAT3, EGR1, C-MYC) qui, de manière constitutive ou induite en réponse à la stimulation antigénique, participent au processus de prolifération et des cellules de MCL. L'ensemble de ces résultats ouvre ainsi la voie vers le développement de nouvelles stratégies thérapeutiques ciblées dans cette pathologieMantle cell lymphoma (MCL) is an aggressive and incurable malignant lymphoma, representing approximately 5% of non Hodgkin lymphomas. Its hallmark is the translocation t(11:14)q (13;32), leading to overexpression of cyclin Dl. However this chromosomal alteration is not sufficient to induce MCL and recent studies suggest the involvement of antigenic stimulation and B-cell receptor (BCR) signaling in this pathogenesis. In this context, we aimed at identifying in primary MCL cells deregulated signaling pathways downstream of BCR and leading to activation of transcription factors and to increased MCL cell survival. We evidenced a constitutive and BCR-induced phosphorylation of the transcription factor STAT3 resulting from an autocrine IL6 and/or IL10 secretion. Inhibition of the JAK/STAT3 pathway increased spontaneous apoptosis and suppressed BCR-induced cell survival. Moreover, treatment with Bortezomib induced apoptosis and a decrease of both IL6/IL10 secretions and STAT3 phosphorylation. In addition, bortezomib inhibited B-cell receptor-triggered STAT3 phosphorylation and cell survival. To further identify early genes involved in BCR-induced survival, we looked at differential expression of genes upon BCR stimulation and found that BCR engagement also led to a quick and transient induction of EGR1 expression, following by the one of c-Myc. We next evaluated the role of EGR1 in MCL cell survival and showed that inhibition of JNK by SP600125 induced a decrease of both constitutive and BCR-induced EGR1 expression, associated with an increase of apoptosis and a suppression of BCR-induced survival. We also showed that primary MCL cells displayed a constitutive and BCR-induced activation of Src family kinases including LYN and that efficient inhibition of these kinases by dasatinib led to apoptosis through inhibition of the downstream JNK/EGR1 pathway. In conclusion, our study performed on primary MCL lymphocytes evidenced that constitutive and BCRinduced signaling provide important survival signal which can be efficiently inhibited by Bortezomib and Dasatinib. Of interest, our result indicated for the first time that Dasatinib through inhibition of SFK/LYN kinases could be used as a new therapeutic agent in MCL by overcoming pro-survival signal emanating from the BCR
20
Desterke, Christophe. "Rôle du couple Flt3-ligand/Flt3 et de l'activation des "Mitogen-activated protein kinases" p38 dans la dysmégacaryopoïèse des patients atteints de myélofibrose primitive." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00652595.
Full textAbstract:
La myélofibrose primitive (MFP) est un néoplasme myéloprolifératif (NMP) chronique BCR-ABL1-négatif associant une dérégulation de l'hématopoïèse (myéloprolifération, dysmégacaryopoïèse et migration des cellules souches et progéniteurs hématopoïétiques (CSH/PH)) à une altération du stroma médullaire et splénique (fibrose ostéomyélosclérose, néoangiogenèse). Le mégacaryocyte (MK) est un acteur majeur de sa pathogenèse, via la production de cytokines et facteurs fibrosants, dans un contexte inflammatoire. Plusieurs arguments suggèrent que les mutations JAK2V617F et MPL515L/K qui caractérisent les NMP ne sont pas les événements initiaux de la MFP car elles ne sont retrouvées que chez la moitié des patients. L'objectif de mon travail a été de rechercher si d'autres anomalies, géniques ou non, pouvaient expliquer la pathogenèse de la MFP. Pour cela, parallèlement à une démarche génomique (transcriptome et CGH array), nous avons développé une approche de biologie cellulaire ciblée sur le rôle du stroma hématopoïétique. Bien que n'ayant pas identifié d'autres anomalies génomiques que celles décrites dans la littérature et en particulier, la délétion 13q, les approches génomiques que nous avons développées nous ont permis de préciser les bornes de cette délétion dans les PH CD34+ et les polynucléaires des patients. Cette délétion (région chromosomique minimale 13q14-13q21) est située à 2 mégabases (télomérique) du cluster FLT où est localisé le gène FLT3. Plusieurs arguments nous ont ensuite conduits à rechercher si le couple Flt3-ligand/Flt3 était impliqué dans la dérégulation de l'hématopoïèse et plus particulièrement dans la dysmégacaryopoïèse observée chez les patients. Parmi ceux-ci, citons : 1) l'existence d'une modulation d'expression de gènes inclus dans la zone de délétion 13q et dans le cluster FLT, dont le gène FLT3 et 2) le fait que Flt3, un récepteur clé de la régulation de l'hématopoïèse primitive, soit souvent impliqué dans la pathogenèse d'hémopathies malignes et que son ligand, Flt3-ligand, soit majoritairement produit par le stroma hématopoïétique. Notre étude montre une dérégulation de Flt3 et des MAPKs p38 dans les PH CD34+ et les MK des patients atteints de MFP et ceci, quelque soit leur statut mutationnel Jak2. Elle démontre également que la persistance de la stimulation de l'axe Flt3/p38 en réponse à une production accrue de Flt3 ligand, participe à la dysmégacaryopoïèse qui caractérise la maladie. En effet, nous avons mis en évidence : 1) une augmentation du taux sérique de Flt3 ligand et de son expression par les cellules du stroma médullaire et splénique ainsi que par les PH des patients atteints de MFP, 2) une surexpression spécifique de son récepteur Flt3 et de sa phosphorylation dans les CSH/PH CD34+ et les progéniteurs mégacaryocytaires (MK), qui persistent au cours de la différenciation MK, quelque soit le statut mutationnel de Jak2 des patients, 3) une activation de Flt3 dans les progéniteurs MK en réponse au Flt3 ligand conduisant à la phosphorylation en cascade de la voie de signalisation des MAPKs p38 et à l'expression de ses gènes cibles tels que AP-1, p53, NFATc4, ATF2, IL-8, 4) une restauration de la mégacaryopoïèse et une inhibition de la migration (Flt3-ligand)-dépendante des progéniteurs MK des patients après inhibition de Flt3 ou de p38.Nos résultats confirment l'importance d'une altération des MAPKs dans une dérégulation de l'hématopoïèse et soulignent le rôle d'une activation persistante de la voie p38, via le couple Flt3-ligand/Flt3, dans la dysmégacaryopoïèse qui caractérise la myélofibrose primitive. Ils suggèrent également que cette dérégulation participe au processus inflammatoire à l'origine de la réaction stromale et " lit " d'une transformation leucémique potentielle. Ce dialogue altéré entre les cellules hématopoïétiques pathologiques (Bad seeds), en particulier mégacaryocytaires et les cellules stromales (Bad soil), conforte notre concept " Bad seeds in Bad soil ". Ce travail pourrait contribuer à l'amélioration de ce dialogue par des approches thérapeutiques ciblées sur l'axe Flt3-ligand/Flt3 médié par l'activation de p38 qui, en réduisant le processus inflammatoire, rétablirait un lien entre le " Seed " et le " Soil ".
21
Whitrow, Helen Rachel. "Expression of amp-activated protein kinase and investigation of the role of the gamma 3 subunit in muscle." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412643.
Full text
22
Edlund, Sofia. "Mechanisms for TGF-β-Mediated Regulation of the Actin Filament System and Apoptosis." Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3378.
Full textAbstract:
Transforming growth factor-β (TGF-β) is a member of a large superfamily of cytokines which participate in many different types of cellular processes, such as growth inhibition, cell migration, differentiation, cell adhesion, wound healing and immunosuppression. Alterations of TGF-β superfamily signalling results in several different disorders, including bone disease, vascular disease and cancer. The TGF-β signalling pathways involve several different proteins, such as the Smad proteins, which upon receptor activation are translocated to the nucleus, where they affect transcriptional responses.
The actin cytoskeleton is an organised network of filaments with a highly dynamic structure, which is under a continuous reconstruction to control the morphology, survival, growth and motility of eukaryotic cells. The members of the family of small GTP-binding proteins have been shown to be important regulators of the actin cytoskeleton.
TGF-β was found to induce short term as well as long term actin reorganisation in prostate cancer cells. The short term response included membrane ruffling, and required signalling by the small GTPases Cdc42 and Rho as well as, the involvement of the mitogen-activated protein kinases p38 (p38 MAPK). The long term response included formation of stress fibers and required a cooperation between Smad and Rho GTPase signalling pathways involving the Rho-associated coiled-coil-containing protein kinase 1 (ROCK1).
The TGF-β-induced activation of Cdc42 was, furthermore, shown to require the inhibitory Smad7 and p38 MAP kinase, via a PI3K-dependent pathway. Mixed lineage kinase 3 (MLK3), a mediator downstream of Cdc42, was necessary for the Cdc42-dependent actin filament reorganisation.
Apoptosis is an important and carefully regulated process in human development and disease, which allows the multicellular organisms to remove cells that are in excess or potentially dangerous. TGF-β family members can induce apoptosis in many different cell types, in the presence or absence of other growth factors. Smad7 had previously been shown to be necessary for TGF-β-induced apoptosis of epithelial cells. We could show that Smad7 is required for TGF-β-induced activation of the TGF-β activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK pathway, which subsequently leads to apoptosis in prostate cancer cells.
Members of the lymphoid enhancer factor-1/T-cell factor (LEF1/TCF) family of transcription factors have, together with β-catenin, been shown to be nuclear effectors in the Wnt-signalling pathway. We investigated a possible cross-talk between the TGF-β and Wnt signalling pathways. We found that TGF-β, in a Smad7-dependent manner induced a nuclear accumulation of β-catenin and enhanced the transcriptional activity of β-catenin and the induction of the downstream target gene c-myc. Since β-catenin and c-Myc has been shown to promote apoptosis, our results suggests the possibility that β-catenin contributes to TGF-β-induced apoptosis
23
Villedieu, Marie. "Etude de l'implication des voies de signalisation dans la chimiorésistance des cancers de l'ovaire et développement de stratégies chimio-sensibilisatrices." Caen, 2005. http://www.theses.fr/2005CAEN4063.
Full text
24
Ellingson, William John. "The Effects of 3-Phosphoglycerate and Other Metabolites on the Activation of AMP-Activated Protein Kinase by LKB1/STRAD/MO25." BYU ScholarsArchive, 2006. https://scholarsarchive.byu.edu/etd/485.
Full textAbstract:
Skeletal muscle contraction results in the phosphorylation and activation of the AMP-activated protein kinase (AMPK) by an upstream kinase, AMPKK. The LKB1-STRAD-MO25 complex is the major AMPKK in skeletal muscle; however, LKB1-STRAD-MO25 activity is not increased by muscle contraction. This relationship suggests that phosphorylation of AMPK by LKB1-STRAD-MO25 during skeletal muscle contraction may be regulated by allosteric mechanisms. In this study we tested an array of metabolites including glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), fructose 1,6-bisphosphate (F1,6-P2), 3-phosphoglycerate (3PG), glucose-1-phosphate (G1P), glucose-1,6-bisphosphate (G1,6-P2), adenosine diphosphate (ADP), carnitine (Carn), acetyl-carnitine (Acarn), inosine monophosphate (IMP), inosine, and ammonia for allosteric regulation. We found that 3PG stimulated LKB1-STRAD-MO25 activity and allowed for increased AMPK phosphorylation. 3PG did not stimulate LKB1-STRAD-MO25 activity toward the peptide substrate LKB1tide. These results have identified 3PG as an AMPK-specific regulator of AMPK phosphorylation and activation by LKB1-STRAD-MO25.
25
Streicher, John Michael. "The role of mitogen activated protein kinase activated protein kinase-2 in regulating p38 mitogen activated protein kinase induced cyclooxygenase-2 induction and heart failure." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1872200951&sid=6&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Full text
26
Davies, Gareth. "Folding of p38 mitogen-activated protein kinase." Thesis, University of Warwick, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412847.
Full text
27
Le, May Nicolas. "Mécanismes de pathogenèse de la protéine non structurale NSs du virus de la Fièvre de la Vallée du Rift." Paris 7, 2005. http://www.theses.fr/2005PA077205.
Full textAbstract:
Le virus de la fièvre de la Vallée du Rift (RVFV) est un arbovirus appartenant à la famille des Bunyaviridae et au genre Phlebovirus. Il est transmis par les moustiques et infecte l'homme et les ruminants. De graves épidémies/épizooties ont eu lieu en Afrique et le virus circule maintenant en Arabie Saoudite ainsi qu'au Yémen. Le génome viral est composé de trois segments d'ARN simple brin: les segments L. M sont de polarité négative et le segment S utilise une stratégie ambisens. Bien que le cycle viral ait heu dans le cytoplasme, la protéine NSs (256 acides aminés, 31 kDa), codée par le segment S, a une localisation nucléaire où elle forme des filaments. NSs est un facteur de pathogenèse du virus qui inhibe la synthèse des ARNm du gène codant pour l'IFN bêta sans perturber pour autant l'enhanceosome (NF-KB, IRF3 et ATF2/cjun). Pour comprendre les mécanismes par lesquels NSs inhibe la réponse anti-virale, nous avons recherché ses partenaires cellulaires. Nous avons montré que l'infection par le VFVR a pour conséquences : i) une rapide diminution de la synthèse des ARN cellulaires parallèle à la décroissance de la concentration du facteur de transcription TFIIH, ii) l'inhibition du recrutement de CBP et de l'acétylation des histones au niveau du promoteur IFNp et iii) la protéolyse de STAT1. Par les techniques du double hybride, d'immunoprécipitations de protéines ou de la chromatine et en microscopie confocale, nous avons démontré que chacun des événements est lié aux interactions de la protéine NSs avec respectivement - la sous unité p44 du TFIIH, la sous unité SAP30 de certains co-répresseurs dont Sin3 et N-coR et la protéine Socs 1 présente dans une E3 ligase : ces différents partenaires de NSs sont présents dans les filaments nucléaires. NSs en interagissant avec p44 empêche la néo-formation du TFIIH. NSs, via SAP30 et son association avec le facteur de transcription YY1, stabilise des co-répresseurs responsables de la déacétylation des histones et empêche l'interaction entre CBP et YY1 au niveau du promoteur IFNp. Enfin NSs provoque l'accumulation de Socs 1 qui recrute un complexe E3 ligase CBCSo' responsable de la dégradation de STAT1 inhibant l'induction par l'IFNy. Ainsi la protéine multifonctionnelle NSs inhibe par trois mécanismes indépendants la réponse anti-virale de l'hôteThe Rift Valley fever virus is a phlebovirus of the Bunyaviridae family transmitted by mosquitoes and affecting cattle, sheep, goats and humans. It causes many dramatic epidémies and epizootics in Africa and recently it was introduced in Yemen and in Saudi Arabia with a high mortality rate. The viral genome is composed of three segments of RNA: the L and M segments are of negative polarity and encode respectively for the RNA polymerase RNA dependent and the precursor of envelope glycoproteins. The S segment utilises an ambisense strategy and codes for the nucleoprotein N and the non structural protein NSs. Although the viral cycle is cytoplasmic, the NSs protein (256 amino acids, 31 kDa) is nuclear and forms filament. Moreover, it was shown that NSs is the major pathogenicity factor, inhibiting IFN beta messenger RNA synthesis but do not disturb the formation of the enhanceosome (NF-KB, IRF3 and ATF2/cjun). We found that infection by RVFV leads to i) a rapid and drastic suppression of host cellular RNA synthesis that parallels a decrease of the TFIIH transcription factor concentration, ii) an inhibition of CBP recruitment and histones acetylation on IFNp promoter and iii) STAT1 proteolysis. Using yeast two hybrid System, immunoprecipitations, Chips and confocal microscopy, we further demonstrated that each event is linked to the association of the nonstructural viral NSs protein with respectively the TFIIH subunit p44, co-repressors subunit SAP30 and Socs 1 in the nuclear filaments. NSs prevents the assembly of newly synthesized TFIIH subunits. NSs, through the interaction between SAP30 and YY1 transcription factor, stabilizes co-repressors like N-coR or Sin3 responsible of histones deacetylation on IFNp promoter and preventing the association between CBP and YY1. Finally NSs provokes Socs 1 accumulation and, through a Socs 1 containing-E3 ligase complex, it degrades STAT1 and inhibes induction by IFNy. These observations shed light on the mechanisms utilized by RVFV to evade the host response
28
Zeng, Qingning. "Dissecting mitogen-activated protein kinase cascades involving arabidopsis MKK6." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/31941.
Full textAbstract:
Mitogen-activated protein (MAP) kinase cascades act as critical components in the signalling pathways of all eukaryotic cells. They play a pivotal role in the transduction of extra- and intra-cellular stimuli and regulate cell growth, proliferation, differentiation and cell death, through sequential activation of MAP kinase kinase kinases (MAPKKKs), MAP kinase kinases (MKKs), and MAP kinases (MPKs). These three components form modules that control the phosphorylation of various substrates including transcription factors, enzymes, and cytoskeleton-associated proteins. In the Arabidopsis genome, over 60 MAPKKKs (AtMKKK), 10 MAPKKs (AtMKK), and 20 MAPKs (AtMPK) have been identified. The smaller number of AtMKKs suggests that diverse signals may converge and be integrated at the level of AtMKK. Among the ten AtMKKs, MKK6 has been proposed to play a role in regulating cytokinesis. However, little is known about the hierarchal phosphorylation system containing MKK6.
In this Ph.D. project, I aimed to dissect the MAP kinase cascades involving MKK6 in Arabidopsis. I investigated potential targets of MKK6. Four MAP kinases were identified to interact with, and be phosphorylated by, MKK6, namely, MPK4, MPK6, MPK11, and MPK13. Among them, MPK13 is developmentally co-expressed with MKK6, and both MPK13 and MKK6 display high Promoter::GUS activity at the primary root tips and at the lateral root primordia. Partial suppression of either MKK6 or MPK13 expression significantly reduces the number of lateral roots in the transgenic lines, suggesting that the MKK6-MPK13 module positively regulates lateral root formation.
Loss-of-function mutants of another potential target of MKK6, MPK4, are severely affected. In mpk4 mutant plants, anthers can develop normal microspore mother cells (MMCs) and peripheral supporting tissues, but the MMCs fail to complete meiotic cytokinesis, a phenotype reminiscent of those observed in both atnack2/tes/stud and anq1/mkk6 mutants. Biochemical analysis defines a putative signalling module linking AtNACK2/TES/STUD with ANP3, MKK6 and MPK4, suggesting a model in which the AtNACK2-ANP3-MKK6-MPK4 cascade specifically facilitates male meiotic cytokinesis in Arabidopsis.
In summary, my PhD work has expanded our understanding of the diversity of MAP kinase cascades. Different MPKs can act as downstream targets of the same MKK with tight spatial and temporal regulation during plant development.
29
Laurent, Anouchka. "Caracterisation et modélisation des pathologies lymphoides présentant des gains du chromosome 21." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7061.
Full textAbstract:
Les gains somatiques du chromosome 21 (+21) sont fréquemment observés dans les hémopathies, et les enfants atteints par le Syndrome de Down (DS, trisomie 21 constitutive) ont un risque plus élevé de développer des leucémies durant l’enfance. Ces observations indiquent que +21 participent au développement leucémique. Cependant, la trisomie 21 seule n’est pas suffisante. L'objectif de cette thèse a été de caractériser et modéliser les altérations génétiques coopérant avec les gains du chromosome 21. Un premier axe a permis d’étudier l’impact de la mutation activatrice JAK3A572V dans un modèle murin (knock-in au locus endogène) dans le développement d’un lymphome cutané à cellules T (CTCL). Croisé avec un modèle de trisomie 21 partiel (Ts1Rhr), la latence de ce CTCL est fortement réduite, indiquant une coopération oncogénique. Dans un deuxième axe, j'ai identifié une forte incidence des altérations activant de la voie RAS/MAPK dans les leucémies aiguës lymphoblastiques B pédiatriques (LAL-B) +21. J'ai démontré que la mutation KRASG12D coopère fonctionnellement avec la trisomie 21 dans le processus de transformation à la fois dans des modèles cellulaires murins et des cellules leucémiques humaines. J’ai également développé 20 modèles de xénogreffes pour tester l’efficacité du trametinib, un inhibiteur de la voie RAS/MAPK. Seul ou en combinaison avec des chimiothérapies conventionnelles (vincristine), j’ai montré que l’inhibition de la voie RAS/MAPK prolonge la survie de ces souris. Ces données indiquent que la caractérisation et le ciblage d’événements de coopération permettent de proposer de nouvelles stratégies thérapeutiques pour les leucémies pédiatriques avec +21Somatic gains of chromosome 21 (+21) are hallmark of hematological malignancies, and children with Down Syndrome (DS, constitutive trisomy 21) are predisposed to develop leukemia. These observations strongly suggest that gains of chromosome 21 promote leukemia development; however, alone, it is not sufficient. The aim of my PhD work was to identify and functionally characterize the genetic alterations cooperating with +21. My first aim was focused on studying the impact of the JAK3A572V activating mutation in the development of cutaneous T cell lymphoma (CTCL), using a new knock-in model carrying this alteration at the endogenous locus. In this study, I showed that partial trisomy 21 (Ts1Rhr) cooperates with the JAK3A572V mutation to reduce the latency of this pathology, thus highlighting a mechanism of oncogenic cooperation. In a second aim, I identified a high incidence of genetic alterations leading to RAS/MAPK pathway activation in B cell leukemia samples carrying +21 (B-ALL+21). I have demonstrated that the KRASG12D mutation functionally cooperates with trisomy 21 in transformation process of both murine and human cellular models. In order to test new molecules to improve the treatment of LAL-B+21, I have also developed 20 xenograft models. Treatment of these models with trametinib, a RAS/MAPK pathway inhibitor, alone or in combination with conventional chemotherapies (vincristine), improve their survival. Together, these data indicate that characterizing and targeting cooperation events allow to propose novel therapeutic strategies in pediatric leukaemia with +21
30
Harrouk, Wafa. "Mitogen-activated protein kinase during oocyte growth in the mouse." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55499.
Full textAbstract:
In this study, the role of MAP kinase in the acquisition of meiotic competence in growing oocytes was investigated. The results presented in this thesis show that two species of MAP kinase, p42 and p44, are present in their unphosphorylated forms in oocytes as early as 5 days of age. At this age, oocytes are small and have not acquired the capacity to resume meiosis. They are referred to as meiotically incompetent. MAP kinase continues to be present throughout the growth phase and up to the acquisition of meiotic competence.In growing mouse oocytes, a group of partially competent oocytes are abundant. Such oocytes arrest at metaphase I where they assemble a morphologically normal spindle. Immunoblotting results of partially competent oocytes show that MAP kinase is present and becomes phosphorylated following culture as is indicated by the retarded mobility on the SDS gels.
Okadaic acid, an inhibitor of protein phospharases 1 and 2A, induces incompetent oocytes to enter metaphase. These oocytes contain the slow migrating phosphorylated forms of p42 and p44, indicating that okadaic acid causes the phosphorylation of MAP kinase. A time course study shows that the okadaic acid-induced phosphorylation of MAP kinase occurs coincidentally with entry into metaphase in incompetent oocytes. In fully competent oocytes, this phosphorylation occurs after entry into metaphase. In addition, these oocytes do not assemble a spindle, indicating that phosphorylation of MAP kinase, although it may be necessary, is not a sufficient event to induce spindle formation.
31
Sakurai, Kenji. "Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis." Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/245835.
Full textAbstract:
京都大学0048
新制・課程博士
博士(医学)
甲第22150号
医博第4541号
新制||医||1039(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授 竹内 理, 教授 稲垣 暢也, 教授 杉田 昌彦
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
32
Valls, Jimena Paola Hochmann. "Análise do impacto das proteínas E6/E7 de diferentes variantes moleculares de HPV-16 sobre as vias de transdução de sinal mediadas por MAPK." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-21092016-084921/.
Full textAbstract:
A infecção persistente por HPV-16 está fortemente associada ao risco de desenvolvimento de neoplasias do colo do útero, vagina, vulva, pênis, canal anal e orofaringe. O estudo detalhado da variabilidade nucleotídica intra-típica de HPV-16 resultou em importantes achados no que concerne à filogenia e evolução viral, e à história natural das infecções. Variantes Asiático-Americanas (AA) e E-350G de HPV-16 foram associadas com maior risco de persistência da infecção viral e desenvolvimento de câncer de colo de útero quando comparadas à variante Européia protótipo (E-P ou E-350T), embora esta ainda apresente alto risco quando comparada aos outros tipos virais. Mais recentemente, diferenças funcionais entre as proteínas E6/E7 das distintas variantes moleculares de HPV- 16 estão sendo descritas, a fim de explicar as diferenças nas associações epidemiológicas observadas. Dados do nosso grupo apontaram para a transcrição aumentada do gene MEK2 especificamente em queratinócitos humanos primários (PHKs) transduzidos com E6/E7 da variante E-350G. Pelo exposto, objetivou-se: (1) Analisar os níveis de ativação de proteínas efetoras das vias de transdução de sinal mediadas por MAPK e PI3K/AKT em queratinócitos imortalizados por E6/E7 de três variantes moleculares de HPV-16 (AA, E-P, E-350G); (2) Analisar os efeitos das proteínas E6/E7 dessas variantes sob as vias de MAPK quanto à indução de fatores de transcrição; (3) Analisar o potencial transformante de PHKs imortalizados pelas diferentes variantes, e em cooperação com a proteína celular c-MYC; (4) Analisar o potencial de migração e invasão em PHKs imortalizados pelas diferentes variantes de HPV-16, e em cooperação com a proteína celular c-MYC. Neste estudo observou-se que a variante AA de HPV-16 induziu a maior ativação das vias de sinalização estudadas (MAPK, e PI3K/AKT). Ademais, PHKs imortalizados por esta variante apresentaram maior capacidade de migração, de invasão através de uma matriz de colágeno, além de maior potencial transformante. Adicionalmente, as células imortalizadas pela variante AA apresentaram maior expressão da proteína mesenquimal vimentina e diminuição dos níveis da proteína epitelial E-caderina, sugerindo ativação parcial de Transição Epitélio Mesênquima (EMT) nestes queratinócitos. Ademais, quando o oncogene c-MYC foi co-transduzido nas diferentes linhagens infectadas por E6/E7 de HPV-16, foi observado que em PHKs imortalizados pela variante AA também houve maior ativação da via de MAPK-ERK, maior migração, e um potencial transformante semelhante, em relação às células co-transduzidas pela variante E-350G e c-MYC. Em conjunto, estes dados sugerem que a variante AA de HPV-16 possui vantagem seletiva sob as outras variantes em promover transformação celular, migração e invasão, e isto poderia explicar, ao menos em parte, a maior prevalência desta variante no câncer cervical. Os resultados gerados neste estudo são de extrema relevância para avaliar o impacto da variabilidade intra-típica de HPV-16 sobre o potencial oncogênico observado em estudos epidemiológicosPersistent infection with HPV-16 is strongly associated with risk of developing neoplasia in the uterine cervix, vagina, vulva, penis, anal canal and oropharynx. The detailed study of HPV-16 intra-typical nucleotide variability resulted in important findings regarding phylogeny and viral evolution, and the natural history of infections. Asian-American (AA) and E-350G variants of HPV-16 were associated with increased risk of persistent viral infection and development of cervical cancer compared to the European prototype (E-P or E-350T), although this variant still presents higher risk when compared to other viral types. More recently, functional differences between the E6/E7 proteins of distinct molecular variants of HPV-16 are being described, in order to explain the differences in the epidemiological associations observed. Data from our group pointed to increased transcription of the MEK2 gene specifically in primary human keratinocytes (PHKs) transducing E6/E7 of the E-350G variant. Consequently, the aims of this study were: 1) To examine the activation levels of effector proteins of the signal transduction pathways mediated by MAPK and PI3K/AKT in PHKs immortalized by E6/E7 of three different molecular variants of HPV-16 (AA, E-P, E-350G); (2) To analyze the effects of E6/E7 of different molecular variants of HPV-16 upon MAPK pathways concerning the induction of transcription factors; (3) To analyze the transforming potential of PHKs immortalized by different molecular variants of HPV-16, and in cooperation with the cellular protein c- MYC; (4) To analyze the potential of migration and invasion in PHKs immortalized by different molecular variants of HPV-16, and in cooperation with the cellular protein c- MYC. In this study we observed that the AA variant of HPV-16 induced higher activation of both signaling pathways studied (MAPK, and PI3K/AKT). Furthermore, this variant presented increased migration capacity, higher invasion through a collagen matrix, and greater transforming potential. Moreover, cells immortalized by the AA variant showed higher expression of the mesenchymal protein vimentin and a decrease of the epithelial protein E-cadherin, suggesting partial activation of Epithelial Mesenchymal Transition (EMT). In addition, when the c-MYC oncogene was co-transduced in the different cells lines infected with HPV-16 E6/E7, we observed that in PHKs immortalized by the AA variant there was also an enhanced activation of the MAPK-ERK pathway, a higher ability to migrate, and similar transformation potential in comparison with cells co-transduced with the E-350G variant and c-MYC. Taken together, this data suggest that the AA molecular variant of the HPV-16 has a selective advantage over the other variants to promote cell transformation, migration and invasion, and this could partly explain the higher prevalence of this variant in cervical cancer. The results generated in this study are very important to assess the impact of intra-typical variability of HPV-16 on the oncogenic potential observed in epidemiological studies
33
Fappi, Alan. "Efeitos de diferentes glicocorticoides sobre as vias moleculares de regulação do trofismo muscular em ratos e o efeito do EPA/DHA na atrofia muscular induzida pela dexametasona." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-14082018-103310/.
Full textAbstract:
Várias condições podem estar relacionadas com a atrofia muscular, tais como inatividade, envelhecimento, septicemia, diabetes, câncer e uso de glicocorticoides. Em tentativa prévia de prevenir tal condição catabólica secundário ao uso de glicocorticoide, através da suplementação de ômega-3 (N-3), observamos um agravamento da atrofia muscular, afetando mais tipos de fibras musculares, usualmente poupadas pelo glicocorticoide, fibras tipo 1 por exemplo. Entretanto, não foi possível determinar quais as propriedades dessa interação. Portanto, o objetivo deste estudo foi de avaliar a ação do Ômega-3 associada a dexametasona e de diferentes glicocorticoides em dose equipotente sobre o peso corporal; área de secção transversa muscular; perfil de ácidos graxos; expressão gênica de fatores de transcrição musculares e atrogenes (Atrogina 1 e MuRF-1); expressão proteica de componentes das vias do IGF-1/Akt/mTOR, Ras/Raf/MEK/ERK e Miostatina/Smad2/3; e expressão de receptores de glicocorticoides na musculatura esquelética de ratos. Metodologia: Ratos Wistar suplementados ou não com ômega-3 (100mg/kg/dia de EPA) por 40 dias receberam dexametasona (DX) subcutânea (2,5 e 1,25mg/kg/dia) nos últimos 10 dias de suplementação. Para estudo dos demais glicocorticoides, ratos sem suplementação receberam deflazacorte (DC), metilprednisolona (MP) em dose/volume equipotente ao de dexametasona (DC 10 e 20mg/kg/dia e MP6,7 e 13,3mg/kg/dia) por 10 dias. Constituindo 10 grupos: CT, N-3, DX1,25, DX2,5, DX1,25+N-3, DX2,5+N-3, MP6, MP13, DC10 e DC20. Através de estudo histológico, imuno-histoquímico, PCR em tempo real e Western blotting, foram avaliados a área transversa dos diferentes tipos de fibras musculares; a expressão de receptor de glicocorticoide na fibra muscular; a expressão gênica dos atrogenes e fatores de transcrição; expressão de proteínas das vias IGF-1, Miostatina e MEK/ERK. Resultados: A administração de N-3 influenciou a atrofia por DX causando maior atrofia em fibras do tipo 1 e 2A, aumento na expressão proteica de FoxO3a total, P-Smad3, LC3-II e gênica (mRNA) de REDD-1, Atrogina-1/MAFbx. De forma isolada o ômega-3 reduziu a expressão de P-FoxO3a, PGC1alfa, a quantidade de ácido araquidônico e a expressão de mRNA do IRS-1 com aumento na expressão de LC3-II. A comparação entre glicocorticoides mostrou que a MP (13mg/kg/dia) acarretou maior impacto no peso corporal e muscular; o DC (10mg/kg/dia) causou menor atrofia em fibras 2B em relação aos demais glicocorticoides. A DX causou maior impacto sobre o Akt total em comparação com os demais glicocorticoides, em P-Akt o grupo DX1,25 teve menor expressão em relação a outros glicocorticoides em dose equipotente. Todos os glicocorticoides afetaram a expressão de P-FOXO3a. Na expressão de ERK1/2 e P-ERK1/2, MP6 foi o grupo com maior prejuízo à fosforilação em relação aos demais em dose equipotente. Já na avaliação da via Miostatina/Smad2/3 os grupos MP 6, MP13 e DC20 mostraram maior expressão de Smad2/3 total e P-Smad3. A expressão gênica de REDD-1 e MYOD foi aumentada nos grupos MP6 e MP13 em relação aos demais grupos; REDD2 no grupo DC20 foi menor em relação ao grupo DX2,5. A expressão de Miostatina foi menor nos grupos DX2,5 e DC20, sendo o DC a droga com menor impacto sobre os atrogenes MuRF-1 e Atrogina-1. DX1,25 e DX2,5 causaram menor expressão de IRS-1 entre os grupos de glicocorticoides. Conclusões: Ômega-3 pode aumentar a atrofia muscular causada por DX em fibras 1 e 2A, possivelmente relacionado com aumento da expressão de FoxO3a, REDD-1 e Atrogina-1, diminuição na expressão de PGC1alfa e P-FoxO3a, nas quantidades de ácido araquidônico com aumento da atividade lisossomal. Comparando diferentes glicocorticoides, a MP tende a produzir maior impacto nos pesos corporal e muscular, o DC é menos prejudicial as fibras do tipo 2B, entretanto, afeta predominantemente fibras do tipo 1, da mesma forma que a DX na dosagem de 1,25mg/kg/dia. A DX tende a afetar mais a expressão de Akt total e fosforilado que os demais glicocorticoides. A MP afeta mais a via Ras/Raf/MEK/ERK e expressão de REDD-1 em relação aos demais glicocorticoides, e o DC e MP mostram maior expressão de Smad2/3 total e fosforilada em relação ao DX após 10 dias de administraçãoSeveral conditions may be related to muscle atrophy, such as inactivity, aging, septicemia, diabetes, cancer and use of glucocorticoids. In a previous attempt to prevent such glucocorticoid catabolic condition, through the supplementation of omega-3 (N-3), we observed a worsening of muscular atrophy, affecting more types of muscle fibers, usually spared by glucocorticoid, type 1 fibers for example. However, it was not possible to determine the properties of this interaction. Therefore, the objective of this study was to evaluate the action of omega-3 associated with dexamethasone and different glucocorticoids in equipotent dose on body weight; muscle cross-sectional area; fatty acid profile; gene expression of muscle transcription factors and atrogenes (Atrogin-1 and MuRF-1); protein expression of IGF-1/Akt/mTOR, Ras/Raf/MEK/ERK and Myostatin/Smad2/3 pathways components; and expression of glucocorticoid receptors in the skeletal musculature of rats. Methods: Wistar rats given orally or not with omega-3 (100mg/kg/day of EPA) for 40 days received subcutaneous dexamethasone (DX) (2.5 or 1.25mg/kg/day) during the last 10 days of supplementation. For the other glucocorticoids, rats without supplementation received deflazacorte (DC) or methylprednisolone (MP) in dose/volume equivalent to that of dexamethasone (DC 10 or 20mg/kg/day and MP6.7 or 13.3mg/kg/day) for 10 days. Comprising 10 groups: CT, N-3, DX1.25, DX2.5, DX1.25 + N-3, DX2.5 + N-3, MP6, MP13, DC10 and DC20. Through histological, immunohistochemical, real-time PCR and Western blotting, we evaluated the transverse area of the different muscle fibers; the expression of glucocorticoid receptor; the gene expression of atrogenes and transcription factors; protein expression of the IGF-1, Myostatin and MEK/ERK pathways. Results: N-3 administration influenced DEXA atrophy causing increased atrophy in type 1 and 2A fibers, increased protein expression of total FoxO3a, P-Smad3, LC3-II, and REDD-1 gene (mRNA), Atrogin-1/MAFbx isolated omega-3 reduced the expression of P-FoxO3a, PGC1alpha, the amount of arachidonic acid and the expression of IRS-1 mRNA with increased expression of LC3-II. The comparison between glucocorticoids showed that MP13 had a greater impact on body and muscle weight; the DC10 caused less atrophy in 2B fibers in relation to the other glucocorticoids. DX, caused greater impact on total Akt compared to the other glucocorticoids, in P-Akt the DX1,25 group had lower expression to other equipotent dose glucocorticoids. All glucocorticoids affect the expression of P-FOXO3a. In the of ERK1/2 and P-ERK1/2 protein expression, the MP6 was the group with the greatest damage to the phosphorylation in relation to the others in equipotent dose. In the evaluation of the Myostatin/Smad2/3 pathway MP 6, MP13 and DC20 showed higher expression of total Smad2/3 and P-Smad3. The gene expression of REDD-1 and MYOD was increased in the MP6 and MP13 groups compared to the other groups, REDD2 in the DC20 group was lower in relation to the DX2.5 group. Myostatin expression was lower in the DX2.5 and DC20 groups, with DC being the drug with less impact on atrogenes MuRF-1 and Atrogin-1. DX1.25 and DX2.5 caused lower IRS-1 expression among the glucocorticoid groups. Conclusions: Omega-3 may increase muscle atrophy caused by DX in fibers 1 and 2A, possibly related to increased expression of FoxO3a, REDD-1 and Atrogin-1, decreased expression of PGC1alpha and P-FoxO3a, in the amounts of acid arachidonic with increased lysosomal activity. Comparing different glucocorticoids, MP tends to produce a greater impact on body and muscular weights, DC is less harmful to type 2B fibers, however, it predominantly affects type 1 fibers, in the same way as DX in the dosage of 1.25mg/kg/day. DX tends to affect total and phosphorylated Akt expression more than other glucocorticoids. MP affects more the Ras/Raf/MEK/ERK pathway and REDD-1 expression in relation to the other glucocorticoids, and DC and MP show a higher expression of total and phosphorylated Smad2/3 compared to DX after 10 days of administration
34
Burt, Andrew Robert. "Regulation of p42/44 mitogen-activated protein kinase by G-protein coupled receptors." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360176.
Full text
35
Walia, Ankit. "Involvement of mitogen-activated protein kinase signalling in plant microtubule function." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/21739.
Full textAbstract:
Plants have developed sophisticated signalling networks that are involved in mediating
developmental transitions and environmental signals. Mitogen-activated protein kinases (MPKs)
are a class of signalling proteins that are involved in cellular processes that help plants to detect and initiate appropriate responses to numerous development and environmental inputs. The
microtubule cytoskeleton plays a pivotal role in plant development and morphogenesis, although
the mechanisms that regulate the microtubule-associated proteins and microtubule functions in
plant cells are not well understood. I investigated whether perturbations in the microtubule organization triggered by the MICROTUBULE ORGANIZATION] temperature-sensitive mutant(morl-l) could lead to altered transcriptional activity, with a particular interest in the genes
encoding signal transduction components. I showed that perturbations in the microtubule
cytoskeleton, achieved through the microtubule disruption phenotype of mor1-1, led to changes
in the expression of gene transcripts associated with diverse cellular processes, including
changes in the expression of the PROPYZAMIDE HYPERSENSITIVE 1(PHS1) gene, a member
of MPK-specific signal transduction pathway, which has been previously implicated in
mediating cortical microtubule functions in plant cells. Through biochemical, cell biological and
genetic tools, I identified MPK18 as one of the MPKs that interacts with the PHS1 phosphatase
and demonstrated through reverse genetics analysis that manipulation of MPK18 results in
conditional and subtle defects in the microtubule functionality. In contrast, analysis of MPK12,
which was shown to also interact with PHS1, identified no microtubule-specific function. My
live cell imaging studies revealed that the absence of MPK18 protein appears to have no effect
on microtubule plus end growth and shrinkage rates, indicating that MPK18 indirectly influences
microtubule functions. Based on the genetic analysis, MOR1 itself does not appear to be a target of the putative MPK18 signalling module. Preliminary attempts to obtain evidence for direct
impacts of PHS activity on MOR1 failed to demonstrate that manipulation of PHS1 altered
either subcellular localization or phosphorylation status of the MOR1 protein. These results
provide a platform that should facilitate future investigations aimed at understanding the role of
MPK signalling in the regulation of plant microtubule functions.
36
Hobbs, Robin Mark. "A role for mitogen-activated protein kinase inepidermal hyperproliferation in inflammation." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399536.
Full text
37
Waskiewicz, Andrew Jan. "Mitogen-activated protein kinase : evolutionary conservation and activation of downstream kinases /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/9216.
Full text
38
Sarafraz, Shekary Negin. "Contribution of p38 mitogen-activated protein kinase isotypes to cardiac physiology." Thesis, King's College London (University of London), 2010. http://kclpure.kcl.ac.uk/portal/en/theses/contribution-of-p38-mitogen-activated-protein-kinase-isotypes-to-cardiac-physiology(9976a51e-2703-4ead-8746-a1bbc3a56326).html.
Full textAbstract:
The isoform-specific functions of the four isoforms of p38 mitogen-activated protein kinase (p38 α-, β-, γ- and δ- MAPK) in the adult heart are largely unknown, partly due to the lack of isotype-specific tools to manipulate or measure p38 MAPK isoform activity. Improved understanding of p38 MAPK isoform regulation will benefit development of selective pharmacological inhibitors and move towards eliminating the potential drawbacks of chronic systematic inhibition of this important kinase. This Thesis describes our investigation of endogenous expression of p38 MAPK in the murine heart; the functional contributions of endogenously expressed p38 MAPK in response to clinically-relevant stimuli such as such as pharmacological preconditioning, ischaemia and reperfusion, and pro- inflammatory cytokines (central in the progression of heart failure, such as TNF-α, IL-1) and osmotic stress; and the involvement of p38 and MAPK isoforms in left ventricular (LV) remodelling in response to in vivo models of cardiac hypertrophy and following myocardial infarction (MI). Using commercially available isoform-specific antibodies we have demonstrated that all p38 MAPK isoforms are expressed in the murine heart with p38α and being the most abundant. p38β and MAPK expressed at lower levels. The transcripts for all the p38 MAPK isoforms were detected. Immunocytochemistry of isolated cardiac myocytes demonstrated a diverse localization of p38 MAPK isoforms which suggest different functions. In isolated perfused hearts, we showed that mice lacking the β isoform (p38β KO) are refractory to pharmacological preconditioning by the carbon monoxide-releasing molecule, CORM-3. Our data demonstrate that CORM-3 pre-treatment followed by a 5 min washout of hearts prior to an in vitro ischaemia-reperfusion results in decreased infarct size and preserved LV function. With respect to p38 and δ isoforms, we observed a significant reduction in left ventricular developed pressure in response to sorbitol (osmotic stressor) in wild type (WT) hearts which was significantly ameliorated in p38 knockout (p38 KO) hearts. This was accompanied by a reduction in the level of p38 MAPK phosphorylation in transgenic mice compared with the WT. A comparable response was observed between WT and p38 KO mice in response to the other stimuli. The potential roles of p38 and δ MAPK were examined in a model of isoproterenol (ISO)-induced cardiac hypertrophy. Our studies revealed no significant differences between the WT and the transgenic phenotypes in response to hypertrophic stimuli. Infusion of ISO resulted in comparable LV remodelling, as assessed by echocardiography. In addition, no differences were observed in the cardiac function (assessed by pressure volume analysis) between the two genotypes. These finding suggest that p38γ and δ MAPK are unlikely to be involved in geometric remodelling of hypertrophy. Investigating the possible contribution of p38γ and δ MAPK in post-MI remodelling in vivo (using a permanent left anterior descending artery ligation model) revealed no apparent difference between WT and p38 KO mice. Echocardiographic and pressure-volume analysis showed comparable LV dilatation in WT and p38δ KO mice. Our data confirmed that p38α MAPK is the dominant isoform in the murine myocardium and is activated in response to ischaemia, ischaemia reperfusion and a number of pro-inflammatory cytokines. We propose that p38β MAPK is implicated in pharmacological preconditioning whereas p38γ and δ isoforms appear to be important in the myocardial response to osmotic stress. p38γ and δ isoforms also seem to be implicated in LV remodelling and somehow contribute to functional changes during cardiac hypertrophy and following-MI.
39
Cheng, Kwan-wai. "Regulation of equilibrative nucleoside transporter-1 by protein kinase C and mitogen-activating protein kinase /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31494912.
Full text
40
Glosse, Philipp [Verfasser], Michael [Gutachter] Föller, Gabriele I. [Gutachter] Stangl, and Lars-Oliver [Gutachter] Klotz. "Identification of novel regulators of fibroblast growth factor 23 (FGF23) production : the role of high-fat diet and AMP-activated protein kinase (AMPK) [kumulative Dissertation] / Philipp Glosse ; Gutachter: Michael Marc Uwe Föller, Gabriele I. Stangl, Lars-Oliver Klotz." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2020. http://nbn-resolving.de/urn:nbn:de:gbv:3:4-1981185920-353921.
Full text
41
Maitra, Sushmit. "The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase activated protein kinase 2." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008r/maitra.pdf.
Full text
42
Sloss, Callum. "Control of subcellular distribution of the MAP kinase phosphatase, MKP-2." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288715.
Full text
43
Kerkelä, R. (Risto). "Signaling pathways in myocyte hypertrophy:role of GATA4, mitogen-activated protein kinases and protein kinase C." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514269950.
Full textAbstract:
Abstract
Cardiac myocytes react to increased workload and hypertrophic neurohumoral stimuli by increasing protein synthesis, reinitiating expression of fetal forms of structural genes, α-skeletal actin (α-SkA) and β-myosin heavy chain (β-MHC), and by increasing expression and secretion of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). Initially, the response is beneficial, but when prolonged, it leads to pathological cardiomyocyte hypertrophy. In this study, cardiomyocyte hypertrophy was initiated by hypertrophic agonists, endothelin-1 (ET-1) and phenylephrine (PE), and by increased stretching of atrial wall.
Transcription factor GATA4 was studied to identify the mechanism leading to increased gene expression of BNP. In BNP promoter, GATA4 binds to cis elements mediating hypertrophic response. Eliminating GATA4 binding by using the decoy approach, basal BNP gene expression was reduced. To identify mechanisms regulating GATA4, the roles of mitogen-activated protein kinases (MAPKs) were studied. Activation of p38 MAPK increased GATA4 binding to BNP gene and led to increased GATA4 dependent BNP gene expression. p38 MAPK was required for ET-1 induced GATA4 binding, whereas extracellular signal-regulated kinase (ERK) was required for maintaining basal GATA4 binding activity. PE and ET-1 activated protein kinase C (PKC) signaling in cardiac myocytes. Antisense oligonucleotide inhibition of PKCα markedly reduced PE induced ANP secretion and ET-1 induced BNP secretion, whereas gene expression of natriuretic peptides was not affected. Antisense PKCα treatment inhibited PE induced expression of α-SkA, while increased protein synthesis or β-MHC gene expression were not affected. Sretching of the perfused rat atria increased BNP, c-fos and BNP gene expression via mechanism involving p38 MAP kinase activation of transcription factor Elk-1. In cultured neonatal rat atrial myocytes stretch induced BNP gene expression was dependent upon transcription factor Elk-1 binding sites within the BNP gene promoter.
In conclusion, hypertrophic signaling in cardiac myocytes involves multiple signaling cascades. Activation of p38 MAPK is required for the development of ET-1 induced hypertrophic phenotype and GATA4 mediated BNP gene expression in cultured ventricular myocytes, and for stretch induced Elk-1 dependent BNP gene expression in atrial myocytes. PKCα is involved in PE induced hypertrophic response and PE induced switch in gene programming inducing expression of α-SkA, the fetal form of cardiac α-actin.
44
Mills, Julia. "Regulation of amyloid precursor protein catabolism in vitro, the role of mitogen-activated protein kinase and protein kinase C." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq27201.pdf.
Full text
45
Haines, Jeffery. "Regulation of oligodendrocyte differentiation and myelination by p38 mitogen-activated protein kinase." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95127.
Full textAbstract:
Oligodendrocytes (OLG) in the central nervous system (CNS) extend multiple processes to ensheath nerve axons with the spiral wrapped membrane known as myelin. The signal transduction pathways that regulate OLG differentiation and CNS myelination are only beginning to be elucidated. We hypothesized that p38 mitogen-activated protein kinase could regulate OLG differentiation, since this kinase has been found to regulate the growth of peripheral nervous system myelinating Schwann cells. Using cultured oligodendrocyte progenitors, we found that treatment with PD169316, a selective p38 MAPK inhibitor, prevented accumulation of mRNA and protein of cell-stage specific markers characteristic of differentiated OLGs, including myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and the glycosphingolipids, galactosylceramide and sulfatide. In addition, the cell cycle regulator p27KIP1 and the transcription factor Sox10 were also significantly reduced. Most significantly, p38 inhibitors completely and irreversibly blocked myelination of dorsal root ganglion neurons by OLGs and prevented the axolemmal organization of the axo-glial adhesion molecule Caspr. Furthermore, we found that a p38 substrate, mitogen-activated protein kinase activated protein kinase 2 (MK2) is a downstream element of the p38 signaling pathway in OLGs responsible for effecting their differentiation. Thus, inhibition of MK2 activity in OLGs decreased the mRNA and protein levels of myelin-specific proteins MAG and MBP and upregulated transcriptional repressors that normally block OLG differentiation, including transcription factor 4, Notch, and inhibitor of differentiation 2. A genome-wide analysis of OLGs treated with PD169316 confirmed that p38 regulates myelin gene expression and identified a large group of upregulated genes involved in cell cycle regulation and cytokinesis. These data suggest that p38 controls OLG differentiation through the repression of genes involved in cell cyDans le système nerveux central (SNC), les oligodendrocytes (OLG) forment de multiples prolongements qui s'enroulent autour des axons formant ainsi la gaine de myéline. Les voies de signalisation qui régulent la différenciation des OLG et la myélinisation du SNC commencent seulement à être élucidées. Nous avons émis l'hypothèse que la MAP-kinase p38 (mitogen-activated protein kinase p38) pouvait réguler la différenciation des OLG puisqu'elle régule la croissance des cellules myélinisantes du système nerveux périphérique, les cellules Schwann. Dans des cultures de progéniteurs d'OLG, nous avons trouvé que le traitement avec un inhibiteur sélectif de MAPK-p38, PD169316, empêchait l'accumulation d'ARNm et de protéines de marqueurs spécifiques du stade cellulaire caractérisants les OLG différenciés, incluant la protéine basique de la myéline (MBP), la glycoprotéine associée à la myéline (MAG) et les glycosphingolipides galactosylceramide et sulfatide. De plus, le régulateur du cycle cellulaire p27KIP1 et le facteur de transcription Sox10 étaient également réduits significativement. De façon plus marquante, les inhibiteurs de p38 ont bloqué complètement et irréversiblement la myélinisation de neurones de ganglions de la racine dorsale par les OLG et ont empêché la localisation axolemmale de la molecule d'adhésion axo-gliale Caspr. En outre, nous avons montré qu'un substrat de p38, la protéine kinase MK2 (MAPK-activated protein kinase 2), est impliqué en aval de la voie de signalisation de p38 dans les OLG et est un effecteur de leur différenciation. Ainsi, l'inhibition de l'activité de MK2 dans les OLG réduit les niveaux d'ARNm et de protéines de MAG et de MBP et sur-régule les répresseurs transcriptionnels qui bloquent normalement la différenciation des OLG, dont le facteur de transcription 4, Notch, et l'inhibiteur de différenciation 2. Une analyse génomique d'OLG traités avec PD169316 a confirmé que p38 ré
46
Davies, Elizabeth Louise. "The role of mitogen-activated protein kinase phosphatase-1 in cardiac hypertrophy." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391714.
Full text
47
Kodituwakku, Jayanie Subhashi. "Mechanisms regulating mitogen-activated protein kinase phosphatase-2 expression in cardiac myocytes." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429111.
Full text
48
Tchen, Rose Carmen. "Regulation of tristetraprolin expression by the mitogen-activated protein kinase p38 pathway." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417449.
Full text
49
Ridley, Simon Hugh. "The role of p38 mitogen-activated protein kinase in interleukin-1 action." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625016.
Full text
50
Engineer, Neelam. "The role of mitogen activated protein kinase in stretch induced preterm labour." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503840.
Full text