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Patterson, Kate Isabel Garvan Institute of Medical Research Faculty of Medicine UNSW. "Characterisation of the atypical dual specificity phosphatase DUSP26". Publisher:University of New South Wales. Garvan Institute of Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43594.
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In many ways cancer is a disease of cellular signalling disequilibrium. When the equilibrium of key signalling pathways is upset, critical biological functions such as cell growth, survival, motility, proliferation, metabolism and apoptosis are affected, and can lead to the initiation of cancer. Reversible protein phosphorylation is an extremely important mechanism by which the activity of enzymes and proteins in signalling cascades can be regulated. Dual specificity phosphatases (DUSPs) are a unique subgroup of the protein tyrosine phosphatases (PTPs) in that they can dephosphorylate both phospho-tyrosine and phospho-serine/threonine residues within the one substrate. Many DUSPs have been implicated in cancer as critical regulators of key cancer- associated signalling cascades including the mitogen activated protein kinase (MAPK) pathway. Transcript profiling of 51 primary ovarian tumours and four normal ovaries as controls identified an uncharacterised atypical DUSP, DUSP26 as being potentially down-regulated in all histological subtypes of ovarian cancer compared with normal ovaries. DUSP26 is located at 8p12, a chromosomal region previously shown to exhibit allelic imbalance in ovarian cancer. DUSP26 is predominantly expressed in neuro-endocrine tissue, with high expression also in skeletal muscle, prostate and ovary. DUSP26 mRNA expression is reduced in brain cancer, neuroblastoma, and ovarian cancer cell lines compared to normal, consistent with a role for DUSP26 as a tumour suppressor gene. Furthermore, DUSP26 can negatively affect the proliferation of epithelial cells, also consistent with a role as a tumour suppressor gene. Expression of DUSP26 in primary ovarian cancer samples is variable however, and analysis of DUSP26 protein expression is required to reconcile these results. Preliminary results suggest that DUSP26 is epigenetically regulated and that hypermethylation may contribute to its silencing in cancer. In the literature, there is great controversy in regards to the substrate specificity of DUSP26. Results presented in this thesis conclusively demonstrate that DUSP26 is not a MAPK phosphatase, despite reports to the contrary. Instead, using a substrate trapping approach, two novel potential DUSP26 substrates were identified: DNA-dependent protein kinase (DNA-PK) and nuclear mitotic apparatus protein (NuMA), which are often dysregulated in cancer. Consequently, DUSP26 may affect the pathogenesis of cancer via DNA-PK and or NuMA.
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Cain, Erica L. "An investigation of the oncogenic potential and function of the dual specificity phosphatase 12". Diss., Kansas State University, 2012. http://hdl.handle.net/2097/16694.
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Doctor of PhilosophyDepartment of Biology
Alexander Beeser
Large-scale genomic approaches have demonstrated many atypical dual specificity phosphatases (DUSPs) are differentially expressed or mutated in cancer. DUSPs are proteins predicted to have the ability to dephosphorylate Ser/Thr and Tyr residues, and the atypical DUSP subgroup contains at least 16 members with diverse substrates that include proteins, nucleic acids, and sugars, and some of the atypical DUSPs function in the cell not as phosphatases but as scaffolds in signal transduction pathways. Of the atypical DUSPs, DUSP12 is one of the most evolutionarily conserved with homologs found in organisms ranging from yeast to humans. DUSP12 is of particular interest as it has been identified to be one of only two candidate genes for the target of a genetic amplification found in liposarcomas. Furthermore, DUSP12 may be an oncogene in that over-expression of dusp12 in cell culture promotes apoptosis resistance, cell motility, and the up-regulation of two established oncogenes, the hepatocyte growth factor receptor (c-met) and integrin alpha 1 (itga1). Additionally, DUSP12 may protect from apoptosis by functioning as a regulator of stress-induced translation repression and stress granule formation that may be due to its interaction with the DEAD Box RNA Helicase, DDX3.
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Buffet, Camille. "Anomalies moléculaires de la voie MAPK et cancer papillaire de la thyroïde : étude de deux phosphatases spécifiques de ERK, DUSP5 et DUSP6". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T049/document.
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Le cancer papillaire de la thyroïde (CPT) est la tumeur endocrine la plus fréquente. Des anomalies moléculaires activant la voie des MAPK (Mitogen-Activated Protein Kinases) sont identifiées, de façon mutuellement exclusive, dans environ 70% des cas. Il s’agit de réarrangements chromosomiques, le plus souvent de type RET/PTC (10%), de mutations ponctuelles activatrices des trois isoformes de l’oncogène RAS (H, N et K-RAS) (10%), ou de l’oncogène B-RAF (50%). La mutation « hot spot » B-RAFV600E est la plus fréquemment identifiée, elle est associée à une plus grande agressivité clinique (diagnostic à un stade tardif, risque de récidives et de décès accru). Ces évènements moléculaires ont pour conséquence commune l’activation de la voie des MAPK, se traduisant en aval par la phosphorylation de MEK (Mitogen-activated Extracellular signal-Regulated Kinase) puis de ERK (Extracellular signal-Regulated Kinase). Cette dernière est régulée négativement par des phosphatases, appartenant à la famille des Dual Specificity Phosphatases (DUSPs), d’expression ubiquitaire, et en particulier de deux phosphatases spécifiques de ERK, l’une cytoplasmique (DUSP6) et l’autre nucléaire (DUSP5). Nous avons fait l’hypothèse que ces phosphatases pouvaient être soit des gènes suppresseurs de tumeurs (leur perte d’expression conduisant à une augmentation de phosphorylation de ERK et une prolifération accrue), soit des marqueurs du degré d’activation de la voie MAPK dans le cadre d’une boucle de rétrocontrôle négatif. Ceci nous a conduits à analyser la régulation et l’expression de ces phosphatases dans trois modèles : la lignée cellulaire PCCL3 (thyroïde de rat), exprimant l’un des trois principaux oncogènes mutés dans les CPT (RET/PTC3 ou H-RASV12 ou B-RAFV600E) sous le contrôle d’un promoteur inductible par la doxycycline, des lignées cellulaires humaines dérivant de CPT et des CPT humains. (...)Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Mutually exclusive and activating alterations of the MAPK pathway (Mitogen-Activated Protein Kinases) are identified in 70% of cases. Common mutations found in PTCs are point mutation of the B-RAF (50%) and RAS genes (10%) as well as RET/PTC chromosomal rearrangements (10%). The hot spot B-RAFV600E mutation is the most frequently alteration identified and is connected with agressive clinical characteristics (high stage at diagnosis, high recurrence risk and death). These molecular events lead to constitutive activation of the MAPK pathway, resulting in MEK (Mitogen-activated Extracellular signal-Regulated Kinase) and ERK (Extracellular signal-Regulated Kinase) phosphorylation. ERK is negatively regulated by phosphatases and among them, Dual Specificity Phosphatases (DUSPs), ubiquitary expressed, in particular two ERK-specific phosphatases DUSP5 (nuclear) and DUSP6 (cytosolic). We hypothesized that these phosphatases could have tumor supressor properties (i.e. their loss would be associated with an increase in MAPK pathway activation) or may serve as a surrogate marker of MAPK pathway activation in the context of a negative feedback loop. We analysed regulation and expression of both phosphatases in 3 models: three PCCL3 cell lines (rat thyroid cells) expressing one of the most common oncogene identified in PTCs (RET/PTC3 or H-RASV12 or B-RAFV600E) under the control of a doxycycline-inducible promoter, human PTC-derived cell lines and human PTC. We demonstrated that MAPK pathway activation was correlated with induction of DUSP5 and DUSP6. These phosphatases are involved in a negative feedback loop that contributes to a tight regulation of phospho-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in B-RAF mutated tumors suggesting a higher MAPK signaling output in these agressive PTCs. Silencing of DUSP5 and/or DUSP6 by small interfering RNA does not affect proliferation of human B-RAFV600E thyroid carcinoma-derived cell lines, suggesting the lack of tumor suppressor gene role. Compensatory changes in expression of DUSPs when a specific one is inactivated may explain this lack of effect. On the opposite, a DUSP6 pharmacological inhibitor induced a concentration dependent decrease in proliferation of human B-RAFV600E cells, suggesting « off-target » effect of this inhibitor. In a second part, we analysed the regulation of DUSP5 expression, which is a target of the MAPK pathway activation. We demonstrated, using pharmacological inhibitors, that DUSP5 is an early response gene, regulated mostly by the MAPK pathway, at the transcriptional level. Two contiguous CArG boxes that bind serum response factor (SRF) were found in a 1Kb promoter region, as well as several E twenty-six transcription factor family binding sites (EBS). These sites potentially bind Elk-1, a transcription factor activated by ERK1/2. Using wild type or mutated DUSP5 promoter reporters, we demonstrated that SRF plays a crucial role in serum induction of DUSP5 promoter activity, the proximal CArG box being important for SRF binding in vitro and in living cells. Moreover Elk-1 was bound in vitro to a promoter region containing the proximal CArG box and a putative EBS. Its specific binding to SRF was necessary to elicit promoter response to dominant positive Elk-VP16 and to enhance the response to serum stimulation. Altogether our results suggest that the MAPK pathway is more active in B-RAFV600E PTC than in PTC with other genetic alteration and could explain their clinical agressivity. DUSP5 and DUSP6, as well as phosphorylated MEK, are markers of activation of the MAPK pathway. Neither phosphatase has tumor suppressor properties in our thyroid cancer cell models. Our results suggest redundancy and functional compensation among DUSPs. (...)
4
Manley, Grace C. A. "The roles of DUSPs in respiratory viral infection". Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/19257/.
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Emond-Boisjoly, Marc-Alexandre. "Rôle de la protéine DUSP5 dans l’autophagie des cardiomyocytes". Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/8908.
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Résumé: L’autophagie est un processus essentiel au maintien de l’homéostasie cellulaire. Elle permet de dégrader et recycler aussi bien des organelles entières que des composants cytoplasmiques non fonctionnels. De plus, l’augmentation d’autophagie en condition de stress constitue une réponse adaptative favorisant la survie cellulaire. Chez les cardiomyocytes, l’autophagie en condition basale est indispensable au renouvellement, entre autres, des mitochondries et des protéines formant les sarcomères. De plus, les stress tels l’ischémie cardiaque ou la carence en nutriments induisent une augmentation de l’autophagie protectrice. Dans certaines conditions extrêmes, il a été suggéré qu’un surcroît d’autophagie puisse toutefois exacerber la pathologie cardiaque en provoquant la mort des cardiomyocytes. Considérant l’importance de ce processus dans la physiopathologie cardiaque, l’identification des mécanismes signalétiques régulant l’autophagie chez les cardiomyocytes a été le sujet de recherches intenses. À cet effet, l’activation des Mitogen-Activated Protein Kinase (MAPK) a été démontrée pour réguler, avec d’autres voies signalétiques, l’autophagie et l’apoptose des cardiomyocytes. Il est donc probable que les Dual-Specificity Phosphatase (DUSP), enzymes clés contrôlant l’activité des MAPK, participent aussi à la régulation de l’autophagie. Afin de vérifier cette hypothèse, nous avons induit l’autophagie chez des cardiomyocytes isolés de rats nouveau-nés en culture. L’analyse de marqueurs d’autophagie par immunobuvardage démontre que l’activation des MAPK ERK1/2 et p38 corrèle avec l’activité autophagique chez les cardiomyocytes. Dans ces conditions, la diminution d’expression de la majorité des ARNm encodant les différentes DUSP retrouvées chez les cardiomyocytes contraste de façon marquée avec l’augmentation d’expression de l’ARNm Dusp5. De plus, nous avons démontré par une étude de gain de fonction que l’activation soutenue de p38 par surexpression d’un mutant MKK6 constitutivement actif stimule l’autophagie chez les cardiomyocytes. De façon surprenante, la perte de fonction de p38 obtenue par surexpression d’un mutant p38 dominant négatif n’altère en rien la réponse autophagique initiatrice dans notre modèle in vitro. Nos résultats suggèrent que les DUSP puissent réguler, via leurs actions sur les MAPK, d’importantes étapes du processus autophagique chez les cardiomyocytes.Abstract: Autophagy is a process essential to the maintenance of cellular homeostasis. It helps degrade and recycle whole organelles and nonfunctional cytoplasmic components. In addition, the adaptative up regulation of autophagy in stress condition promotes cell survival. In cardiomyocytes basal autophagy is essential to the renewal of, among others, mitochondria and proteins forming sarcomeres. In addition, stresses such as ischemic heart or nutrient deficiency induce an increase in protective autophagy. In extreme conditions, it has been suggested that autophagy may exacerbate cardiac disease causing the death of cardiomyocytes. Considering the importance of this process in cardiac pathophysiology, identify ing safety mechanisms regulating autophagy in cardiomyocytes has been the subject of intense research. To this end, activation of mitogen-activated protein kinase (MAPK) has been demonstrated to regulate, with other signaling pathways, autophagy and cardiomyocyte apoptosis. It is therefore likely that Dual-Specificity Phosphatases (DUSPs), key enzymes that control the activity of MAPKs, also participate in the regulation of autophagy. To test this hypothesis, we have induced autophagy in isolated cardiomyocytes of newborn rats in culture. Analysis of autophagy markers by immunoblotting demonstrated that the activation of MAPKs ERK1/2 and p38 correlates with autophagic activity in cardiomyocytes. Under these conditions, the decrease in expression of the majority of mRNAs encoding different DUSPs found in cardiomyocytes contrast sharply with the increase mRNA expression of Dusp5. Furthermore, we demonstrated by again of function study that sustained activation of p38 by overexpression of a constitutively active MKK6 mutant stimulates autophagy in cardiomyocytes. Surprisingly, the loss of p38 function obtained by overexpression of a dominant negative p38 mutant does not affect the autophagic response in our in vitro model, but increases the lipidation of autophagosomes marker LC3. Our results suggest that DUSPs can regulate, through their actions on MAPKs, important stages of autophagy in cardiomyocytes.
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Moreaux, Guenievre. "Investigating downstream effectors of KRas signalling in vivo : Dusp6 and Fra1". Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/4056/.
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Arkell, Rebecca Sarah. "Investigations into the regulation of DUSP6 expression in normal and tumour cells". Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611087.
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Li, Weiling. "Genetic changes in melanoma progression". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5595.
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Melanoma is a highly aggressive tumour with a poor prognosis for patients with advanced disease because it is resistant to current therapies. Therefore, the development of novel strategies for melanoma treatment is important. The characterization of the molecular mechanisms underlying melanoma proliferation, progression, and survival could help the development of novel targeted melanoma treatments. The MAPK and PI3K pathways both play important roles in melanoma progression. In the MAPK pathway, DUSP6, which acts as a phosphatase to negatively control the activation of ERK1/2, is involved in the development of human cancers. The MAPK pathway also regulates expression of the DNA repair gene ERCC1 following EGF treatment. ERCC1 is essential for nucleotide excision repair, which is one of the major systems for removal of cisplatin induced DNA lesions. The aims of this project were: 1, to investigate the molecular changes in our immortal mouse melanocyte cell lines that were needed for them to form tumours in a xenograft model; 2, to investigate whether the MAPK pathway regulates ERCC1 following cisplatin treatment and protects melanoma cells from death. Through comparison of the RAS/RAF/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways between our immortal mouse melanocyte cell lines and their tumour derivatives in our xenograft model, we identified a molecularly distinct subtype of mouse melanoma characterized by reduced ERK and AKT activity and increased expression of DUSP6. Functional analyses employing ectopic overexpression indicated that increased expression of DUSP6 enhanced anchorage independent growth ability and invasive ability in our mouse melanocytes, suggesting that increased DUSP6 expression may contribute to melanoma formation in the xenograft assay. We also demonstrated that higher expression of p-ERK suppressed invasion, but not anchorage independent growth, in our subtype of mouse melanoma by enforced expression of constitutively active MEK1 and MEK2. In addition, the role of DUSP6 in classical human melanoma was investigated in this Genetic changes in melanoma progression study. Inhibition of anchorage independent growth and invasion were observed after exogenous expression of DUSP6 in human melanoma cells. This suggested that DUSP6 played different roles in classic human melanoma than in our distinct subtype of mouse melanoma. Our study also investigated the phosphorylation level of ERK1/2 and the mRNA and protein level of ERCC1 and its partner XPF in the human melanoma cell line following cisplatin treatment. Significant increases in expression of p-ERK, ERCC1 and XPF were found in cisplatin treated cells. Moreover, a MEK inhibitor inhibited ERCC1 induction by cisplatin, but did not significantly affect XPF induction. This suggested that the MAPK pathway was involved in regulation of ERCC1 but not XPF. Furthermore, the DUSP6 level decreased after cisplatin treatment and overexpression of DUSP6 inhibited ERCC1 and XPF induction and reduced resistance to cisplatin. DUSP6 seems to play a crucial role in resistance of melanoma to cisplatin. In addition, a novel larger ERCC1 transcript was identified in human cell lines and was found to be upregulated by cisplatin. The ratio of larger ERCC1 transcript relative to the normal ERCC1 transcript increased following cisplatin treatment. The functions of this larger ERCC1 transcript in cisplatin resistance deserve further study.
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Casteel, Maximilian Wilhelm. "Bedeutung von DUSP1 und Expression MAPKinasen-spezifischer Transkriptionsfaktoren während der zellulären Antwort auf Deoxynivalenol". Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-128239.
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Intriago, Rachel Elizabeth. "Role and regulation of DUSP-1 in GnRH signaling". Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465076.
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Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed June 19, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 55-57).
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Abraham, Sonya Marie. "Dual specificity phosphatase 1 (DUSP1): an important regulator of the anti-inflammatory actions of glucocorticoids?" Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486756.
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The Mitogen Activated Protein Kinases (MAPKs) are a family of serine/threonine kinases that orchestrate changes in gene expression in response to extracellular stimuli. The c-Jun N-terminal kinase (JNK) and p38 MAPK subfamilies are strongly activated by pro-inflammatory stimuli such as UV light, cytokines such as Interleukin-l (IL-I), and pathogen-associated molecules, for example lipopolysaccharide (LPS). The JNK and p38 signalling pathways control the expression of many inflammatory mediators, including tumour necrosis factor a (lNFa) and cyclooxygenase 2 (COX-2). Activation of MAPKs requires their phosphorylation at particular threonine and tyrosine residues. Conversely, inactivation of the MAPKs is achieved by removal of the activating phosphate groups by various threonine / serine-, tyrosine-, or dual specificity phosphatases. This phosphatase-mediated inactivation ofp38 and JNK is thought to be critical for limiting the strength and duration ofan inflammatory response.We and others have shown that the dual-specificity phosphatase, DUSPI is transiently upregulated by proinflammatory stimuli such as UV light, IL-I or LPS. It is also upregulated in a more sustained fashion by the glucocorticoid dexamethasone, a powerful anti-inflammatory agonist. The induction of DUSPI gene expression coincides with the inactivation of JNK and p38. We hypothesised that DUSPI plays a role in the limitation of inflammatory responses via a negative feedback loop, and that the sustained induction of DUSPI contributes to the anti-inflammatory effects ofglucocorticoids. To test these hypotheses we have investigated inflammatory responses of cells from a DUSPI knock-out mouse.
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Beaudry, Katia. "Le rôle de la phosphatase DUSP6 dans le contrôle de la tumorigenèse et de l’inflammation intestinale". Mémoire, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11413.
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La voie de signalisation ERK/MAPK est connue pour son implication dans la progression du cycle cellulaire et dans le contrôle de la différenciation dans les cellules épithéliales intestinales. La phosphatase cytoplasmique DUSP6 a pour seuls substrats les kinases ERK1/2, kinases effectrices de la voie ERK/MAPK. Son rôle dans le contrôle des différents processus influencés par la signalisation ERK/MAPK n’a encore jamais été étudié dans l’épithélium intestinal et colique, malgré l’implication connue de cette voie de signalisation dans le contrôle de la prolifération et de la différenciation des cellules épithéliales intestinales. Pour étudier son rôle dans le maintien de l’homéostasie intestinale, un modèle de souris invalidée pour Dusp6 a été utilisé. De façon intéressante, une augmentation de la prolifération cryptale et un allongement des cryptes ont été observés dans le côlon de souris Dusp6-/- comparé aux souris Dusp6+/+. Cette augmentation de la prolifération cryptale permet notamment un développement plus rapide d’organoïdes de côlon démontrant ainsi une meilleure capacité de régénération épithéliale. De plus, une augmentation du nombre de cellules caliciformes a été observée dans le côlon des souris invalidées pour Dusp6. Une augmentation du nombre de cellules de Paneth et des cellules intermédiaires Paneth/caliciformes a été aussi observée dans l’iléon des souris Dusp6-/-. Cette augmentation de la prolifération, de la différenciation des cellules à mucus et de la capacité de régénération protège l’épithélium colique d’un stress induit par un traitement au dextran sulfate (DSS). Pour étudier l’implication de la phosphatase DUSP6 dans la tumorigenèse colorectale, un modèle de souris ApcMin/+;Dusp6-/- a été généré. De façon intéressante, ces souris ont développé plus de polypes dans l’intestin grêle et dans le côlon que les souris ApcMin/+;Dusp6+/+. De plus, l’expression de DUSP6 en ARNm a été analysée dans des tumeurs colorectales humaines et pairées avec une marge saine. De manière intéressante, le niveau des transcrits de DUSP6 est diminué dans les tumeurs colorectales et ce, de façon plus prononcée dans les stades avancés. Finalement, le rôle de DUSP6 dans différents processus associés à la carcinogenèse a été étudié dans des cellules cancéreuses colorectales sous-exprimant DUSP6 grâce à un ARN interférant. Une augmentation de l’activité ERK1/2, de la capacité de croissance en indépendance d’ancrage et de la capacité invasive a été observée chez les cellules HT29 sous-exprimant DUSP6, mais pas chez les HCT116. En conclusion, DUSP6 est impliqué dans le maintien de l’homéostasie grâce à son contrôle de la prolifération cryptale et de la différenciation cellulaire. De plus, en inhibant l’activité ERK1/2, cette phosphatase régularise négativement la tumorigenèse intestinale.
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Bermudez, Olga. "Régulation post-transcriptionnelle et post-traductionnelle de DUSP6, une phosphatase des MAP kinases ERK 1/2". Nice, 2009. http://www.theses.fr/2009NICE4054.
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Les MAP kinases phosphatases (MKPs) appartiennent à la famille des Dual-Specificity Phosphatases (DUSP) et déphosphorylent les résidus thréonine et tyrosine des MAP kinases activées. DUSP6/MKP-3 est une phosphatase cytoplasmique qui déphosphoryle et donc inactive de façon spécifique les MAP kinases ERK1/2. DUSP6 a un rôle important au cours du développement, particulièrement dans la régulation du signal induit par le FGF, et son absence provoque des effet phénotypiques majeurs chez la Drosophile, le poulet, le poisson-zèbre et la souris. DUSP6 pourrait jouer également un rôle important au cours de la formation et du développement des tumeurs car son expression se trouve altérée dans divers cancers. Pour ces raisons, je me suis intéressée aux mécanismes moléculaires impliqués dans la régulation de son expression, au niveau post-transcriptionnel et post-traductionnel. Des données antérieures du laboratoire ont indiqué que DUSP6 était phosphorylée et dégradée après stimulation des cellules avec des facteurs de croissance, de façon MEK/ERK-dépendante (Marchetti et al. , 2005). Dans la première partie de ma thèse, j’ai étudié le rôle d’autres voies de signalisation dans la régulation de DUSP6. Nous avons montré qu’une autre voie de signalisation, la voie PI3K/mTOR, est responsable d’une partie de la phosphorylation et de la dégradation de DUSP6 induite par les facteurs de croissance (Bermudez et al. , 2008). Toutefois, une activité basale de MEK est nécessaire pour que la phosphorylation de DUSP6 par mTOR ait lieu. Des études de mutagenèse ont montré que la sérine 159 est le résidu phosphorylé par mTOR. La phosphatase DUSP6 pourrait donc constituer un nouveau point d’interaction entre deux grandes voies de signalisation cellulaire activées par les facteurs de croissance, la voie MEK/ERK et la voie PI3K/mTOR. Dans la deuxième partie de mon travail, je me suis intéressée à la régulation de dusp6 au niveau de son ARNm. D’autres équipes ont montré que la voie MEK/ERK jouait un rôle dans l’activation transcriptionnelle de dusp6. Nous avons confirmé que l’inhibition de MEK/ERK réduit fortement les quantités d’ARNm de dusp6. Afin d’étudier la régulation de la stabilité de l’ARNm de dusp6, nous avons cloné dans un vecteur d’expression un gène rapporteur luciférase en amont de la région non codante 3’UTR de dusp6, qui contient des sites consensus pour différents facteurs qui déstabilisent/stabilisent les ARNm. Nous avons trouvé que la voie MEK/ERK stabilise l’ARNm de dusp6. Par ailleurs, des conditions d’hypoxie, une caractéristique de nombreuses tumeurs in vivo, induisent une augmentation des niveaux d’ARNm de dusp6, augmentation qui dépend de HIF-1alpha. Finalement, nous avons identifié deux facteurs qui déstabilisent l’ARNm de dusp6, TTP (tristetraprolin) et PUM2, un homologue du gène pumilio de la drosophile. Les résultats présentés dans cette thèse montrent donc que la voie MEK/ERK est impliquée dans la régulation de DUSP6 à différents niveaux, de la régulation de son ARNm au niveau post-traductionnel, dans une boucle de rétrocontrôle. L’étude de la régulation de DUSP6 apporte des éléments supplémentaires pour la compréhension des mécanismes complexes impliqués dans l’activation d’ERK1/2 au sein du réseau de signalisation des MAPKs, où des régulations positives et négatives contribuent à un contrôle subtil de l’activation des MAP Kinases ERKs dans l’espace et le tempsMAP kinases phosphatases (MKPs) belong to the Dual-Specificity Phophatase family (DUSP) and dephosphorylate phospho-threonine and phospho-tyrosine within MAP kinases. DUSP6/MKP-3 is a cytoplasmic phosphatase that specifically dephosphorylates and inactivates the MAP Kinases ERK ½. DUSP6 has an important role during animal embryogenesis, specially in the regulation of FGF signaling, and its absence leads to major phenotypic effects in Drosophila, chicken, zebrafish and mice. The expression of DUSP6 can also be regulated in some cancers: its expression is upregulated in melanoma and myeloma but downregulated in invasive stages of pancreas cancer. Given the importance of dusp6 regulation in physiological and pathological cases, I focused my attention on studying the molecular mechanisms underlying the expression of dusp6. As the transcriptional regulation of dusp6 has been previously reported, I concentrated on dusp6 mRNA stability and the degradation of the protein DUSP6. Previous results in the lab have shown that at the protein level, DUSP6 was phosphorylated and degraded upon growth factor stimulation, in a MEK-dependent manner (Marchetti et al. , 2005). In the first part of my PhD, I studied the role of other signaling pathways in DUSP6 regulation and I showed that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, also accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors (Bermudez et al. , 2008, Oncogene). However, a basal activity of MEK was required for the mTOR pathway-mediated phosphorylation to occur. Mutagenesis studies identified serine 159 within DUSP6 as the target of the mTOR pathway. The ERK phosphatase DUSP6 may thus constitute a novel branch-point of the cross-talk between two major signaling pathways induced by growth factors, the MEK/ERK pathway and the PI3K/mTOR pathway. In a second part of my work, I investigate the molecular basis of dusp6 regulation at the mRNA level. Others have shown a role for the MEK/ERK pathway in transcriptional activation of dusp6, and we confirmed that their inhibition strongly diminished the amount of dusp6 mRNA. To determine whether the stability of dusp6 mRNA could be subjected to regulation, a luciferase reporter was cloned upstream of the non coding 3’UTR of dusp6, which contains consensus sequences for various stabilization/destabilization factors. The MEK/ERK pathway was found to stabilize dusp6 mRNA. Hypoxic conditions, a hallmark of many tumors in vivo, induce a modest but reproducible increase in dusp6 mRNA levels, which is HIF1-alpha dependent. Consistent with increased dusp6 mRNA levels in hypoxia, we found that pERK levels are diminished under hypoxia in several albeit not all cancer cell lines tested. Finally, I identified two different mRNA-binding proteins, tristetraprolin (TTP) and PUM2 as factors destabilizing dusp6 mRNA. Altogether, these results indicate that the regulation of DUSP6 involves the MEK/ERK pathway at different levels, at the mRNA level as well as at the post-translation level, in a feedback loop. The study of dusp6 expression brings additional information about the complex mechanisms involved in ERK1/2 activity within the network of MAPKs, where positive and negative regulations lead to a subtle but tight control of ERK activation in space and time
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Derigs, Marcus [Verfasser], Roland [Akademischer Betreuer] Lang, Roland [Gutachter] Lang i Jochen [Gutachter] Mattner. "Die Auswirkung von Dusp16 auf die Proliferation von Knochenmark-derivierten dendritischen Zellen / Marcus Derigs ; Gutachter: Roland Lang, Jochen Mattner ; Betreuer: Roland Lang". Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1215343221/34.
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Haddock, Ashley Noel. "Transcriptional Regulation of Dual-Specificity Phosphatase 4 (Dusp4) by Muscle RING Finger 1 (MuRF1) and Myogenic Regulatory Factors". UNF Digital Commons, 2016. http://digitalcommons.unf.edu/etd/618.
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Skeletal muscle atrophy can occur at any age and as a result of numerous physiological conditions and thus, it was necessary to better identify the molecular underpinnings of the atrophy cascade so that new therapeutic targets to treat muscle wasting might be identified. MuRF1 was first identified as a marker of skeletal muscle atrophy over a decade ago; however, recent work suggests that this E3 ubiquitin ligase may participate in muscle wasting by regulating the transcriptional activity of genes differentially expressed in response to muscle atrophy. Dusp4, a dual-specificity phosphatase and member of the MAPK cascade, is induced in response to neurogenic atrophy; however, this induction is significantly blunted in the MuRF1-null mice which are resistant to muscle atrophy. The research presented in this thesis aims to characterize the mechanism by which MuRF1 may transcriptionally regulate Dusp4 and characterizes the function of Dusp4 in skeletal muscle.
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Tong, Tin-wing, i 唐天穎. "Investigation of transcript expression of PRKAR2A, DUSP1, STMN2 and MAPT genes in nasopharyngeal carcinoma, ovarian cancer and benignovarian tumor". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632700.
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Bassalert, Cécilia. "Influence des voies de signalisation IGF et MAPK sur la spécification des lignages de l'embryon de souris préimplantatoire". Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAC029.
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Au cours de la préimplantation, l'embryon de souris produit deux lignages cellulaires, le trophectoderme (TE), et la masse cellulaire interne (MCI) qui elle-même se différencie en épiblaste (Epi) et en endoderme primitif (EPr), caractérisés respectivement par l'expression exclusive de Nanog et de Gata6. La voie FGF/MAPK joue un rôle critique dans l’acquisition de l’identité EPr. J’ai examiné l’expression de pERK, DUSP4 et ETV5 qui permettent de visualiser l'activité des MAPK. Ces analyses ont été effectuées en activant ou inhibant la voie FGF/MAPK, ainsi que dans des embryons mutants pour Nanog et/ou Gata6. Ceci a permis d’observer l’activation de la voie FGF/MAPK dès E3,25. Un autre volet de mon travail a été d'analyser la voie de l’IGF dans les embryons préimplantatoires afin de comprendre l’influence de cette voie dans les différents lignages. J’ai montré que le récepteur activé pIGF1R est exprimé de manière différentielle dans le TE, l’EPr et l’Epi au cours du développement. Une supplémentation d’IGF1 induit une augmentation du nombre de cellules en deux phases, d'abord de l’Epi puis de l’EPr. A l’inverse, une perte de fonction d’IGF1R induit une diminution du nombre de cellules entre E3,75 et E4,25During preimplantation, mouse embryo produces two cellular lineages, the trophectoderm (TE), and the inner cell mass (ICM), which differentiates in epiblast (Epi) and primitive endoderm (PrE), characterized respectively by the complementary expression of Nanog and Gata6. FGF/MAPK pathway plays a critical role in the acquisition of a PrE identity. I examined the expression of the markers of MAPK activity pERK, DUSP4 and ETV5. The analyze was performed with activation or inhibition of FGF/MAPK pathway and in mutant embryos for Nanog or Gata6. This showed that FGF/MAPK pathway is activated as soon as E3,25. I have also analyzed the IGF pathway in preimplantation embryos in order to understand the role of this pathway in embryonic lineages. I showed that active receptor pIGF1R is differentially expressed in TE, PrE and Epi during embryonic development. Supplementation with IGF1 induces an increase in cell number in two phases, first in Epi then in PrE. Conversely, loss of function of IGF1R induces a decrease in cell number between E3,75 and E4,25
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Prager, Briana C. "THE MENINGIOMA ENHANCER LANDSCAPE DELINEATES PROGNOSTIC SUBGROUPS AND DRIVES DRUGGABLE DEPENDENCIES". Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1595620620551252.
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Gröschl, Benedikt [Verfasser], i Wolfgang [Akademischer Betreuer] Dietmaier. "Molekularbiologische und funktionelle Charakterisierung der von Maspin regulierten Gene DUSP4 (MKP-2) und IQGAP2 im kolorektalen Karzinom / Benedikt Gröschl. Betreuer: Wolfgang Dietmaier". Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1076160964/34.
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Miura, Haruko. "Live-Cell Imaging of Stress Signaling Dynamics in a Cell Fate Decision". Kyoto University, 2019. http://hdl.handle.net/2433/236635.
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Zhang, Zhenfeng. "Study of Molecular Mechanisms of Sensitivity and Resistance to EGFR-Targeted Therapy in Lung Cancer". Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278615774.
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Wagner, Stephanie [Verfasser], i Anja-Katrin [Akademischer Betreuer] Bosserhoff. "Reduzierte Expression der miRNA196a2 führt über den Transkriptionsfaktor ERG zu einer Hochregulation der Transkriptionsvariante 1 von DUSP4 im malignen Melanom / Stephanie Wagner. Betreuer: Anja-Katrin Bosserhoff". Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/1054802289/34.
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Jenner, Stefan [Verfasser], i Anette [Akademischer Betreuer] Preiss. "Beiträge zur Verbesserung der Analytik von Mutationen im Protoonkogen Kirsten-ras und epigenetische Untersuchungen zur Eignung von DUSP9/MKP4 als CIMP-Marker / Stefan Jenner. Betreuer: Anette Preiss". Hohenheim : Kommunikations-, Informations- und Medienzentrum der Universität Hohenheim, 2012. http://d-nb.info/1027760422/34.
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Eger, Glenda. "Regulation and Function of MAP Kinases in PDGF Signaling". Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-301057.
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Platelet-derived growth factor (PDGF) is a family of signaling molecules that stimulates cell growth, survival and migration. PDGF is recognized by specific transmembrane proteins, the PDGF receptors, which relay the signals to the cell activating the Mitogen-activated protein (MAP) kinases and other signaling pathways. Aberrant activation of these pathways is frequently detected in cancer. Hence, the study of these processes is essential for identifying potential drug targets or diagnostic markers. In paper I, we identified Receptor Subfamily 4 Group A Member 1 NR4A1 to be regulated by PDGF via MAP kinases, clarifying the role of Extracellular signal–regulated kinases (Erk) 1/2, Erk5 and Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in its regulation. NR4A1 was found to be important for the tumorigenic potential, measured as anchorage-independent growth, of glioblastoma cells. Since the cellular responses elicited by PDGF result from the balance between phosphorylation and dephosphorylation events, we investigated the role of the dual specificity phosphatases DUSP4/MKP-2 and DUSP6/MKP-3. In paper II, we describe the crucial role of Erk1/2 and p53 in the expression of DUSP4/MKP2. Moreover, we observed that DUSP4/MKP-2 downregulation decreases Erk5 activation and accelerates PDGFRβ internalization and downregulation resulting in a specific inhibition of Signal transducers and activators of transcription (Stat) 3, Src and protein kinase C (PKC), and partially of p38, Stat1/5 and Phoshoplipase Cγ (PLCγ). In paper III, we report that DUSP6/MKP-3 creates a negative cross-talk between Erk1/2 and Erk5 and an auto-inhibitory feedback loop on the PI3-kinase/Akt pathway. In paper IV, we identify a new regulative mechanism of the PDGF pathway. PDGF induces Erk5 expression and activation that modulates the PDGFRβ activity. After Erk5 downregulation, the receptor undergoes to a faster and stronger activation that results in a faster internalization and degradation. In conclusion, we present a mechanism through which the PDGF/MAP kinases support tumor growth, and elucidate different regulatory pathways involved in PDGF signaling.
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Panico, Karine. "Interações moleculares da protéina tirosina fosfatase de dupla especificidade 3 em células HeLa submetidas a estresse genotóxico". reponame:Repositório Institucional da UFABC, 2012.
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Bhansali, Priyanka. "Investigating the role of an atypical dual-specificity phosphatase DUSP28 in mammalian cells". Thesis, 2023. https://etd.iisc.ac.in/handle/2005/6147.
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Dual-specificity phosphatases (DUSPs) belong to the protein tyrosine phosphatases (PTP)
subfamily and dephosphorylate, both serine/threonine and tyrosine residues of proteins and
non-protein substrates. A subgroup of DUSPs called ‘atypical’ are associated with cellular
processes such as apoptosis and proliferation. Atypical DUSPs share a high degree of
similarity with the MKP (mitogen-activated protein kinase) phosphatase subfamily but lack
the N-terminal regulatory domain responsible for substrate specificity. Therefore, the
atypical-DUSPs possess a single catalytic PTP domain. Recent approaches show that atypical
DUSPs are differentially expressed in various cancers. A member of this family is DUSP28,
whose biological function remains unexplored. The level of expression (mRNA and protein)
of DUSP28 has been shown to be elevated in hepatocellular carcinoma (HCC), pancreatic
and breast cancers. Further, its expression has been shown to increase migration, invasion,
and viability through the activation of CREB, AKT, and ERK1/2 signaling pathways in
pancreatic and breast cancers. DUSP28 also modulates the cell cycle in HCC by arresting the
cells in the S phase with a concomitant decrease in G1 phase cells. In this study, we have
endeavoured to characterize the localization, function, substrate recognition, and pathways
associated with DUSP28 in HeLa cells.
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Yeh, Yi-Yan, i 葉宜艷. "The role of DUSP21 in chronic myeloid leukemia cells and its potential application". Thesis, 2018. http://ndltd.ncl.edu.tw/handle/vrnq4j.
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Min, Su Fang, i 蘇芳民. "The difference of solvent-free microwave extraction and hydro-distillation extraction from Lychee (Litchi chinensis Sonn.) leaves in the compositions and biological activities". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/dusud8.
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碩士嘉南藥理大學
化粧品應用與管理系
103
Hei Yeh lychee (Litchi chinensis) was originated in Southern China. Now this fruit distributes in subtropical areas, and was the first kind of lychee introduced into Taiwan. The harvest season of Hei Yeh lychee is June to early July. In appropriate seasons, the lychee is pruned, and the cut leaves are thrown away. However, it seems a shame to throw away these leaves. Thus, this study employed hydrodistillation (HD) and solvent-free microwave extraction (SFME) to extract lychee-leaf essential oil from the pruned leaves of Hei Yeh lychee. To endow the oil with economic value, the oil’s activity was examined to evaluate its anti-bacterial, anti-inflammatory, antioxidant, and whitening characteristics. Before HD and SFME were employed to extract the essential oil, lychee leaves were cleaned, washed, dried in shade, and shredded. Gas chromatography–mass spectrometry (GC-MS) was adopted to analyze the components of the lychee-leaf essential oil, and the oil was also examined to evaluate its anti-bacterial, anti-inflammatory, antioxidant, and whitening characteristics. Finally, the two extraction methods were compared. The average yield of the lychee-leaf essential oil was 0.88 g/kg using HD, and 0.35 g/kg using SFME. The GC-MS analysis results indicated that the major components extracted by HD were α-Curcumene (27.815%), β-Bisabolene (27.198%), and (-)-α-zingiberene (19.385%), and were α-Curcumene (41.100%) and β-Bisabolene (28.214%) using SFME. α-Curcumene was the primary element extracted by both the two extraction methods. In the anti-inflammatory test, the essential oil extracted by SFME was superior in inhibiting 5-Lipoxygenase to that by HD; and the essential oil extracted by SFME was superior in removing NO free radicals to that by HD. In the antioxidant test, the essential oil extracted SFME was superior in removing DPPH free radicals to that by HD; the essential oil extracted by SFME was superior in inhibiting β-Carotene oxidation to that by HD; and the essential oil extracted by SFME was superior in inhibiting tyrosinase to that by HD. In the anti-bacteria activity test, the essential oil extracted by SFME was superior in the minimum inhibitory concentration (MIC) of P.acnes, P.ovale, E.coli, and S.aureus to that by HD; and the essential oil extracted by HD was superior in the minimum inhibitory concentration (MIC) of C.albicans and P.aeruginosa to that by SFME.
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Liu, Fan-Hua, i 劉凡華. "The Career Exploration and Choice of Mathematically and Scientifically Talented Senior High School Students". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/duspnu.
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碩士臺北市立大學
特殊教育學系
107
The study was to discuss the status quo of mathematically and scientifically talented senior high school students in developing and choosing careers, checking whether there were differences between the backgrounds of student, such as sex, living area, and schools, through questionnaire survey. The questionnaire was compiled through the research of Lin in 2007, which was based on the theory of vocational choice. In detail, the research objects were 184 mathematically and scientifically talented senior high school students randomly scattered over northern, central, southern, and eastern Taiwan. The collected data were analyzed through descriptive statistical analysis, chi-square analysis, independent sample t-test, homogeneity of variance, and one-way ANOVA, under 100% effective returned ratio of questionnaire. The results revealed that most students belonged to research personality, and personal need achievement, moreover, they valued their family and credence in life and interpersonal relationship respectively. Those students also loved their ways of living embedded in working values, with the moderate or slightly lower consistency between personality and environment and the high consistency between personality and expected work, activity interest, what I could do, work interest, personality, self-assessment of ability. As for the differences between the backgrounds of career explorations, female students were significantly scored higher than males in artistic type; students in central area were significantly scored higher than students in northern and southern area in artistic type; there were significantly differences between schools in artistic type, no significant differences after ad hoc analysis, however. As for the differences between the backgrounds of career choice, there was no significant difference between personality and expected work, activity interest, what I could do, work interest, personality, self-assessment of ability consistency whereas there were significant differences between living are and schools, and personality and activity interest. Male students were significant scored higher than females between personality and environmental harmony in the harmony of personality and environment, and no significant differences in living area, significant differences between schools. At last, recommendations were delivered through the results: providing career counseling and more diverse curriculum, thereby enhancing the humanities culture and thinking level, refering for practical education consulting and relevant research in the future.
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Shih-ChiehLin i 林世杰. "The roles of dual specificity phosphatase-2 (DUSP2) in tumor progression and drug resistance". Thesis, 2011. http://ndltd.ncl.edu.tw/handle/34067369840209549548.
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Pei-ChiHou i 侯沛琪. "The functional role of dual-specificity phosphatase 2 (DUSP2) in cancer-stemness and epithelial-mesenchymal transition (EMT)". Thesis, 2017. http://ndltd.ncl.edu.tw/handle/8uj4u3.
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Wang, Hsiao-Chun, i 王筱珺. "Development of Anti-DUSP13 Antibody for Acquired Gefitinib Resistance in Lung Adenocarcinoma". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/42891389523009595536.
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碩士國立臺灣大學
醫學檢驗暨生物技術學研究所
102
Gefitinib is an EGFR-tyrosine kinase inhibitor that has excellent antitumor activity in the advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the dramatic response to such inhibitors, 30-40% of patients seem to have intrinsic resistance and ultimately get a rapid relapse. However, the underlying mechanisms of such resistance to gefitinib are not completely understood. In our previous study, we used a pooled-based RNAi library screening which contains 16,000 shRNAs targeting all of known human kinases, phosphatases, and deubiquitinase to discover new candidates that confer acquired resistance to gefitinib. We identified a novel gene, dual-specificity phosphatase 13 (DUSP13), may be involved in the mechanism of acquired-gefitinib resistance. DUSP13 encodes two different functional proteins: DUSP13A and DUSP13B. Previous studies showed that DUSP13A functions as a novel regulator of apoptosis signal-regulating kinase 1 (ASK1) and DUSP13B has phosphatase activity that inactivates mitogen-activated protein kinase (MAPK) activation, but both of them have not been reported to involve in drug resistance of lung cancer. To investigate the role of DUSP13 in acquired-gefitinib resistance, detecting the protein expression of DUSP13A and DUSP13B specifically is necessary. Due to there is neither commercially available anti-DUSP13A nor anti-DUSP13B antibody, we generated two specific antibodies that specifically react DUSP13A and DUSP13B proteins by New Zealand white rabbit immunization, and try to elucidate which protein plays the important role conferring acquired resistance to gefitinib. On the other hand, the in vitro colony formation assay showed that knockdown of DUSP13 inhibited colony forming ability in gefitinib treated gefitinib-resistance cells PC9. Two increased apoptosis markers, cleaved poly ADP-ribose polymerase (PARP) and cleaved caspase 3, assayed by Western blot and increase of subG1 phase assayed by flow cytometry are observed in the DUSP13 silenced gefitinib-resistance cells in presence of gefitinib. The previous study in our laboratory found that knockdown of DUSP13 not only restored gefitinib sensitivity in vitro but also decreased in vivo tumor growth in low dose gefitinib (10 mg/kg/day) in the xenograft mouse model. Previous study indicated that the mechanism of acquired resistance to gefitinib in PC9/gef cells may be due to activating ERK pathway induced by NRAS mutation. Another study reported that DUSP13B inactivates MAPK activation. We suppose that DUSP13B may play an important role in MAPK pathway activation in the acquired gefitinib-resistance PC9 cells.
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Sladeček, Stanislava. "Hledání substrátové specifity DUSP fosfatáz". Master's thesis, 2016. http://www.nusl.cz/ntk/nusl-345023.
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Dual specificity phosphatases (DUSP) are enzymes that dephosphorylate both phosphoserine/threonine and phosphotyrosine residues on one substrate. Most of them specifically dephosphorylate family mitogen-activated protein kinases (MAPK). Number of DUSPs increases with complexity of organisms and in human genome there are 25 DUSPs described. Some DUSPs can dephosphorylate only one protein while other interact with wider spectrum of substrates. Except for substrate specificity DUSPs differ in expression, subcellular localization etc. Although first DUSPs were described about 20 years ago, a clear factor responsible for their substrate specificity is not known. This works uses in silico methods to discover and describe similarities and differences between DUSPs which may be important in determining DUSP specificity. Key words: phosphatase, kinase, DUSP, MAPK, substrate specificity, conservation of residues, phylogenetic tree, in silico methods
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Wang, Han-Yu, i 王函悠. "Study of the roles of DUSP1 in autophagy regulation in macrophages". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/67678870408209188940.
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碩士國立臺灣大學
動物學研究所
101
Autophagy, a degradation system conserved from yeast to human, helps cells survive many stress conditions, such as starvation and pathogen infection. Under stress conditions, cells react and perform appropriate stress responses in order to increase the survival rates of cells or an individual. To best response to different stress conditions, there are many pathways reacting to different stresses. The mitogen-activated protein kinases (MAPK) cascade, which is activated after the stimulation of Toll-like receptors (TLR), responds to pathogen infection, and plays an important role in innate immunity. After MAPK activation, DUal Specificity Phosphatase 1 (DUSP1) is up-regulated, and it will down-regulate MAPK activities to decrease the immune responses. This negative feedback loop could maintain the activities of immune responses within a suitable level. Because autophagy is also correlated to the control of immune responses, it is of interests to know if DUSP1 affect autophagy activity. In this study, I found that DUSP1 regulated autophagy via controlling MAPKs activities. Inhibiting DUSP1 in raw 264.7 cells up regulated the activities of autophagy and two subsets of MAPKs (ERK and p38), and this activation of autophagy was not related to the change of the activity of mammalian target of rapamycin (mTOR) complex, which is the main regulator of starvation-induced autophagy. Furthermore, inhibiting ERK activity could block inhibiting DUSP1-induced autophagy. I also found that an autophagy inhibitor regulated IL-6 secretion and DUSP1 mRNA expression after TLR stimulation. Overall, these results suggest that DUSP1 and autophagy may mutually affect each other to maintain cellular physical homeostasis.
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Hsu, Chia-lun, i 許家倫. "Biological characterization of RBMS3 transgenic mice and biochemical analysis of the interactions between RBMS3 and Spindlin-3, DUSP14". Thesis, 2008. http://ndltd.ncl.edu.tw/handle/05462469237196100702.
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碩士國立中正大學
分子生物研究所
96
Many gene products that are essential to pancreas development, such as Pdx-1、Ptf1a、Ngn3 and Nkx family, generally show strong expression specifically in developing pancreas. Previously, a protein with RNA binding motif, named RBMS3, was found to be expressed strongly in early embryonic pancreas. Although RBMS3 was first identified and cloned by screening of a fibroblast expression library with the labeled DNA fragment derived from the promoter of the mouse collagen ?(I) gene, its specific presence in developing pancreas has been confirmed by in situ hybridization and immunofluorescence staining. In order to study the function of RBMS3, a yeast two-hybrid system had been applied to identify RBMS3-interacting proteins, and several genes including SPIN3 (Spindlin 3), DUSP14 (dual specificity phosphatase 14) were identified from the screening. I have confirmed the interactions between SPIN3 and DUSP14 with RBMS3 by pull down assay and co-immunoprecipitation. In addition, I have generated a transgenic construct that contains the RBMS3 cDNA under the control of Pdx-1 promoter. This construct had been used to generate transgenic mice that overexpress RBMS3 in developing pancreas. I have measured blood sugar of fasted transgenic mice when they were 6 weeks old. However, there was no significant difference between wild and transgenic mice. I have also attempted to observe differences in cell-type composition in the embryonic, postnatal and adult pancreas. However, no apparent influence of the ectopic RBMS3 was observed on these transgenic mice. It is likely RBMS3 modulates pancreas development with a more subtle mechanism. The results described above may provide some information of RNA-binding protein’s function and regulation in pancreas development. This is a beginning for researchers to note the role of RNA-binding proteins in organogenesis.
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Hammer, Michael [Verfasser]. "The MAPK phosphatase DUSP1 : an IL-10-induced negative regulator of macrophage activation / Michael Hammer". 2007. http://d-nb.info/988068958/34.
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Varela, Tatiana. "Analysis of transcriptional and post-transcriptional regulation of DUSP4, a human gene associated with colorectal cancer (CRC)". Master's thesis, 2017. http://hdl.handle.net/10400.1/10554.
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Dissertação de mestrado, Biologia Molecular e Microbiana, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2017Colorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of death worldwide. Dual specificity phosphatase 4 (DUSP4) – a regulator of the mitogen-activated protein kinase activity – has been recently associated with CRC after its expression was found to be up-regulated in tumour tissue. However, expression data are limited and mechanisms underlying DUSP4 regulation poorly understood. Objectives of this work were to collect basic data on the expression of the different transcript variants in CRC samples and on the transcriptional and post-transcriptional regulation of human DUSP4. The expression of transcript variants 1, 2 and X1 was determined by qPCR in tumour and TAN tissues from 28 patients. All transcripts were overexpressed in tumour tissues, although to different extents. Variant X1 was the most up-regulated (>13 folds) and associated with several clinicopathological parameters (KRAS mutation and poorly differentiated tumour). DUSP4 transcript overexpression was also found to be possibly associated with a reduced overall survival and a more severe tumour stage. DUSP4 promoters activity was assessed using reporter promoter constructs and vectors expressing cancer-related transcription factors. While CTCF and FOXA1 regulated promoter#2 activity (i.e. transcription of variants 2 and X1) and STAT3 promoter#1 activity (i.e. the transcription of variant 1), SP1 and YY1 regulated both promoter activity, although to different extent. Preliminary data collected from the in silico analysis of DUSP4 3’-UTR revealed putative binding sites for miR-137, a microRNA acting as tumour suppressor in several cancers, including CRC. In conclusion, DUSP4 transcripts are all overexpressed in CRC tissues and have therefore the potential to serve as disease markers, especially variant X1. DUSP4 expression is regulated by cancer-related transcription factors in a promoter-specific manner, i.e. the expression of variant 1 and variants 2/X1 is controlled by different regulatory mechanisms, although up-regulated in a CRC context.
Existem mais de duzentos tipos diferentes de cancro, podendo-se desenvolver em qualquer parte do corpo humano. O cancro colorretal (CCR) é o terceiro tipo de cancro mais comum em todo o mundo, após o cancro do pulmão e da mama, com aproximadamente 1,3 milhões de novos casos diagnosticados por ano, e a quarta causa principal de morte relacionada com o cancro, sendo responsável por cerca de 690 mil mortes por ano no mundo. Em Portugal, é o segundo tipo de cancro mais frequente, sendo que a mortalidade associada ao CCR tem vindo a aumentar constituindo um problema crescente na nossa sociedade. Relativamente às suas características moleculares, manifestações clínicas, sensibilidade aos tratamentos e prognóstico, o CCR é uma doença complexa e heterogénea, que se desenvolve de uma forma lenta, nas células epiteliais do revestimento do cólon ou do reto, como consequência da acumulação progressiva de alterações genéticas e epigenéticas em genes envolvidos na proliferação celular, diferenciação e reparação do ADN. As principais vias envolvidas na patogénese do CCR são a via de instabilidade cromossómica (CIN), a via de instabilidade de microssatélites (MSI) e a via do fenótipo metilador de ilhas CpG (CIMP), embora a via mais comum e melhor caracterizada seja a CIN, sendo identificada em quase 85% de todos os casos. Existem três padrões de ocorrência do CCR: esporádico (70-85% dos casos), hereditário e familiar. Não existe uma causa específica para o CCR, no entanto, vários fatores de risco estão associados ao seu desenvolvimento, incluindo fatores genéticos e ambientais. O risco de desenvolver CCR aumenta com a idade, sendo que mais de 90% dos casos são diagnosticados em indivíduos com mais de 50 anos, embora a sua incidência esteja a aumentar entre as pessoas mais jovens. Recentemente, a proteína DUSP4 (fosfatase de dupla especificidade 4) tem sido associada a mecanismos de doenças, inclusivamente no cancro. Esta fosfatase regula negativamente a atividade das MAPKs (proteínas quinase ativadas por mitógenos), que desempenham um papel crucial na proliferação e diferenciação celular e apoptose, através da desfosforilação de ambos os resíduos fosfoserina/treonina e fosfotirosina. A proteína DUSP4 é localizada estritamente no núcleo e expressa em diversos tecidos, tais como: mama, cérebro, pulmão, cólon e reto. Existem evidências de que a expressão do DUSP4 é desregulada em alguns tumores, como por exemplo no CCR. Vários estudos mostraram a sobre-expressão do DUSP4 em tecidos e linhas celulares de cancro colorretal em comparação com tecidos e linhas celulares normais. No entanto, se a DUSP4 funciona como um supressor de tumor ou um promotor de tumor ainda é controverso. Uma vez que, os dados sobre a expressão do DUSP4 são limitados e os mecanismos subjacentes à sua regulação são pouco compreendidos, são necessários mais dados para decifrar a complexidade dos mecanismos subjacentes ao papel do DUSP4 no CCR e a identificação de fatores que regulam a expressão do DUSP4 ao nível transcricional e pós-transcricional representa um passo importante para uma melhor compreensão desses mecanismos. Portanto, o objetivo principal deste trabalho consistiu em analisar a expressão dos diversos transcritos do DUSP4 num conjunto de amostras humanas de CCR e correlacioná-la com fatores clinico-patológicos, e coletar dados valiosos sobre a regulação transcricional e pós-transcricional do DUSP4 humano. A expressão dos transcritos 1, 2 e X1 do DUSP4 foi determinada por qPCR em tecidos colorretais de nove pacientes saudáveis e em tecidos normais associados ao tumor (TAN) e tumorais de 28 pacientes com cancro colorretal. Os resultados mostraram que todos os transcritos analisados estavam significativamente sobre-expressos (p<0.0001) nos tecidos tumorais em comparação com os tecidos TAN, embora em diferentes extensões, sendo o transcrito X1 o mais sobre-expresso (> 13 vezes) e também o que apresentou mais associações com parâmetros clinico-patológicos do CCR (mutação no gene KRAS e tumor pouco diferenciado). Apesar de não ser estatisticamente significante, a sobre-expressão de todos os transcritos parece ter sido associada a uma reduzida sobrevivência e a um estadio tumoral mais grave. Para determinar a significância destas associações, deverá ser avaliado um maior conjunto de amostras. A análise funcional das duas regiões promotoras do DUSP4 (promotor 1 – montante do exão 1; promotor 2 – montante do exão 2), que provavelmente levam à transcrição das diferentes variantes, foi realizada através de transfecções transientes, em células HEK-293, usando construções contendo os fragmentos das duas regiões promotoras a montante do gene da luciferase. Embora numa extensão diferente, ambas as regiões promotoras do DUSP4 mostraram serem funcionais pois induziram a transcrição do gene da luciferase. Efetuou-se uma análise in silico que indicou a possível presença de sequências de reconhecimento de fatores de transcrição relacionados com o cancro nestas regiões promotoras do DUSP4. A funcionalidade de vários destes locais de ligação foi confirmada in vitro, através de co-transfecções das construções repórter contendo cada fragmento dos promotores com vetores de expressão contendo cada fator de transcrição. Os nossos resultados mostraram que, enquanto o CTCF ativou e o FOXA1 reprimiu, especificamente, as construções do promotor 2 (levando à transcrição das variantes 2 e X1), o STAT3 regulou positivamente o promotor 1 (levando à transcrição da variante 1). O SP1 e YY1 regularam positivamente construções de ambos os promotores, embora as do promotor 2 numa maior dimensão. A análise in silico da região 3'-UTR do DUSP4 identificou locais de ligação putativos promissores para o miR-137, um microRNA que tem sido implicado como um supressor de tumor em vários tipos de cancro, inclusivamente no cancro colorretal. Em conclusão, todas os transcritos do DUSP4 analisados neste estudo (1, 2 e X1) encontraram-se sobre-expressos em tecidos de cancro colorretal, em comparação com as amostras de tecido normal dos mesmos pacientes e, portanto, têm potencial para servir como marcadores da doença, especialmente a variante X1. A expressão do DUSP4 é regulada de uma forma específica por fatores de transcrição relacionados com o cancro, isto é, a expressão da variante 2 e das variantes 2/X1 são controladas por diferentes mecanismos reguladores. Portanto, no âmbito deste trabalho foram obtidos dados valiosos sobre a expressão dos diversos transcritos do DUSP4 em amostras de CCR, que no nosso melhor conhecimento consistiu no primeiro estudo a avaliá-las separadamente, e sobre a regulação transcricional e pós-transcrição do DUSP4.
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Zih-ChunWu i 吳姿錞. "Roles of Oct4 in Regulation of Dual-Specificity Phosphatase 6 (DUSP6) Expression and Its Relevance to Lung Cancer". Thesis, 2010. http://ndltd.ncl.edu.tw/handle/41615854058981949384.
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碩士國立成功大學
生物化學研究所
98
Octamer 4 (Oct4) is a POU domain-containing transcription factor encoded by Pou5f1 and required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells. However, Oct4 has been detected in several human tumors, suggesting a potentially critical role in tumorigenesis. Dual-specificity phosphatase 6 (DUSP6) is one of the mitogen-activated protein kinase (MAPK) phosphatases (MKPs) and its inactivation of extracellular signal-regulated kinases 2 (ERK-2) is believed as to function as a tumor suppressor in pancreatic cancer. In contrast, DUSP6 is closely associated with an increased risk of recurrence and decreased overall survival among patients with non-small cell lung cancer. Moreover, chromatin immunoprecipitation (ChIP) assay revealed that DUSP6 may be a potential downstream target of Oct4 in undifferentiated mouse ES cells. Down-regulation of DUSP6 mRNA expression in Oct4-knockdown mouse ES cells was also demonstrated in the public domain database. However, the mechanism underlying the regulation of DUSP6 expression by Oct4 is still unclear. The aim of this study was to study the association of Oct4 and DUSP6 in lung cancer and to elucidate its mechanism of action. My results revealed that there was a positive correlation between the expression of Oct4 and DUSP6 in lung cancer cells. Overexpression of Oct4 enhanced the expression of DUSP6 at both mRNA and protein levels. Chromatin immunoprecipitation (ChIP) and reporter assays showed that Oct4 enhanced the promoter activity of DUSP6 through direct binding to its promoter to regulate DUSP6 gene expression. Oct4 also enhanced the proliferation rate and migratory ability of lung cancer cells in vivo. Taken together, these results suggest that Oct4 regulates DUSP6 expression to initiate signal transduction cascades, leading to promoting the metastasis of non-small lung cancer cells. In the future, I will focus on studying the effects of Oct4-mediated DUSP6 expression on enhancing tumor migration and invasion in vitro and in vivo.
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Casteel, Maximilian Wilhelm [Verfasser]. "Bedeutung von DUSP1 und Expression MAPKinasen-spezifischer Transkriptionsfaktoren während der zellulären Antwort auf Deoxynivalenol / von Maximilian Wilhelm Casteel". 2011. http://d-nb.info/1011042738/34.
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Chu, Hsiao-Chuen, i 朱曉芊. "The Biochemical and Biological Functions of DUSP 23 In Lung Cancer Cells". Thesis, 2009. http://ndltd.ncl.edu.tw/handle/77424694831569273286.
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碩士國立清華大學
分子醫學研究所
97
Dual-specificity phosphatases (DUSPs) have the ability to dephosphorylate both phosphotyrosine and phosphoserine/threonine residues. DUSPs are currently known to be involved in the negative regulation of MAPKs (mitogen-activated protein kinases) signaling pathway and cell cycle transitions. However, there are some small DUSPs whose functions remain unknown. Some DUSPs are called atypical DUSPs, because they contain only the consensus DUSP catalytic domain. DUSP23 contains 151 amino acids with molecular mass of 15~16 kDa, and it’s the smallest atypical DUSPs whose function is unknown. According to a previous, DUSP23 was expressed in most fetal tissues but in only testis and colon during adulthood. According to our microarray, RT-PCR, and Western blotting data, we showed that DUSP23 was transcriptionally inhibited when EGFR or mutant EGFR was overexpressed in H1299 non-small cell lung cancer cell line. Moreover, DUSP23 could reduce EGF-induced activation of EGFR and inhibit Src activity. Protein phosphatase assay showed that EGFR and Src were not direct substrates of DUSP23. As for functional assays, we found that DUSP23 could not alter cell growth and migration, but could affect cell morphology in a 3D culture model. And we found there is no significant correlation between the expression levels of EGFR and DUSP23 in several NSCLC cell lines. These results indicated that DUSP23 might be the negative regulator of EGFR signaling pathway in H1299. However, whether DUSP23 reduces EGF-induced activation of EGFR through the inhibition of Src activity is still under investigation.
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Chen, Hsin-Yu, i 陳辛羽. "Regulation of Cell Migration and Focal adhesion complexes Phosphorylation by An Atypical Dual specificity phosphatase (DUSP) VHR". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/21913737814118242392.
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碩士東海大學
生命科學系
102
Protein tyrosine phosphorylation is important for signaling transduction pathways. Dysfunction of protein tyrosine phosphorylation may cause diseases from cancer to immune disorders in human beings. Vaccinia H1-related phosphatase (VHR) is the first identified mammalian dual-specificity phosphatase (DUSP). Unlike typical DUSPs, VHR lacks mitogen-activated protein kinase (MAPK)-binding domain, and shows poor activity against MAPKs. Recent study shows that epidermal growth factor receptor (EGFR) is a direct substrate of VHR, and that overexpression of VHR down-regulates EGFR phosphorylation and signaling. VHR expression is significantly lower in non-small cell lung cancer (NSCLC) tissues suggesting that down-regulation of VHR expression is involved in NSCLC pathogenesis. However, the biological functions of VHR in NSCLC cell is still not clear. My results showed that expression of VHR suppressed cell migration in Trans-well assays. In the presence of EGFR kinase inhibitor (Gefitinib), VHR still can suppress cell migration, indicating that VHR may regulate cell migration through molecules other than EGFR. I identified that Src, paxillin and focal adhesion kinase (FAK) are potential direct substrates of VHR. VHR dephosphorylated FAK on tyrosine 397, 576/577 residues and dephosphorylated paxillin on tyrosine 31 and 118 residues. VHR may affect cell migration through regulating integrin-dependent pathway to affect cell migration ability.
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Huang, Bi-Qiang, i 黃筆強. "Investigation the role of miR-378 in regulation between DUSP and MAPK pathway by using fatty acid as an inducer". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/eyjdb7.
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碩士國立臺北科技大學
化學工程與生物科技系生化與生醫工程碩士班
103
MicroRNAs nowadays are widely used in pharmaceutical industries for cancer therapy. According to our pervious findings, transfected miR-378 into KRAS and BRAF mutated colorectal cancer (CRC) cells could increase cells’ sensitivity to targeted drug- anti-EGFR antibody (Certuximab). Furthermore, fatty acid such as eicosapentaenoic acid (EPA) could significantly induce the expression of miR-378 in cells, consequently regulated the expression level of total protein and phosphorylation of ERK1/2 and result in cell apoptosis. Herein, we hypothesized that miR-378 might negatively regulate the protein of DUSP expression, and further increase the phosphorylation of ERK1/2. The aim of current study reveals the role of miR-378 might involve in regulation of MAPK pathway. Western blotting and phosphatidylserine assay were performed on five CRC cell lines, and the results showed that expression of total protein and phosphorylated ERK1/2, as well DUSP3 protein were consist expression level in all CRC cells either induced by EPA or transfected miR-378. The lower expressed level of total ERK1/2 protein were observed in KRAS and BRAF mutants and wild type CRC cells; however, the level of phosphorylated ERK1/2 protein of KRAS mutants and wild type CRC cells were shown high expression level, but not in BRAF mutant CRC cells. This provided an evidence of increasing sensitivity to anti-EGFR antibody in KRAS mutant cells could result from restoring miR-378. Similarly, lower expression level of DUSP 3 protein only presented in KRAS CRC cells but not in BRAF CRC cells. Accordingly, our findings strongly suggested the tumor development of KRAS mutants and BRAF mutants of CRC might not under the same molecular activities of MAPK pathway. This study also provides a possible concept of treatment strategy for KRAS mutant CRC.
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Robitaille, Alexa. "Étude du rôle de la phosphatase DUSP1 dans la régulation de la réponse immunitaire innée autonome dans les cellules épithéliales pulmonaires lors de l'infection par le virus respiratoire syncytial et le virus Sendai". Thèse, 2017. http://hdl.handle.net/1866/20413.
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Villanueva, Alexander Ian. "The influence of Toll-like receptors on murine invariant natural killer T cell activation". Thesis, 2013. http://hdl.handle.net/10214/7252.
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Invariant natural killer T (iNKT) cells are a versatile subclass of T lymphocytes which recognize glycolipid antigens. iNKT cells are capable of rapidly producing a broad array of cytokines in response to stimulation; thus, they play an important role in the early regulation of a variety of immune responses. It was hypothesized that iNKT cells express functional Toll-like receptors (TLRs) and that stimulation of TLRs by their ligands modulates iNKT cells responses. In the first objective, it was revealed that upon stimulation with anti-CD3 monoclonal antibody and interferon (IFN)-α, expression of TLRs was enhanced in iNKT cells. Furthermore, stimulation of iNKT cells with TLR ligands led to a significant increase in the expression of several cytokines. In the second objective, the mechanisms behind the modulatory effects of the TLR9 ligand (CpG-ODN) on iNKT cells were determined. Altogether, these findings suggest a direct role for TLRs in iNKT cell activation.Ontario Graduate Scholarship