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AMARU, CALZADA ARIEL. "Mechanism of action of Histone Deacetylase inhibitor. Givinostat in Chronic Myeloproliferative neplasm." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/44363.
Texte intégralRésumé :
We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2)V617F myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2V617F MPN compared to JAK2 wild- type myeloid leukemia cell lines. By global gene expression analysis, we observed that GVS modulated 293 common genes in the JAK2V617F cell lines HEL and UKE1. In particular, the hematopoietic transcription factors NF-E2 and C-MYB were downmodulated by the drug specifically in JAK2V617F cells at both the RNA and protein level. GVS had a direct effect on the NF-E2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NF-E2 was also observed in freshly isolated CD34+ cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-STAT 5-extracellular signal- regulated kinase 1/2 inhibition and downmodulation of NF-E2 and C-MYB transcription. In the second part of the thesis we investigated whether clinically achievable concentrations of the histone deacetylase (HDAC) inhibitors givinostat and hydroxyurea induce synergistic cytotoxicity in Jak2V617F cells in vitro and through which possible mechanism. The results suggest that combined treatment with givinostat and hydroxyurea is a potential strategy for the management of Jak2V617F myeloproliferative neoplasms.
2
Ellingsen, Rikke. "Nonlinear Isogeometric Analysis vs NFEA of Tubular Joints." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for konstruksjonsteknikk, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-21878.
Texte intégralRésumé :
In 2005, Hughes et al. introduced the isogeometric analysis. One purpose was to eliminate the conversion between geometry model and analysis model in finite element analyses. NURBS (Non-Uniform Rational B-Splines) were adopted as shape functions and the isoparametric concept was utilized, resulting in the above mentioned analysis method.In this thesis, the differences between traditional finite element analysis and isogeometric analysis have been examined through nonlinear analyses of a gap K-joint subjected to prescribed displacements. The K-joint has been modelled both with solid and thin shell elements in Abaqus/Standard and with solid elements in IFEM. It has been focused on obtaining a mesh of similar refinement for both of the methods to easier be able to compare the results.The results show, as expected, that the thin shell element representation is unsuitable for a three dimensional stress state as around the intersection of the braces and the chord. The analyses with solid elements show a dependence on the continuity of the shape functions. The continuity in an isogeometric analysis is Cp-1 over element borders for basis functions of degree p. In traditional finite element analysis the continuity for solid elements is only C0. This results in differences in the differentiated variables like stresses and strain. Also the calculation of derived values, such as the von Mises stress and principal stresses, has shown to generate differences in the results because this is done differently in Abaqus/Standard and IFEM. The computational time for the isogeometric analyses is higher than for the traditional finite element analyses, and increasing with increasing degree of basis functions because the continuity affects the average bandwidth of the global matrices, and must also be included in the discussions.The conclusion is that more analysis results are needed to be able to make a substantiated conclusion as to which analysis method that is preferable for analyzing a gap K-joint.Regarding which method that is more accurate or conservative, the findings are not consequent.
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Dahmani, Younes. "Uttryck av Nfr2 och dess kliniska roll i klarcellig njurcancer." Thesis, Umeå universitet, Biomedicinsk laboratorievetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-58605.
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Chesney, James R., Nicholas J. Speciale, and Anil K. Agrawal. "Design of the TOPEX-NFEP Utilizing the Functional Component Approach." International Foundation for Telemetering, 1989. http://hdl.handle.net/10150/614728.
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International Telemetering Conference Proceedings / October 30-November 02, 1989 / Town & Country Hotel & Convention Center, San Diego, California<br>TOPEX/POSEIDON is a joint American/French Ocean Topography Experiment undertaken by the National Aeronautics and Space Administration (NASA) and Center National d'Etudes Spatiales (CNES) to acquire, process and verify altimetric sea surface height data so that mean and variable geotropic surface currents of the world's oceans can be mapped. This paper describes the functions and the architecture of the proposed front end to the Telemetry, Command and Communication System (TCCS) used for monitoring the spacecraft health, real time analysis required for supporting satellite analysis, collecting the telemetry data, and commanding the satellite. The system uses specialized hardware developed (herewith called as NFEP) at Goddard Space Flight Center to offload the Host processing and to support the data acquisition in a stand alone mode even in case of failure of the Host machine. The NFEP utilizes the semi-custom and custom very large scale integration (VLSI) devices, microprocessor control, and programmable logic designed to provide a generic NASA Communication (NASCOM) block processing and telemetry frame synchronization.
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Bruder, Carl E. G. "Genetic analysis of neurofibromatosis type 2 (NF2) patients and NF2-associated tumors with emphasis on chromosome 22 deletions /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4370-2/.
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Vahldiek, Kai-Felix. "Allelverluste bei Neurofibromatose Typ 2 (NF2) assoziierten Meningeomen." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=965649512.
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Klungsupya, P. "Nucleotide excision repair of the plasmid borne NFA2 gene in Saccharomyces cerevisiae." Thesis, Swansea University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.637808.
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The role of transcription in repair of UV-induced CPD was investigated in the <I>Saccharomyces cerevisiae</I> <I>MFA2</I> gene. <I>MFA2</I> mutants were constructed for cloning into a yeast artificial chromosome (YAC) by deletion of either the 22nt TATA box sequences (T2Δ<I>MFA2</I>) or 55nt Mcm1 binding site (MΔ<I>MFA2</I>) from its promoter. <I>In vivo</I> transcription analysis using eGFP reporter system reveals a 10-fold reduction in transcription activity for the T2Δ<I>MFA2</I> a cells compared to the WT<I>MFA2 </I>a cells. This reduced transcription level is very close to the level found in α cells where <I>MFA2</I> is inactive. A 7-fold reduction in transcription activity was found for MΔ<I>MFA2</I> in both a and α cells. This result indicates the deletion of the MBS eliminates Mcm1/α2-mediated <I>MFA2</I> repression in α cells dramatically reduced <I>MFA2 </I>expression in a cells. Among 13 CPDs found in the promoter region, three CPDs are increasingly induced following the deletion of the TATA box and MBS sequences. However, their repair rates are not affected. Analysis of NER was performed on individual CPDs in both the transcribed (TS) and non-transcribed (NTS) strands by comparison between the YAC-borne <I>MFA2 </I>and the endogenous gene for each construct. The endogenous <I>MFA2</I> in YAC strains harbouring the WT<I>MFA2</I> and MΔ<I>MFA2</I> constructs, exhibit an identical repair profile. This suggests no genetic variation occurs within the isogenic strain harbouring the three promoter element deletion constructs. The repair results on the TS indicate the fastest rate with t<SUB>50%</SUB> of 1.5 hr for some CPDs in the transcription region of the transcribed strand of the WT<I>MFA2</I>.
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Vigorito, Christian. "Implementazione di algoritmi di stima della distanza con segnali a bassa frequenza." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amslaurea.unibo.it/3534/.
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L’obiettivo di questo lavoro di tesi è stato quello di definire degli algoritmi in grado di comprendere le prestazioni raggiungibili dalla tecnica NFER alternativa in termini di ranging e accuratezza e, di conseguenza, dedurre se il sistema sia utilizzabile o meno.
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Schmid, M. C. "The role of focal adhesion kinase (FAK) in NF2 -/- turmourigenesis." Thesis, Exeter and Plymouth Peninsula Medical School, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701076.
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Johnson, Kristen C. (Kristen Carrie) 1976. "Analysis of the function of the Nf2 tumor suppressor protein, Merlin." Thesis, Massachusetts Institute of Technology, 2003. http://hdl.handle.net/1721.1/29763.
Texte intégralRésumé :
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2003.<br>Vita.<br>Includes bibliographical references.<br>The Neurofibromatosis type 2 tumor suppressor gene (NF2) is mutated in inherited and sporadically occurring central nervous system tumors. The NF2 encoded protein, merlin, shares close sequence similarity in its amino-terminal domain to members of the band 4.1 family of membrane-cytoskeletal linkers. Similarities between merlin and this family suggest a role for merlin in regulating cytoskeletal function. Thus, NF2 may be a novel type of tumor suppressor gene that mediates its tumor suppressor function through interactions with the actin cytoskeleton. However, the molecular and cellular functions of this tumor suppressor gene were largely unknown when the work described here began. Mutational analysis of Nf2 in flies has lead to the identification of a dominant-negative allele, which harbors mutations in the amino-terminal domain of the protein. The work presented here demonstrates that expression of a murine analog of this amino-terminal mutant of Nf2 (termed, Nf2BBA) leads to complete transformation of NIH3T3 fibroblasts in culture. Cells that express Nf2BBA display disruptions of the actin cytoskeleton, lack of contact inhibition of growth, and anchorage-independent growth. In addition, Nf2-deficient mouse embryo fibroblasts (MEFs) exhibited similar contact inhibition and cell-matrix adhesion defects to Nf2BBA expressing cells. Nf2BBA cells continue to cycle under normal growth inhibitory conditions, such as serum withdrawal, and exhibit high levels of the cell cycle regulator, cyclin D1. Elevated levels of cyclin D1 are necessary for cellular transformation following Nf2BBA expression. Nevertheless, the exact mechanism by which Nf2BBA results in cellular transformation remains elusive. Recently published studies have revealed that merlin may regulate members of the RhoGTPase<br>(cont.) family, as absence of Nf2 expression in fibroblasts leads to many phenotypes reminiscent of overactive Rac, such as increased membrane ruffling and increased activity of the c-jun N- terminal kinase (JNK). Our work has extended to the analysis of the role of merlin in the regulation of the Rac pathway. Using rat schwannoma cells and N2-deficient MEFs, we have demonstrated that merlin exerts its inhibitory effects downstream of Rac, through a direct interaction with the p21 activated kinase, Pak. We demonstrate that in the absence of merlin, Pak is active and hyperphosphorylated, and, conversely, when merlin is overexpressed, Pak activity is diminished. The N-terminal half of merlin binds to the functionally conserved Rac/Cdc42 interaction binding (CRIB) domain of Pak. Several models for merlin regulation of Pak activity will be discussed. Finally, the identification of Pak as a kinase that is misregulated in the absence of NF2 may lead to possible avenues for therapeutic intervention.<br>by Kristen C. Johnson.<br>Ph.D.
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Schulze, Karin Marlies Marion. "Herstellung rekombinanter Retroviren, In-vitro-Gentransfer und Expressionsanalyse des NF2-Gens Merlin." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=962345210.
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Mason, Susan. "Investigating pathological mutations in the neurofibromatosis type 2 tumour suppressor gene." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245083.
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Flynn, Sara Jane. "A comparative and exploratory study of the Nfer-Nelson Emotional Literacy Scale in an Irish context." Thesis, University of Exeter, 2010. http://hdl.handle.net/10036/3041.
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Culturally specific development of Emotional Literacy (EL) skills suggest that self report and observer ratings on EL scales would differ across cultures. This study is the first of two which explores and compares the Nfer-Nelson Emotional Literacy scale (Faupel, 2003) scores reported in the manual with those found in an Irish sample with a view to demonstrating its appropriateness as a cross cultural measure of EL. The three part scale comprise student (N=188), teacher (N=163) and parent (N=175) scales. The scales were completed in schools with a disadvantaged (74% of sample) or non-disadvantaged status (26%). Irish scores were organised into categories using percentile ranges to allow for comparative analysis with the original UK sample. Overall patterns of scores were similar but the cut off point for children in need of intervention was higher in the Irish sample. Within sample differences were explored using t-tests and children from disadvantaged backgrounds rated themselves with statistically lower EL than their non-disadvantaged counterparts. Inter-correlations were run to explore the relationships between and within the three scales. A mixed pattern of correlations was found and some evidence supporting Goleman’s construct of EL came from strong consistent relationships (correlation range 0.41-0.77) between the empathy and self-regulation subscales in the three scales. Differences between teacher scores suggests cultural differences in perception of EL and strong relationships between parent and student scales suggests a qualitatively stronger understanding of emotions shared between Irish children and parents compared with their counterparts in the UK. A major limitation of this study is that the Irish sample was largely disadvantaged (74%), whereas the UK sample was nationally representative. Abstract (paper 2/2) This is the second of two papers which explores and compares the Nfer-Nelson Emotional Literacy scale in an Irish context. Emotional Literacy (EL) Scores obtained in paper one are used to explore the reliability (Study 1) and predictive validity (study 2) of the tripartite Nfer-Nelson scale. This scale is comprised of parent, teacher and student scales. Reliability is established, using internal consistency measures for the Total EL for all three scales (α range 0.77-0.92) and also for the majority of component subscales in the teacher scale (α range 0.77-0.88). The children (n= 153) who completed the student scale for paper one were assessed for their academic achievement using a reading attainment test, the Mary Immaculate College Reading Attainment Test (MICRA-T) and also for self esteem using The Culture Fair Self Esteem Inventory (CFSEI). Bivariate regression analysis indicated that academic achievement is predicted by the majority of the components (r range 0.247-0.329) comprising EL and the Total EL (r=0.314) from the teacher scale. Self esteem is predicted by all the components (r range 0.212-0.272) and the Total EL (r=0.285) from the teacher scale and the majority of components (r range 0.2-0.361) and the Total EL (r= 0.384) from the student scale. The items which constitute the scales were investigated and overlaps between the: self-awareness subscale and self esteem items as well as: motivation subscale and aspects of academic achievement bring the discreteness of the associated EL subscales into question. Statistical findings suggest the cross cultural use of the Nfer-Nelson scale. However, difficulties with the face validity of the scale items question the appropriateness of the items used to assess the EL construct. These findings suggest the EL construct to be otherwise acceptable
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Chen, Yaxiong. "Characterization of chicken NF2/merlin and its functions in early limb muscle development /." free to MU campus, to others for purchase, 2003. http://wwwlib.umi.com/cr/mo/fullcit?p3115532.
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Zhan, Yu. "Mixed Lineage Kinase 3 Signaling in Ovarian Cancer and Neurofibromatosis-2." University of Toledo / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1310127039.
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Thaxton, Courtney Lynn. "Mechanisms Promoting Phosphorylation of the NF2 Tumor Suppressor and its Effects on Schwann Cell Development." Doctoral diss., University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2154.
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Neurofibromatosis type 2 is an autosomal dominant disease characterized by the formation of schwannomas and other peripheral neuropathies. The nf2 gene encodes the protein Schwannomin, or merlin. Schwannomin (Sch) is a membrane-cytoskeletal linking protein that suppresses cell proliferation at high cell density and modulates cell shape. Sch's tumor suppressive activity is regulated by its localization, conformation, and phosphorylation at serine 518 (S518). Sch's localization is dependent on binding the scaffold protein, paxillin. Phosphorylation of Sch at S518 regulates its conformation and tumor suppressor function. In a negative feedback loop, unphosphorylated Sch restricts cell proliferation downstream of Rac and p21-activated kinase (Pak), whereas Pak-induced phosphorylation inactivates Sch's ability to inhibit Pak and cell proliferation. Little is known about the function of the phosphorylated form of Sch, or the molecular mechanisms leading to its phosphorylation. Here we demonstrate that Sch-S518 phosphorylation is dependent on paxillin-binding and plasma membrane localization in SCs. Phosphorylation of Sch at the plasma membrane is mediated by Cdc42-Pak and results in altered SC morphology and polarity. Moreover, we have identified two extracellular stimuli that trigger Sch-S518 phosphorylation; these are neuregulin (NRG) and laminin, two potent activators of SC proliferation and myelination. NRG promotes Sch-S518 phosphorylation downstream of ErbB2/ErbB3 through PKA, whereas laminin-1 stimulation of β1 integrin promotes Pak- dependent phosphorylation of Sch-S518. Additionally, we find that Sch promotes process formation and elongation in primary and myelinating SCs, independent of Sch S518 phosphorylation. However, Sch phosphorylation was found to influence SC differentiation, as expression of an unphosphorylatable variant, Sch-S518A, facilitated SC myelination, whereas expression of a phospho-mimicking variant, Sch-S518D, reduced the SC's ability to myelinate. Together, these findings have identified receptor-mediated and paxillin-dependent pathways that regulate phosphorylation and inactivation of Sch's tumor suppressor function. Additionally, these results have elucidated novel normal functions for Sch during peripheral nerve development and myelination, and identify novel therapeutic targets for treatment of NF2 and other peripheral neuropathies.<br>Ph.D.<br>Department of Biomolecular Science<br>Burnett College of Biomedical Sciences<br>Biomolecular Sciences PhD
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Manent, Jan. "Analyse fonctionnelle du gène suppresseur de tumeur NF2 impliqué dans la Neurofibromatose de type 2." Paris 6, 2006. http://www.theses.fr/2006PA066296.
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DEGUEN, BRIGITTE. "Modeles cellulaires permettant l'etude fonctionnelle de la schwannomine, produit du gene suppresseur de tumeurs nf2." Paris 11, 1998. http://www.theses.fr/1998PA112158.
Texte intégralRésumé :
La neurofibromatose de type 2 est une maladie a transmission autosomique dominante qui predispose a la survenue de schwannomes et de meningiomes. Le gene suppresseur de tumeurs nf2, dont les alterations constitutionnelles sont responsables de ce syndrome tumoral hereditaire, code une proteine, la schwannomine, homologue aux proteines erm impliquees dans l'ancrage du cytosquelette d'actine a la membrane plasmique. Afin d'initier l'etude fonctionnelle de la schwannomine, nous avons dans un premier temps genere des reactifs immunologiques specifiques de cette proteine. Par la suite, notre travail de recherche s'est oriente vers le developpement de modeles cellulaires. Nous avons ainsi determine l'effet de mutations du gene nf2 sur la localisation et les proprietes de la schwannomine surexprimee transitoirement dans des cellules hela. Les resultats obtenus suggerent que le domaine n-terminal de la schwannomine est indispensable a la localisation de la proteine sous la membrane ; ce domaine serait de plus implique dans une interaction avec le cytosquelette d'actine que le domaine c-terminal viendrait renforcer. Nous avons egalement entrepris la mise au point de systemes d'expression inductible de la schwannomine dans une lignee de schwannome de rat (systemes tetvp16 et lac switch). Une premiere caracterisation des transfectants stables que nous avons obtenus n'a pas permis de demontrer un effet de la surexpression de la schwannomine sur la proliferation des cellules. Enfin, deux equipes ayant rapporte la presence de mutations du gene nf2 dans des mesotheliomes humains, nous avons decide d'analyser la structure et l'expression du gene nf2 dans dix-huit lignees derivees de ces tumeurs. Nous avons ainsi mis en evidence une extinction du gene nf2 dans onze lignees. Ces lignees, qui presentent differentes modalites d'inactivation du gene nf2, constituent de bons outils pour explorer le mecanisme par lequel la schwannomine exerce son activite suppressive de tumeurs.
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Mani, Timmy. "The Role of Phosphoinositide Binding in Merlin Function." University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1299181100.
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Beltrami, Sarah. "NEUROFIBROMATOSIS TYPE 2 PROTEIN (NF2) AS A REGULATOR OF TUMOR SUPPRESSORS AND VIRAL ONCOPROTEINS IN HUMAN GLIOBLASTOMA." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/239188.
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Biomedical Neuroscience<br>Ph.D.<br>Glioblastomas are the most common brain malignancy occurring in adults with the worst prognosis. Several obstacles have prevented the development of efficacious treatment strategies. Due to the insidious nature of these malignancies, tumors are not typically detected until late in the disease. Further, the delicate nature of surrounding normal brain tissue makes surgery and treatment with cytotoxic chemotherapeutics detrimental to the patient's quality of life. Despite decades of research and aggressive therapeutic strategies, most patients will develop recurrent tumors and succumb to the disease within 1 year of diagnosis. An enhanced understanding of the molecular interplay among tumor suppressors and oncoproteins can greatly contribute to the development of novel therapeutics that will extend life expectancies. The most common abnormality in these tumors is mutation of the p53 gene (TP53). Due to the expansive network of p53-responsive genes, loss of functional p53 prohibits the cell to the ability to regain control of aberrant proliferation in response to oncogenic stresses. Accordingly, glioblastomas have developed several mechanisms to inactivate this potent tumor suppressor. Similar to oncoproteins, viral regulatory proteins utilize p53 to prevent cell cycle arrest. One such example is the protein associated with the human polyoma virus, JC Virus (JCV). JCV is the etiologic agent of the fatal demyelinating disorder, Progressive Multifocal Leukoencephalopathy (PML), seen in severely immunocompromised patients. Infection of oligodendrocytes with JCV leads to their lytic destruction and the development of white matter lesions in PML patients. Its main regulatory protein, large tumor antigen (T-antigen), targets p53 to retain cells in a virus-producing state, thereby conveying an accidental oncogenicity. JCV T-antigen transgenic mice develop a multitude of CNS tumors, including malignant peripheral nerve sheath tumors similar to patients with a form of Neurofibromatosis. Neurofibromatosis types 1 and 2 are inherited cancer disorders resulting from the inactivation of their specific tumor suppressor genes, NF1 and NF2, respectively. Inactivation of the NF2 gene, results in the development of several multiple benign nervous system tumors. Traditionally, NF2 is viewed as a scaffolding protein primarily located at the plasma membrane, where it prevents excessive signaling via several cell surface receptors and their cytoplasmic kinases. NF2 links receptors at the plasma membrane to their cytoplasmic kinases to facilitate contact inhibition. However, NF2 can also interact with an array of cytoplasmic and a few nuclear proteins. To date, little is known about the function of NF2 in tumors not associated with NF2 syndrome. Loss of functional NF2 protein has become a staple of several sporadic cancers including mesotheliomas, and meningiomas. In glial cells, NF2 depletion results in hyperproliferation and development of oncogenic features. In the only prior report addressing the role of NF2 inactivation in glioblastoma, another group demonstrated that NF2 is a potent inhibitor of glioblastoma growth. Previously, our group has identified JCV T-antigen as a nuclear binding partner for NF2 in tumors derived from JCV T-antigen transgenic mice. The association of NF2 with T-antigen in neuronal origin tumors led us to hypothesize that NF2 could regulate the expression of the JCV T-antigen. Here, we report that NF2 suppresses T-antigen protein expression in U-87 MG human glioblastoma cells, which subsequently reduces T-antigen-mediated regulation of the JCV promoter. When T-antigen mRNA was quantified, it was determined that increasing expression of NF2 correlated with an accumulation of T-antigen mRNA; however, a decrease in T-antigen at the protein level was observed. NF2 was found to promote degradation of ubiquitin-bound T-antigen protein via a proteasome dependent pathway concomitant with the accumulation of the JCV early mRNA encoding T-antigen. The interaction between T-antigen and NF2 maps to the FERM domain of NF2 domain of NF2, which has been shown previously to be responsible for its tumor suppressor activity. Co-immunoprecipitation assays performed on a glioblastoma cell line revealed a ternary complex consisting of NF2, T-antigen, and the tumor suppressor protein, p53. Furthermore, these proteins were detected in various degrees in tumor specimens from patients, suggesting that these associations may occur in vivo. Collectively, these results demonstrate that NF2 negatively regulates JCV T-antigen expression by proteasome-mediated degradation, and suggest a novel role for NF2 as a suppressor of JCV T-antigen-induced oncogenesis. Studies in mouse and human tumors have inferred a relationship between NF2 and the primary target for JCV T-antigen, p53. In mouse models of cancer, concurrent loss of NF2 and p53 genes generates a highly malignant phenotype. Other groups reported that loss of NF2 and p53 in human tumors correlated with enhanced tumor grade. In transformed fibroblasts, NF2 can enhance the expression of p53 and promote p53-mediated apoptosis. However, the molecular details of the NF2 and p53 relationship have not yet been elucidated. Based on our data and previous literature, we believed that there is a tumor suppressive synergy that exists between NF2 and p53. Contrary to our expectations, we discovered that NF2 overexpression in U-87 MG cells results in the decline in p53 expression. We observed this effect in the p53-null cell line, Saos2, and in the presence of proteasome inhibitors. Further, we determined that NF2 utilizes cysteine proteases as part of a post translational mechanism to suppress p53 expression. Mutant p53, present in many glioblastomas, was resistant to NF2-mediated degradation. Additionally, we determined that p53 can reciprocally repress NF2 expression, by a post translational mechanism, independent of the proteasome, lysosome, or cysteine proteases. NF2 conformation mutants, S518A and S518D, can both degrade p53 and localize to the cytoplasm. However, the constitutively inactive, open form of NF2, S518D is resistant to p53-mediated degradation. NF2 and p53 do not directly interact, yet we were able to detect these proteins in the same patient glioblastoma samples. Using a conformation-specific antibody, we speculate that the majority of our glioblastoma samples may contain mutated p53. This novel relationship between NF2 and p53 we believe will have strong implications for chemotherapeutic sensitization of these typically resistant tumors. Cumulatively, these studies will provide evidence for novel tumor suppressive roles for NF2 and a greater understanding of the molecular events that shape glioblastoma progression.<br>Temple University--Theses
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Kukuyan, Anna-Mariya. "ROLE OF BAP1 IN MESOTHELIOMA AND MELANOMA PREDISPOSITION." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/556760.
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Biomedical Sciences<br>Ph.D.<br>BAP1 (BRCA-Associated Protein1) is a tumor suppressor gene encoding a deubiquitinating enzyme (DUB) that regulates many facets of cellular biology. Genetic studies have demonstrated that somatic BAP1 mutations occur in numerous cancer types and that germline BAP1 mutations lead to a cancer susceptibility disorder that predisposes individuals to various tumors, in particular malignant mesothelioma (MM) and both uveal melanoma (UM) and cutaneous melanoma (CM). The Testa laboratory has identified several families (including one in Louisiana, designated Lou) with germline BAP1 mutations, in which there were recurrent cases of MM, UM, and CM. We generated a Bap1 mutant mouse model with a knockin mutation identical to that observed in the Lou family (Bap1+/Lou ) to test whether this mutation alone confers susceptibility to ultraviolet (UV) light-induced melanomagenesis either alone or in combination with a mutation found in a well-established Hepatocyte Growth Factor (HGF)/Scatter Factor transgenic mouse model. Neither Bap1+/Lou, HGF, nor Bap1+/Lou;HGF mice showed a significantly higher incidence or shorter latency of UV light-induced melanoma than wild type (WT) mice. The study also suggests that germline mutation of Bap1 alone does not cause an increased incidence of UV-induced melanomas under the conditions used in this investigation. Recent evidence indicates that BAP1 participates in the DNA damage repair response, suggesting that BAP1’s role in tumorigenesis could be particularly important in cancers associated with environmental carcinogens such as ultraviolet irradiation (UVR). To further investigate the role of BAP1 (Bap1 in the mouse) in DNA damage, we first knocked down BAP1 in human melanocytes as well as Melan-A and Melan-C mouse melanocytes and then exposed the cells to UVR, followed by analysis of DNA damage repair. UVR-induced and steady state levels of DNA damage were higher in BAP1-knockdown cells compared to shGFP-control cells. Levels of UVR-related DNA damage markers such as p53, γH2AX and CPD (cyclobutane pyrimidine dimers) were increased following BAP1 loss and UVR treatment. Cell cycle analysis by flow cytometry demonstrated that cells with knockdown of BAP1 and post UVR treatment showed a higher proportion of cells in S/G2 phase. Such an effect could be due to BAP1 loss and consequent inability to repair DNA damage and/or cell cycle progression. These data are consistent with a role for BAP1 in UVR-induced DNA damage repair. In MM, it is unclear to what extent BAP1 mutations cooperate tumorigenically with mutations of other tumor suppressor genes (TSGs) implicated in MM, such as CDKN2A and NF2. While germline mutations of BAP1 clearly predispose to MM, whether somatic mutations of BAP1 drive a more aggressive, metastatic tumor phenotype may depend on the disease type. For such studies, we used conditional knockout (CKO) mice along with intrathoracic (IT) or intraperitoneal (IP) injection of adenovirus expressing Cre recombinase (Adeno-Cre) to excise critical homozygously floxed TSGs in the mesothelial lining. These labor-intensive experiments demonstrated that while homozygous deletion of Bap1, Cdkn2a, or Nf2 alone in the pleural cavity (IT) of genetically engineered mouse (GEM) models gave rise to few or no MMs, inactivation of Bap1 cooperated with loss of either Nf2 or Cdkn2a to drive development of MM in ~20% of double CKO mice, and a high incidence (22/26, 85%) of MMs with short latency (12 weeks) was observed in Bap1;Nf2;Cdkn2a (triple)-CKO mice. The same trend was confirmed when the same gene combinations were homozygously deleted IP in these same GEM models, except that a much higher incidence of MM was observed in homozygously floxed Bap1 (Bap1f/f) mice injected IP versus IT, which may be due to a larger cell surface area of the peritoneum. Adeno-Cre treatment of normal mesothelial cells from Bap1f/f;Nf2 f/f;Cdkn2 f/f mice, but not from mice with knockout of one or any two of these tumor suppressor genes, resulted in robust spheroid formation in vitro, suggesting that homozygous deletion of all three of these TSGs is sufficient to drive a cancer stem cell-like potential. RNA-seq analysis of pleural MMs from triple-CKO mice revealed enrichment of many genes transcriptionally regulated by the polycomb repressive complex 2 (PRC2). Other genes upregulated in MMs from triple-CKO mice included Vegfd and Pak3, which encode proteins involved in angiogenic and cell motility pathways. In conclusion, we hypothesize that inherited mutations of BAP1 may increase susceptibility to certain environmental factors that may induce DNA damage and contribute to cancer development. Our data also indicate that cooperative somatic inactivation of Bap1, Nf2, and Cdkn2a results in rapid, highly aggressive MMs, and that deletion of Bap1 contributes to tumorigenesis, in part, by loss of PRC2-mediated gene repression of tumorigenic target genes and by acquisition of stem-cell potential. Thus, our studies suggest a potential avenue for therapeutic intervention.<br>Temple University--Theses
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Worseck, Josephine Maria. "Characterization of phosphorylation-dependent interactions involving neurofibromin 2 (NF2, merlin) isoforms and the Parkinson protein 7 (PARK7, DJ1)." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16533.
Texte intégralRésumé :
Veränderungen in phosphorylierungsabhängigen Signalwegen, Akkumulation von Proteinaggregaten im Gehirn und neuronaler Zelltod sind Neurodegenerationskennzeichen und Indikatoren für überlappende molekulare Mechanismen. Um Einblicke in die involvierten Signalwege zu erhalten, wurde mit Hilfe eines modifizierten Hefe-Zwei-Hybrid (Y2H)-Systems für 71 Proteine, die mit neurologischen Erkrankungen assoziiert sind, proteomweit nach Protein-Protein Interaktionen (PPIs) gesucht. Für 21 dieser Proteine wurden PPIs identifiziert. Das Gesamtnetzwerk besteht aus 79 Proteinen und 90 PPIs von denen 5 phosphorylierungsabhängig sind. Ein Teil dieser PPIs wurde in unabhängigen Interaktionsassays mit einer Validierungsrate von 66 % getestet. Der netzwerkbasierte Versuch verbindet erfolgreich neurologische Erkrankungen untereinander aber auch mit zellulären Prozessen. Ser/Thr-Kinase abhängige PPIs verknüpfen zum Beispiel das Parkinson Protein 7 (PARK7, DJ1) mit den E3 Ligase Komponenten ASB3 und RNF31 (HOIP). Die Funktion dieser Proteine bekräftigt den Zusammenhang zwischen dem Ubiquitin-Proteasom-System und der Parkinson Krankheit (PD). Neurofibromin 2 (NF2, merlin) Isoformen und PARK7 interagieren mit der regulatorischen PI3K Untereinheit p55-gamma (PIK3R3). Diese PPIs basieren auf Tyr-Kinase Aktivität im modifizierten Y2H System und funktionellen PIK3R3 pTyr-Erkennungsmodulen (SH2 Domänen) in co-IP und Venus PCA Versuchen. Dies verknüpft den PI3K/AKT Überlebenssignalweg mit zwei unterschiedlichen neurologischen Erkrankungsphenotypen: dem PD assoziierten neuronalen Zelltod und der Neurofibromatose Typ 2-assoziierten Tumorentstehung. Die vergleichende Beobachtung von PIK3R3, AOF2 (KDM1A, LSD1) Interaktionen auf NF2 Isoformlevel offenbart eine Bevorzugung von Isoform 7 bei zytoplasmatischer Lokalisation, wohingegen Isoform 1 PPIs an der Membran lokalisiert sind. Das modifizierungsabhängige und isoformspezifische PPI Netzwerk ermöglichte neue Hypothesen zu molekularen Pathomechanismen.<br>Alterations in phosphorylation-dependent signalling pathways, accumulation of aggregated proteins in the brain and neuronal apoptosis are common to neurodegeneration and implicate overlapping molecular mechanism. To gain insight into involved pathways, a modified yeast-two hybrid (Y2H) system was applied to screen 71 proteins associated with neurological disorders in a proteome-wide manner. For 21 of these proteins interactions were identified including 5 phosphorylation-dependent ones. In total, the network connected 79 proteins through 90 protein-protein interactions (PPIs). A fraction of these Y2H PPIs was tested in secondary interaction assays with a validation rate of 66 %. The described network-based approach successfully identified proteins associated with more than one disorder and cellular functions connected to specific disorders. In particular, the network revealed Ser/Thr kinase-dependent PPIs between the Parkinson protein 7 (PARK7, DJ1) and the E3 ligase components ASB3 and RNF31 (HOIP). The function of these proteins further substantiates the established connection between Parkinson’s disease (PD) and ubiquitination-mediated proteasome (dis)functions. Neurofibromin 2 (NF2, merlin) isoforms and PARK7 were identified as PI3K regulatory subunit p55-gamma (PIK3R3) interactors. These PPIs required Tyr kinase coexpression in the modified Y2H system and functional PIK3R3 pTyr-recognition modules (SH2 domains) in co-IP and Venus PCA experiments. This finding implicates the PI3K/AKT survival pathway in PD-associated neuronal apoptosis and Neurofibromatosis type 2-associated tumour formation. Investigation of PIK3R3, AOF2 (KDM1A, LSD1) and EMILIN1 PPIs on NF2 isoform level revealed preferential isoform 7 binding and cytoplasmic or membrane localisation of these PPIs for isoform 7 or 1, respectively. The generated modification-dependent and isoform-specific PPI network triggered many hypotheses on the molecular mechanisms implicated in neurological disorders.
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Hamza, Kankia Ibrahim. "Design and development of novel tools for the screening and identification of inhibitors of HER receptor family and NFR2 for ovarian cancer therapy." Thesis, Abertay University, 2017. https://rke.abertay.ac.uk/en/studentTheses/441e2039-1bde-448b-9c87-d2845ac1da96.
Texte intégralRésumé :
Cancer, which is characterised by aggressiveness and increased capacity for metastatic spread still requires basic researchers and clinicians to direct enormous efforts toward the development of novel therapeutic targets. Potential novel targets can be identified and exploited in combination with currently existing therapeutic approaches to improve their efficacy and overcome treatment resistance of tumour cells, protecting the patient from recurrence. To achieve this, different strategies and techniques can be proposed to identify the most promising candidate molecules for further exploitation as therapeutic targets. Human epidermal growth factor receptors (HERs) and NF-E2-related factor 2 (NRF2) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents. Nevertheless, there is limited understanding of the regulation of HER expression and activation, and the link between NRF2 and HER signalling pathways. This research has demonstrated that pharmacological activation of NRF2 by tert-butyl hydroquinone (tBHQ) upregulates the expression of HER family receptors, HER1 and HER4, elevates phospho protein kinase B (pAKT) levels, and enhances the proliferation of ovarian cancer cells. Pharmacological inhibition using retinoic acid (RA) and bexarotene and genetic inhibition using small interfering RNA (siRNA), did the opposite. Further, tBHQ caused transcriptional induction of HER1 and HER4 with different levels of expression, while siRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression. A panel of potent NRF2 inhibitors were screened with the hope of finding the most potent for further investigation. Bexarotene was found to be the most potent and was used either alone, or in combination with lapatinib or erlotinib. The use of these drugs in combination with bexarotene resulted in the repression of HER1, HER2, HER3 and HER4 expression, inhibition of NRF2, elevation of ROS, depletion of glutathione and enhanced cytotoxicity in PEO1, OVCAR3, SKOV3 and MCF7-AREc32 cell lines. This explained the crosstalk mechanism between HER receptor family and NRF2 and the role of NRF2 in drug resistance and as a relevant anti-cancer target which opens up novel avenues of targeting HER receptor kinase family and NRF2 pathways for improving cancer therapy.
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Sperka, Tobias [Verfasser]. "Ein neuer, regulierter Komplex des NF2-Tumorsuppressor-Genproduktes Merlin mit p190RhoGAP und p120RasGAP / Forschungszentrum Karlsruhe GmbH, Karlsruhe. Tobias Sperka." Karlsruhe : FZKA, 2006. http://d-nb.info/978199979/34.
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Peyre, Matthieu. "Modélisation de la tumorigenèse méningée chez la souris : progression tumorale liée à Nf2 et Cdkn2ab et voies alternatives d'oncogenèse." Paris 7, 2013. http://www.theses.fr/2013PA077109.
Texte intégralRésumé :
Les méningiomes constituent la tumeur primitive la plus fréquente du système nerveux central. Bien que ces tumeurs soient majoritairement bénignes, elles peuvent récidiver après exérèse complète et conduire à une importante morbidité, et il existe une fraction croissante, jusqu'à 30%, de formes histologiquement agressives (OMS Grades II et III). La création de modèles souris génétiquement modifiés de méningiomes est un outil précieux dans la compréhension des mécanismes de tumorigenèse méningée et la réalisation d'essais pré-cliniques prédisant avec exactitude la réponse tumorale chez l'homme. Nous présentons ici la création et la caractérisation de deux nouveaux modèles génétiquement modifiés de méningiomes souris : l'un par inactivation bi-allélique simultanée de A//2 et Cdkn2ab, le second par activation de PDGF-(3, avec ou sans inactivation bi-allélique de A//2. En comparaison des cohortes contrôle, ces deux modèles conduisent à une diminution de la latence de survenue des tumeurs, une augmentation de leur fréquence et permettent l'obtention de méningiomes murins de Grade H/NI. Dans le sillage des récentes études de génomique haut débit, cette thèse permet également de jeter les bases de deux futurs modèles de méningiomes non liés à A//2, par activation à'Akt et de Smo. Parallèlement, l'établissement de lignées cellulaires de méningiomes murins et d'un modèle souris orthotopique syngénique nous a permis d'évaluer un nouvel outil d'imagerie confocale miniaturisée et va prochainement conduire à l'établissement d'une plateforme d'essais pré-cliniques en vue d'un futur « essai jumelé » dans le traitement des méningiomes de Grade ll-lll<br>Meningioma is the most common primary nervous System tumor. Although most tumors are benign , they can recur even after total resection, present with significant morbidity and there is a growing proportion, up to 30%, of aggressive variants (WHO grade II and III). The creation of relevant genetically engineered mouse models is the cornerstone of future advances in meningioma treatment through pre-clinical testing and thorough dissection of molecular mechanisms of tumorigenesis. We here present the creation and characterization in vivo and in vitro of two new genetically engineered mouse models of meningioma : one model of Grade ll-lll meningioma through bi-allelic A//2 inactivation and homozygous Cdkn2ab deletion and one model of PDGF-(3-induced meningioma, with or without bi-allelic A//2 inactivation. On the basis of recent whole genome studies, we also set the bases of two future A//2-independant GEM meningioma models through Akt and Smo activation. The establishment of mouse meningioma cell lines and a syngenic orthotopic meningioma mouse model allowed the evaluation of a new handheld confocal imaging device and will eventually lead to future « co-trials »
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Boin, Alizée. "Le rôle de la voie Hippo dans la fonction suppresseur de tumeur associée au gène NF2 et la régulation de Yap par Merlin dans les cellules de Schwann." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112282.
Texte intégralRésumé :
Les schwannomes sont des tumeurs bénignes se développant à partir d’une hyper-prolifération des cellules de Schwann suite à l’inactivation bi-allélique du gène NF2. Signe pathogonomique d’une pathologie rare et héréditaire, la Neurofibromatose de type 2 (NF2), ils peuvent aussi apparaître de façon sporadique. Hormis la chirurgie ou la radiothérapie, peu d’options pharmacologiques sont proposées aux patients porteurs de schwannomes, principalement à cause du peu de cibles thérapeutiques identifiées. Dans les cellules de Schwann, le phénotype cellulaire associé à la perte NF2 est une perte d’inhibition de la prolifération par le contact. Deux fonctions majeures de Merlin, produit de NF2, ont émergé au cours de ces dix dernières années. La première, démontrée par notre groupe, concerne la régulation de l’expression membranaire des récepteurs à activité tyrosine kinase (RTK) qui s’accumulent à la membrane plasmique des schwannomes humains. Le second implique Merlin dans la régulation de la voie de signalisation Hippo. Cette dernière, activée par le contact cellulaire réprime l’activité de deux co-facteurs de transcription, Yap et Taz, et régule ainsi et aussi l’inhibition de contact. Les mécanismes moléculaires par lesquels Merlin inhibe l’activité de Yap/Taz sont toutefois méconnus. Le but de nos études a été de déterminer une signature moléculaire associée à la croissance des schwannomes humains et l’importance relative de Yap/Taz. Dans une analyse protéomique à grande échelle sur des biopsies humaines, nous avons identifié à la fois l’activation spécifique de cinq RTKs que sont le PDGFRβ, Her2, Her3, Axl et Tie2 ainsi qu’une accumulation nucléaire spécifique de Yap. Nous montrons que sur la totalité des protéines étudiées, seules Yap, le PDGFRβ et P-Her3 corrèlent avec la prolifération des cellules de schwannomes humain. De plus, Yap induit la transcription des RTK activés (à l’exception de Tie2). Nous plaçons donc Yap au centre des mécanismes de régulation de la croissance des schwannomes humains et proposons que son inhibition pourrait représenter une nouvelle et prometteuse stratégie thérapeutique pour réduire la croissance de ces tumeurs. Nous apportons une nouvelle lecture des fonctions de Merlin, qui, par une potentielle interaction directe avec Yap, inhibe spécifiquement sa translocation dans le noyau indépendamment d’une régulation par la densité cellulaire ou par la voie Hippo. Par ailleurs, Merlin ne semble pas essentiel à l’activation de la voie Hippo dans les cellules de Schwann soulignant une fonction nouvelle et inattendue de Merlin dans la régulation de Yap et de la voie Hippo. Enfin nous avons étudié le rôle d’AmotL1, un puissant partenaire de Merlin et membre de la voie Hippo, dans la migration et la progression des cancers du sein. Nous mettons en évidence une fonction antagoniste de Merlin et AmotL1 dans la promotion de ces mécanismes soulignant une autre fonction nouvelle de Merlin en tant que suppresseur de la progression de cancers non associés à NF2<br>Schwannomas are benign tumors arising from Schwann cell hyper-proliferation under NF2 bi-allelic inactivation. They appear in the context of a rare hereditary disease called Neurofibromatosis type 2 (NF2) or in sporadic cases. To this day, surgery and radiotherapy remain the only options to treat these patients, mainly due to the lack of therapeutical targets identified. The NF2 loss associated cellular phenotype is the loss of cell contact inhibition. Two main functions of Merlin, the NF2 product, have emerged in the last decade. The first was shown by our group and consists in the accumulation of tyrosine kinase receptors (RTK) at the plasma membrane in schwannomas. The second involves Merlin in the regulation of the Hippo signaling pathway. This pathway is activated by cell contact and inactivates a couple of transcription co-factors, Yap and Taz, then participating in cell contact inhibition of proliferation. However, the mechanisms by which Merlin inactivates Yap and Taz remain unknown. In our studies, we aimed to determine both the molecular signature of human schwannomas taking advantage of a large proteomic study, and the relative importance of Yap in the tumor suppressor function of Merlin. We could show both a specific activation of five RTKs : PDGFRβ, Her 3, Her2, Axl and Tie2 and a specific nuclear accumulation of Yap in human schwannoma. Among all the protein studied, Yap, PDGFRβ and P-Her3 are the only ones to correlate with the proliferation of human schwannoma cells. Furthermore, the activated RTK (excepted Tie2) are transcriptional targets of Yap. Hence, we found Yap as a pivotal regulator of schwannoma growth and proposed its inhibition as a new and promising therapeutical target to reduce human schwannoma growth. In addition, we show that Merlin specifically inhibits Yap nuclear translocation into the nucleus of Schwann cells by a direct interaction which is independent from the regulation by cell density and by the Hippo pathway. Moreover, Merlin expression seems not to be essential for Hippo activation in Schwann cells which brings a new and unexpected role of Merlin in Yap and Hippo regulation. In the end, we studied the role of AmotL1, a strong Hippo partner of Merlin in the migration and progression of breast cancer. We could show an antagonist function of Merlin and AmotL1 in the promotion of these mechanisms highlighting a new progression suppressor function of Merlin in cancer which are not linked to NF2 mutations
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Provenzano, Lucy. "The role of cellular prion protein in the development of schwannomas and other Merlin-deficient tumours." Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/10784.
Texte intégralRésumé :
Neurofibromatosis type 2 (NF2) is an inherited, multiple tumour disease caused by loss of the tumour suppressor protein, Merlin. There are several tumours associated with NF2 including; ependymomas, meningiomas and schwannomas. Merlin loss can also occur sporadically in all of these tumours and is associated with upregulation of various growth factor receptors and their relevant signalling pathways. At present the only treatment options for NF2 are surgery or radiosurgery, both of which incur serious morbidity and are unable to prevent recurrence of tumours. Either new drug treatments, or re-profiling of other drugs already commercially available, are urgently needed to improve outcome for NF2 patients. Cellular prion protein (PrPC), encoded by PRNP gene, is involved in tumour development by altering proliferation, adhesion, and survival in some cancers via focal adhesion kinase (FAK) /Src/ NFκB, cyclin D1 and p53 -proteins. Our group previously showed a strong elevation of PRNP gene activity in schwannoma. I hypothesise that PrPC may contribute to schwannoma development. To study the role of PrPC in schwannoma development I have used the well-established in vitro model of schwannoma that comprises primary human Schwann and schwannoma cells. I show that PrPC is upregulated in schwannoma as well as in Merlin-deficient meningiomas and human malignant mesotheliomas. In schwannoma PrPC is released both via exosomes and by α-cleavage which forms biologically active N- and C-terminal portions of the protein. PrPC contributes to pathological proliferation, adhesion and survival of schwannoma cells by activating ERK1/2, PI3K/AKT, cyclin D1, FAK, p53 pathways via the 37/67kDa non-integrin laminin receptor (LR/37/67kDa) and CD44. Furthermore, schwannoma cells appear to be intrinsically drug-resistant due to upregulation of MDR1 protein p-glycoprotein (p-gp) expression. P-gp expression is dependent on PrPC thus, inhibiting PrPC may be a good potential new therapeutic option for schwannoma patients, either alone or in combination with Sorafenib and p-gp inhibitor Valspodar (PSC833). An inhibitor of LR/37/67kDa/PrP interaction, NSC47924, or Bortezomib, a proteasome/NFκB inhibitor which has been approved for the treatment of multiple myeloma, could also be of beneficial therapeutic effect and is something to investigate in future work. I conclude that PrPC is an interesting new therapeutic target through its involvement with schwannoma patholgenesis and resistance to drug treatments PrPC may prove to be a good therapeutic target in other NF2-related tumours like meningiomas and schwannomas.
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Andersson, Malin, and Daniel Svensson. "Impacts on teachers' lives of a capacity building course: A case study in rural Rajasthan, India." Thesis, Linnéuniversitetet, Institutionen för pedagogik, psykologi och idrottsvetenskap, PPI, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-12807.
Texte intégralRésumé :
This case study is conducted on teachers working in Non-Formal Education centers (NFE's), for the Non-Governmental Organization Seva Mandir, in the Udaipur district in Rajasthan, India. The setting for the study is remote rural villages around the small city Udaipur, with one million inhabitants. The purpose of this case study is to investigate what impact the capacity building course that Seva Mandir offers the teachers, the NFE certification course, have had on the teacher’s lives. The aim is to get a picture of the overall impact of the course on a professional level and on the individual NFE teachers’ personal life. The case study was conducted on a sample of eleven out of 50 NFE teachers working for Seva Mandir in the Jhadol block. The empirical data was collected through qualitative interviews conducted in the NFE schools. The NFE centers that are run by Seva Mandir are a complement to malfunctioning government schools in areas where most of the children are first generation learners. The schools aim to keep children from working or starting to work, through giving them an educational base. The teachers have no previous teachers training and are having an average prior education of 8th to 10th class. The general findings of the study are that a majority of the teachers felt an increase in self-confidence after participating in the course. They generally had more concrete and ambitious future plans after the course than before it, and they were highly dominated of plans for further education for themselves and their children. It was also found that the teachers felt major changes in their teaching approach after the course. They had learnt new teaching strategies and seemed to have changed their attitude against the children. The teachers used activities like games, songs and stories in their teaching as well as taking help of the local surroundings when teaching.
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Schulz, Alexander [Verfasser], Reinhard [Akademischer Betreuer] Wetzker, Reinhard [Akademischer Betreuer] Bauer, and Stephan [Akademischer Betreuer] Baader. "Die Rolle des Tumorsuppressorproteins Merlin bei der Pathogenese von NF2-assoziierter Polyneuropathie / Alexander Schulz. Gutachter: Reinhard Wetzker ; Reinhard Bauer ; Stephan Baader." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2015. http://d-nb.info/1066238359/34.
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McLain, John. "The Deletion of Exon 2 in the Nf2 Gene Leads to Changes in Morphology, Protein Expression, and Localization in Mouse Schwann Cells." Honors in the Major Thesis, University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1179.
Texte intégralRésumé :
This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.<br>Bachelors<br>Burnett School of Biomedical Sciences<br>Molecular Biology & Microbiology
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Islam, Mohammed Mehrul. "An analysis of the role of extension methodology on poverty reduction : a comparative study of aquaculture extension programmes in the Northwest Fisheries Extension Project (NFEP) command area, Bangladesh." Thesis, University of Wolverhampton, 2002. http://hdl.handle.net/2436/29559.
Texte intégralRésumé :
The current deficiencies of extension interventions in aquaculture in Bangladesh, in particular, in the North-west have been examined. The importance of the inclusion of a social dimension in development interventions has been reviewed. Aquaculture, extension, social development and poverty are defined in the context of the study and a model of their interactions is proposed and used to elucidate the role of aquaculture in poverty reduction. Research questions were generated to examine the contention that ‘Aquaculture Extension Approaches that fail to substantially address social development will lead to no more than a superficial reduction of poverty’. The study approach chosen was comparative case study (the first use of its' kind in this context). Within the study, communities representing four different aquaculture extension approaches and a, null-case, control were selected and then engaged in the research process. The findings that emerged from the study were matched and linked to the proposed model to establish patterns and linkages between aquaculture and poverty; extension and aquaculture; aquaculture and social development; social development and poverty; extension and poverty. The study suggests that all these aspects go hand in hand within communities, and that it is the degree of marginalisation that defines the success of any intervention as much as the intervention approach itself. The study indicates that aquaculture could be an entry point for a poverty alleviation strategy but the inclusion of a social dimension, together with the chosen technical intervention, is essential in achieving higher impacts on a sustainable basis. A number of recommendations for greater poverty impact through aquaculture intervention as an entry point are put forward, including the targeting of women as well as men, emphasise a learning approach, and the building of networks through forming community producers groups, fish clubs, Fry Traders and fingerling producers groups.
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Lyons, Rimmer Jade. "The potential of CRL4-DCAF1 and KSR1 as therapeutic targets in low-grade Merlin-deficient tumours." Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/12833.
Texte intégralRésumé :
Merlin is a tumour suppressor protein that is frequently mutated or downregulated in cancer. Biallelic Merlin inactivation is causative of tumour formation, including schwannoma, meningioma and ependymoma. These tumours can occur sporadically or as part of the genetic condition Neurofibromatosis type 2 (NF2) and cause significant morbidity. The current treatment options are restricted to surgery and radiotherapy, which are invasive and may cause further tumour development. The activity of both the E3 ubiquitin ligase complex Cullin 4 really interesting new gene (RING) E3 ubiquitin ligase- DNA damage binding protein (DDB1) and Cullin 4 associated factor 1 (CRL4-DCAF1) and Kinase suppressor of RAS 1 (KSR1) have been shown to be upregulated in schwannoma to drive tumour growth. KSR1 has also been shown to interact with components of the CRL4-DCAF1 complex. We investigated the expression, interaction and therapeutic potential of targeting these proteins in Merlin deficient schwannoma and meningioma using a primary human cell model and relevant cell lines. We found that DCAF1 and KSR1 protein were overexpressed in schwannoma and meningioma and confirmed that targeting both DCAF1 and KSR1 in meningioma had additive effects on proliferation. We also identified that CRL4-DCAF1 facilitates KSR1 dependent RAF/Mitogen-activated protein kinase (MAPK)/ Extracellular signal regulated kinase (ERK) kinase (MEK)/ERK pathway activity. We showed MLN3651, a neddylation inhibitor that targets ubiquitin ligase activity, reduced proliferation and activated apoptosis in Merlin-deficient tumours. We also showed that Merlin-positive tumours were less sensitive to MLN3651 than Merlin-deficient tumours; therefore, MLN3651 sensitivity may be CRL4-DCAF1-dependent. Finally, combination of MLN3651 and the MEK1/2 inhibitor AZD6244 had additive effects, particularly in meningioma. Combinatorial therapy activated the Hippo pathway, inhibited RAF/MEK/ERK pathway activity and proliferation demonstrating that targeting the activity and downstream pathways of both DCAF1 and KSR1 represents an attractive novel therapeutic strategy in Merlin-deficient tumours.
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Mönch, Dina [Verfasser], and German [Akademischer Betreuer] Ott. "Identifizierung von Zielmolekülen für die innovative Therapie pleuraler Mesotheliome : Untersuchung von Tyrosinkinasen sowie Komponenten der NF2/mTOR- und p14/p16-Signalwege / Dina Mönch ; Betreuer: German Ott." Hohenheim : Kommunikations-, Informations- und Medienzentrum der Universität Hohenheim, 2020. http://d-nb.info/1220774723/34.
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Andujar, Pascal. "Altérations génétiques des tumeurs respiratoires humaines et murines après exposition à des fibres minérales." Thesis, Paris Est, 2008. http://www.theses.fr/2008PEST0030.
Texte intégralRésumé :
L’objectif était de mieux définir les relations entre l’exposition à certaines fibres minérales et les anomalies génétiques somatiques associées à la transformation tumorale de cellules de l’appareil respiratoire. Deux études indépendantes ont été conduites à partir du modèle murin Nf2+/- de mésothéliome malin (MM) développé dans le laboratoire, exposé par inoculation intrapéritonéale à des fibres d’amiante crocidolite (souris abs-Nf2+/- et abs-Nf2+/+) et à des fibres céramiques réfractaires (FCR) (souris ceram-Nf2+/-).Ce choix a été fondé selon une stratégie raisonnée à partir de la connaissance des anomalies génétiques observées dans le MM. La validité de ce modèle a été vérifiée en comparant les MM murins et humains. Des MM ont été induits par le crocidolite chez des souris abs-Nf2+/- et abs-Nf2+/+. Les souris abs-Nf2+/- ont significativement développé plus de MM que les souris abs-Nf2+/+. Les caractéristiques histologiques des MM murins sont analogues aux MM humains, avec des altérations génétiques similaires, en terme de fréquence et de mécanismes d’inactivation (mutations ponctuelles pour le gène TP53, délétions pour les gènes NF2 et P16/CDKN2A). Ce modèle murin a été ensuite utilisé pour évaluer la toxicité de FCR. Les souris ceram-Nf2+/- ont développé des MM similaires aux MM humains du point de vue histologique et moléculaire. Ainsi, le profil des altérations génétiques des MM murins ceram-Nf2+/- est semblable à celui des MM murins abs-Nf2+/- et abs-Nf2+/+, et humains. Les cellules mésotheliales des souris exposées aux FCR et à l’amiante semblent suivre les mêmes voies de transformation néoplasique. Une étude à la recherche d’altérations génétiques de ces 3 gènes et des gènes Ki-ras et EGFr fréquemment mutés dans le cancer broncho-pulmonaire (CBP) a été conduite à partir de cas de CBP sélectionnés (50 sujets exposés à l’amiante (E+) et 50 sujets non exposés (E-) appariés sur l’âge, le sexe, le type histologique et le tabagisme) provenant d’une série de cas opérés. A l’instar du MM, l’analyse du gène P16/CDKN2A suggère que le mécanisme d’inactivation pourrait être différent chez les sujets E+ (par délétion) par rapport aux sujets E- (par hyperméthylation du promoteur), indépendamment de l’âge et du tabagisme. Deux SNP (rs12947788 et rs12951053) du gène TP53 sont plus fréquemment retrouvés chez les sujets E+. En revanche, aucune différence significative n’est retrouvée pour les autres gènes entre ces 2 groupes. Ainsi, les mutations du gène NF2 dans le MM seraient plus liées à une spécificité cellulaire et à une fonction particulière de la protéine nf2 dans ces cellules<br>Résumé en anglais non communiqué
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Frykholm, Carina. "Clinical and Genetic Studies of Hearing Impairment." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8290.
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Moncrieffe, Melissa Lucille. "Analyzing a model of non-formal education for young people : a comparative case study of national programs in the United States and Scotland." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23568.
Texte intégralRésumé :
Non-formal education (NFE) has the potential to provide diverse learning opportunities for personal and professional development. Proponents of NFE conclude that it creatively and flexibly responds to ever-changing socio-economic challenges. In practice, these contributions are highly dependent upon the viability of NFE and the context in which it is delivered. This research studied US and Scottish national community education programs, designed for vulnerable and disadvantaged youth, in order to examine NFE. As a comparative case study, the research developed a model of NFE from the literature reviewed. This model was applied to explain and analyze governance, the use of social and human capital theories as well as other important concepts related to each program. Interviews (with policy leaders, community level program administrators and young people) as well as national and local documents informed the analysis. The top-down construct of community education programs demonstrated that policy influenced implementation within communities. Community level administrators could also plan programs, however, within the limits of policy. Both case studies were primarily similar in their norms and goals but also had interesting differences at national and local levels. The findings showed how history, western ideologies and youth narratives have a pervasive impact on programs. The case studies revealed contributions of NFE to lifelong learning, seen through the lens of social and human capital. Furthermore, a critical discussion was interwoven throughout the thesis and revealed challenges and tensions at all levels of the model. NFE is a complex and variable concept, and it continues to struggle for legitimacy and recognition within the wider education narrative. However, NFE’s relationship with government policy, its use within communities and the experienced outcomes for youth are testament that it is integral and influential within the narrative. Further NFE research and practices should be encouraged in order to understand its role and impact. There is an emphasis made here to expand the research on NFE because socio-economic inequality, concerns about youth transition and the importance of learning beyond the formal educational sector are universal and consistent issues.
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Worseck, Josephine [Verfasser], Christian [Akademischer Betreuer] Spahn, Erich E. [Akademischer Betreuer] Wanker, and Hans [Akademischer Betreuer] Lehrach. "Characterization of phosphorylation-dependent interactions involving neurofibromin 2 (NF2, merlin) isoforms and the Parkinson protein 7 (PARK7, DJ1) / Josephine Maria Worseck. Gutachter: Christian Spahn ; Erich E. Wanker ; Hans Lehrach." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://d-nb.info/1023931621/34.
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Ivins, Tiffany. "Localization of Open Educational Resources (OER) in Nepal: Strategies of Himalayan Knowledge-Workers." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2616.
Texte intégralRésumé :
This dissertation examines localization of Open Educational Resources (OER) in Himalayan community technology centers of Nepal. Specifically, I examine strategies and practices that local knowledge-workers utilize in order to localize educational content for the disparate needs, interests, and ability-levels of learners in rural villages. This study draws on insights from non-formal education (NFE) stakeholders in Nepal, including government, UN, international and national NGOs, local knowledge-workers, and learners from different villages. I specifically focus on a sample of seven technology centers to better understand how localization is defined, designed, and executed at a ground level. I illuminate obstacles knowledge-workers face while localizing content and strategies to overcome such barriers. I conclude by offering key principles to support theory development related to OER localization. This study is anchored in hermeneutic inquiry and is augmented by interpretive phenomenological analysis and quasi-ethnographic research methods. This qualitative study employed interviews, focus group discussions, observations, and artifact reviews to identify patterns of localization practices and themes related to localization of critical content in Himalayan community technology centers of Nepal. This dissertation provides valuable evidence not only why localization matters (a statement that has been hypothesized for the past decade); but also provides proof of how localization is executed and concrete ways that localization could be improved in order for OER to reap efficacious learning gains for more rural people in developing countries and in other rural communities across the globe. The full text of this dissertation may be downloaded for free from http://etd.byu.edu/
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横山, 俊彦, 啓隆 長田, 秀樹 村上 та ін. "O-28 YAP1は悪性胸膜中皮腫の増殖を促進し,NF2腫瘍抑制遺伝子で機能阻害される". 日本肺癌学会, 2007. http://hdl.handle.net/2237/11031.
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Buckley, Patrick. "Development and Application of Microarray-Based Comparative Genomic Hybridization : Analysis of Neurofibromatosis Type-2, Schwannomatosis and Related Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4786.
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Wu, Yi-Ci, and 巫逸琦. "NFE2-related factor 2 (Nrf2) in neurodegenerative disease: promoter polymorphism and therapeutic strategy targeting oxidative stress." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/52764583766979550531.
Texte intégralRésumé :
碩士<br>國立臺灣師範大學<br>生命科學研究所<br>100<br>Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a member of the basic leucine zipper transcription factors that regulate the expression of many antioxidant pathway genes and maintains cellular redox homeostasis. Increased oxidative stress is involved in the pathogenesis of many neurodegenerative diseases. For example, oxidative stress has been implicated as a major contributing factor in Parkinson’s disease (PD) and varying efficiency in the oxidative protection by Nrf2 may influence PD pathogenesis. In polyQ-mediated spinocerebellar ataxias, the expansions of translated CAG repeats in the disease genes result in long polyQ tracts in the respective proteins, leading to accumulation of aggregated polyQ proteins and increased oxidative stress. In this study, PCR-RFLP test was developed to examine the frequency of Nrf2 -653 A/G, -651 G/A and -617 C/A promoter polymorphisms in a larger cohort of PD (n = 480, 49.2% female, age at onset 61.8±11.2 years) and age- and gender-matched controls (n = 526, 50.5% female, age 60.3±13.1 years). No association between polymorphic genotype, allele or haplotype and PD was observed. In addition, Flp-In SH-SY5Y cells with ATXN3/Q14~75 expression in an inducible fashion were established. In retinoic acid-induced differentiated SH-SY5Y cells, the expressed ATXN3/Q75 formed aggregates, accompanying with reducing neurite outgrowth. By combining high content image analysis and immunoblotting, treatment of ATXN3/Q75 cells with Chinese herbs NH004, NH008, NH021 and NH008 derivative NH008-1 activate Nrf2 expression, accompanying decreasing ATXN3/Q75 aggregates. Thus NH004, NH008, NH021 and NH008-1 may be potential therapeutic strategies for polyQ-mediated disease.
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Huang, Zih-Ming, and 黃梓銘. "Utilized NFES piezoelectric fibers to fabricate all-directional or transparent graphene-based generators." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/61732667263805846646.
Texte intégralRésumé :
碩士<br>國立中央大學<br>機械工程學系<br>103<br>In this thesis, the near-field electrospinning (NFES) technique was used to investigate the piezoelectric fibers and fabricated the nanogenerators. The major research focused on (1) Massively aligned nanofibers-based nanogenerator deposited via near-field electrospinning, (2) An arbitrarily directional piezoelectric fiber-based nanogenerator with concentric circle topography via near-field electrospinning, (3) A transparent and flexible graphene-piezoelectric fiber generator. We demonstrate a direct-write, in-situ poled polyvinylidene fluoride (PVDF) nanofiber arrays that could functions as a self-powered active deformation sensor or harvester. This research is different from previous electrospinning research, however the fibers were mostly patterned in parallel lines and they could be actuated in limited direction only. We fabricated this apparatus precisely via near field electrospinning which has a spectacular concentric circle topography which made it possible to collect the mechanical energy from various directions. Furthermore, we also utilized the graphene as electrode to fabricate a flexible and transparent NG. Compared to previous opaque Cu-foil electrode, the graphene based NG has a promising future in the applications of smart phone or wearable electronics as a self-power system.
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Fan, Kai-Chun, and 范凱鈞. "Linkage Identification by NFE Estimation: A Practical View of Building Blocks." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/75775699893946234753.
Texte intégralRésumé :
碩士<br>國立臺灣大學<br>電機工程學研究所<br>99<br>Competent genetic algorithms (competent GAs) identify linkages between genes and build models via various mechanisms to solve problems. They have been applied
for real world applications, but whether the models given by them match what are really preferred to solve the problems is yet unknown. This thesis proposes using the number of function evaluation (Nfe) to measure the performance of models and defines the optimal model to be the one that consumes the fewest Nfe for GAs to solve a specific problem. Then the building blocks (BBs) that construct the optimal model are defined as the correct BBs, and correct linkages exist between any two genes which locate in the same BB. The capabilities of existing linkage-identification metrics, including non-linearity, entropy, simultaneity and DMC, are compared based on this definition. We find that all these metrics fail to identify
correct linkages for some typical problems intrinsically. This thesis then proposes a new metric, named eNFE, directly based on the idea of Nfe to enhance the existing
linkage-identification metrics. Experiment results show that eNFE is able to identify correct linkages for examined problems. The preliminary success suggests another view on learning linkage.
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Wiederhold, Thorsten [Verfasser]. "Characterization of neurofibromatosis 2 (NF2) tumor suppreor binding proteins / vorgelegt von Thorsten Wiederhold." 2001. http://d-nb.info/966515188/34.
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Vahldiek, Kai-Felix [Verfasser]. "Allelverluste bei Neurofibromatose Typ 2 (NF2) assoziierten Meningeomen / vorgelegt von Kai-Felix Vahldiek." 2001. http://d-nb.info/965649512/34.
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鄧旭真. "Molecular Characterization of Germline Mutations in Brain Tumor NF2 Gene and Breast Cancer BRCA2 Gene from Taiwan." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/31752464570994698246.
Texte intégralRésumé :
碩士<br>國立中山大學<br>生命科學研究所<br>85<br>Neurofibromatosis type 2 (NF2) is an autosomal dominantly inherited disease by bilateral vestibular schwannomas and other tumor of the brain, spinal cord, and central nervous system. NF2 disease is caused by germline mutations in the NF2 tumor suppressor gene on chromosome 22q12. Although the tumors of NF2 are histologically benign, their anatomical location and multiplicity lead to great morbidity and early mortality.
Breast cancer is the most common malignancy among women in developed countries. Recently, the incidence of breast cancer increases n Taiwan and the occurrence of breast cancer tends to be early onset. Familial breast cancer is characterized by early onset, an increased risk of bilateral breast cancer, an increasing risk and numbers of affected family members. The second breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, has recently been cloned. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with early onset female breast cancer, and they are also associated with an increased risk of male breast cancer.
To identify the nature of genetic mutations in familial brain tumor and breast cancer in Taiwan and develop simple diagnosis procedures for detecting these genetic mutations, we have analyzed germline mutations in the NF2 gene and BRCA2 gene by PCR (polymerase chain reaction) -based SSCP (single strand conformation polymorphism) analysis followed by cloning and sequencing of related PCR products.
In this study, nonsense mutations or frameshift deletions in NF2 and BRCA2 genes had been found, and these mutations are all predicted to lead to the truncated proteins which are usually associated with severe phenotypes. Moreover, polymorphic changes of several missense and silent mutations were also observed among breast cancer patients and normal individuals. The search for genotype-phenotype correlation in NF2 and BRCA2 mutations is important not only to increase understanding of how mutated genes function, but also to improve presymptomatic detection of patients. DNA diagnosis of NF2 gene and BRCA2 gene can improve quality of genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.
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Schulze, Karin Marlies Marion [Verfasser]. "Herstellung rekombinanter Retroviren, In-vitro-Gentransfer und Expressionsanalyse des NF2-Gens Merlin / vorgelegt von Karin Marlies Marion Schulze." 2001. http://d-nb.info/962345210/34.
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Gehlhausen, Jeff R. "Phenotypic and molecular characterization of a novel mouse model of neurofibromatosis type 2." Thesis, 2015. http://hdl.handle.net/1805/7947.
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Nguyen, Hoa Bich. "The tumor suppressing roles of tissue structure in cervical cancer development." Thesis, 2013. http://hdl.handle.net/1805/3627.
Texte intégralRésumé :
Indiana University-Purdue University Indianapolis (IUPUI)<br>Cervical cancer is caused by the persistent infection of human papilloma virus (HPV) in the cervix epithelium. Although effective preventative care is available, the widespread nature of infection and the variety of HPV strains unprotected by HPV vaccines necessitate a better understanding of the disease for development of new therapies. A major tumor suppressing mechanism is the inhibition of cell division by tissue structure; however, the underlining molecular circuitry for this regulation remains unclear. Recently, the Yap transcriptional co-activator has emerged as a key growth promoter that mediates contact growth arrest and limits organ size. Thus, we aimed to uncover upstream signals that connect tissue organization to Yap regulation in the inhibition of cervical cancer. Two events that disrupt tissue structure were examined including the loss of the tumor suppressor LKB1 and the expression of the viral oncogene HPV16-E6. We identified that Yap mediates cell growth regulation downstream of both LKB1 and E6. Restoration of LKB1 expression in HeLa cervical cancer cells, which lack this tumor suppressor, or shRNA knockdown of LKB1 in NTERT immortalized normal human dermal keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion, and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). Interestingly, LKB1’s suppression of Yap activity required neither the canonical Yap kinases, Lats1/2, nor metabolic downstream targets of LKB1, AMPK and mTORC1. Instead, the scaffolding protein NF2 was required for LKB1 to induce a specific actin cytoskeleton structure that associates with Yap suppression. Meanwhile, HPV16-E6 promoted Yap activation in all stages of keratinocyte differentiation. E6 activated the Rap1 small GTPase, which in turn promoted Yap activity. Since Rap1 does not mediate differentiation inhibition caused by E6, E6 may play a role in promoting cell growth through Rap1-Yap activation rather than preventing growth arrest through the disruption of differentiation. Altogether, the LKB1-NF2-Yap and E6-Rap1-Yap pathways represent two examples of a novel phenomenon, whereby the structure of a cell directly influences its gene expression and proliferation.