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1
Medeiros, Ana Carla. « Caracterização parcial do complexo SCF1 contendo a proteína FBXO25 fosforilada ». Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-09092015-110529/.
Texte intégralRésumé :
A FBXO25 é parte de uma E3 ligase do tipo RING, (Really Interesting New Gene), oligomérica do tipo SCF, responsável pelo reconhecimento específico do substrato a ser degradado via Sistema Ubiquitina-Proteassoma (SUP). O SUP é o principal mecanismo proteolítico intracelular, responsável pela degradação de 80-90% das proteínas citosólicas e nucleares. A FBXO25 é capaz de formar um complexo SCF1 ativo (formado pela interação das proteínas Skp1, Cul1, Roc1 e uma proteína do tipo F-box), capaz de ubiquitinar seus substratos. Essa proteína se acumula no núcleo celular formando uma nova estrutura subnuclear denominada FANDs (FBXO25 Associated Nuclear Domains) que estão envolvidos na ubiquitinação nuclear. Nesse trabalho, purificamos complexos SCF1 (WT ou sem o domínio de interação com Skp1 (F)), tratados ou não com PMA, pela técnica de imunoprecipitação. Identificamos por espectrometria de massas um sítio de fosforilação essencial para FBXO25, quando células transfectadas são tratadas com o mitógeno PMA. Buscamos também por substratos diferencialmente ubiquitinados por esses complexos, por meio de ensaios em ProtoArrays®, identificando substratos envolvidos na via de sinalização ERK1/2.The FBXO25 is an E3 ligase RING type (Really Interesting New Gene), SCF oligomeric type, responsible for the specific recognition of the substrate to be degraded via the ubiquitin-proteasome system (SUP). SUP is the main intracellular proteolytic mechanism responsible for 80-90% degradation of cytosolic and nuclear proteins. The FBXO25 is capable of forming a complex SCF1 (formed by the interaction of proteins Skp1, Cul1, Roc1 protein and a type F-box), resulting in an active SCF complex which is able to ubiquitinate their substrates. This protein accumulates in the nucleus forming a subnuclear structure called FANDs (FBXO25 Associated Nuclear Domains) that are involved in nuclear ubiquitination. In this work, we purify complex SCF1 (WT or F- box, which is not able to interact with Skp1), treated or not with PMA, by immunoprecipitation technique. We identified by mass spectrometry, an essential phosphorylation site for FBXO25, when it is phosphorylated under the action of the mitogenic reagent PMA. We also search for differentially ubiquitinated substrates for these complexes, by testing in ProtoArrays® identifying substrates involved in the signaling pathway ERK1 / 2.
2
Vieira, Nichelle Antunes. « Caracterização de células humanas Hap1 nocaute para FBXO25 : via de sinalização da ERK quinase e proliferação celular ». Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-25042018-143544/.
Texte intégralRésumé :
A proteína FBXO25 é uma E3-ligase do tipo SCF, responsável pela seletividade da ligação da Ub à proteína substrato e pelo direcionamento da proteína marcada para o barril proteassomal 26s. Sabe-se que FBXO25 é capaz de interagir e ubiquitinar a proteína Elk-1 em células HEK293T e, assim, inibir a expressão de genes importantes na regulação da proliferação celular, como C-FOS e EGR-1, após estímulo com o mitógeno PMA. Aqui mostramos que FBXO25 atua em um outro ponto da via das MAPKs, modulando os níveis de fosforilação de ERK1/2. Por meio da utilização de células nocaute para FBXO25 (FBXO25KO) foi possível observar que o tratamento com PMA promoveu aumento dos níveis de fosforilação de ERK1/2 nestas células quando comparadas com sua linhagem parental. Observouse também que o estímulo com os mitógenos PMA ou ATP levou a um aumento da proliferação celular não relacionada à modulação direta do ciclo celular nas células nocautes, sendo que estas apresentaram uma redução significativa dos seus níveis de apoptose. Tomando esses resultados em conjunto, mostramos que FBXO25 atua sobre a sinalização de MAPK por meio de redução da ativação ERK1/2 e, dessa forma, promove uma resposta secundária sobre o fenótipo de proliferação celularThe FBXO25 protein is an SCF-type E3-ligase responsible for the selectivity of Ub binding to the protein and the targeting of the labeled protein to the 26s proteasome barrel. FBXO25 has been long known to be able to interact and ubiquitinate the Elk-1 protein in HEK293T cells, thereby inducing a decrease in the expression of important genes in the regulation of cell proliferation such as CFOS and EGR-1 after stimulation with the mitogen PMA. Here we show that FBXO25 acts at another point in the MAPK pathway by modulating the ERK1/2 phosphorylation levels. We observed that the treatment with PMA rised the phosphorylated levels of ERK1/2 in knockout cells for FBXO25 (FBXO25KO) when compared to its parental lineage. Stimulation with the mitogens PMA or ATP also led to an increase in cell proliferation unrelated to a direct modulation of the cell cycle in knockout cells, with a significant weight of apoptosis levels being observed. Taking these results together, we show that FBXO25 acts on MAPK signaling by reducing ERK1/2 activation and thus promotes a secondary response on the cell proliferation phenotype.
3
Tsui, Hoyee. « The role of p21-activated kinase 1 (Pak1) in the heart ». Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-p21activated-kinase-1-pak1-in-the-heart(8c34d7bc-a2aa-4ae0-a197-91ed905212f5).html.
Texte intégralRésumé :
Heart failure is associated with a high mortality rate and is one of the most prevalent diseases worldwide whereby susceptibility increases with age. The development of heart failure occurs over an extensive period of time in which arrhythmias and hypertrophy are both very prevalent manifestations throughout this progression. Arrhythmias are defined as an irregular rhythm originating from intracellular calcium dysregulation, which can be fatal. Cardiac hypertrophy is a compensatory condition induced by increased workload involving augmented cardiomyocyte growth accompanied by myocardial remodelling. However, under prolonged periods of increased stress this compensatory mechanism can lead to cardiac dysfunction. The current treatments for heart failure are mainly aimed at relieving symptoms or itself possess proarrhythmic ability. Therefore it is fundamental to elucidate the pathways involved in arrhythmias and hypertrophy for the development of more effective treatment. p21 activated protein kinase (Pak1) is a novel gene involved in the regulation of cardiac function, however, the mechanisms involved remain inconclusive. This study has demonstrated Pak1 to be both antiarrhythmic and antihypertrophic, emphasizing Pak1 as a credible therapeutic target for simultaneously treating both manifestations. The antiarrhythmic properties of Pak1 were demonstrated through cardiomyocyte-specific Pak1 knockout (Pak1cko) mouse model which underwent Isoproterenol (ISO) stimulation for 2 weeks. Compared with ISO treated control group, the Pak1cko group had increased calcium irregularities and particularly a prolongation in sarcoplasmic reticulum (SR) calcium refill. The absence of Pak1 abrogated the transcriptional up-regulation of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) under stressed conditions. Further analysis in neonatal rat cardiomyocytes (NRCMs) revealed this regulation to be through activation of the transcription factor, SRF. The antihypertrophic effects of Pak1 were further illustrated through cardiomyocyte-specific overexpressed constitutively-active Pak1 (Pak1cTG) mice which were subjected to transverse aortic constriction (TAC) for 3 weeks. Compared to TAC control group, Pak1cTG mice had improved cardiac performance accompanied with diminished fibrosis. Further analysis led to the discovery of a novel antihypertrophic pathway of Pak1 involving positive regulation of the E3ligase, Fbxo32 through activation of Smad3. This pathway is vital in the prevention of calcineurin (PP2B) accretion. Berberine administration in TAC treated mice corroborated that Fbxo32 up-regulation is sufficient in the prevention of hypertrophy. In conclusion, my study has demonstrated that Pak1 conveys antiarrhythmic influence through the up-regulation of SERCA2a. In the prevention of pathological hypertrophy, Pak1 inhibits PP2B through positive regulation of Fbxo32. Overall, my thesis has advanced the knowledge about cardioprotective pathways initiated by Pak1 under stressed conditions, presenting Pak1 as a promising therapeutic target.
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Stavropoulou, Alexandra Vassiliki. « Histone deacetylase (HDAC) inhibitors and FBXL20 in breast cancer ». Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/7389.
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Research performed over the last decade has highlighted the role of HDAC inhibitors (HDACis) as modulators of transcriptional activity and as a potential new class of therapeutic agents against many types of malignacies including breast cancer. These drugs inhibit histone deacetylases, leading to derepression of transcription of various genes that are important for cell cycle arrest and cell death. Trichostatin A (TSA) is one of the best established HDAC inhibitors and has been shown to exhibit potent differentiating and anti-proliferative properties. My data demonstrated that treatment of the MCF-7 breast cancer cell line with TSA causes G2/M phase cell cycle arrest. I characterised the novel F-Box protein called FBXL20 and identified it as a direct target of TSA. This protein is part of a novel E3 ligase complex as it binds Skpl, CUL-I and ROC-I and forms a classical SCF complex that is responsible for ubiquitination and targeting proteins for degradation by the 26S proteasome. I further studied the differences between FBXL20 in human cells and its isoform in rat cells. My data showed that FBXL20 is localised in the cytoplasm, concentrated around the nucleus and plays a role in the TSA-induced effects in MCF-7 cells, through regulating the pro-apoptotic protein Bim. Silencing FBXL20 abolished the G2/M arrest caused by TSA treatment. Although FBXL20 is a similar protein to Skp2 they are regulated by different proteins and exert different functions. These findings provide novel data to demonstrate that known and novel HDACis induce G2/M arrest followed by cell death and that this arrest is dependent on the novel FBXL20 protein in breast cancer cells. Using these newly defined properties of HDACis, I screened a panel of potential HDACis and identified at least one to be more potent than SAHA, which is currently used in the clinical setting and showed that it is able to inhibit proliferation, cause cell cycle arrest and cell death of breast cancer cells.
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Patel, Shachi. « Fbxo7 in T cell development and oncogenesis ». Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709293.
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Rowicka, Paulina Aiko. « The role of FBXO7 in mitochondrial biology and Parkinson's disease ». Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/282989.
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Parkinson's disease is a progressive neurodegenerative disorder of the central nervous system, manifesting with both motor and non-motor symptoms. Autosomal recessive mutations in the FBXO7 gene have been identified to cause a rapidly progressing early-onset form of PD. Canonically, FBXO7 functions as a substrate-recruiting subunit of the SCF-type E3 ubiquitin ligase. However, it also has a variety of other atypical functions, such as cell cycle regulation, proteasome regulation, and mitophagy. The overall aim of this research was to characterise the functional role of FBXO7 in various in vitro and in vivo PD models. The models examined included FBXO7 shRNA knockdown SH-SY5Y cell lines, FBXO7 CRISPR knockout SH-SY5Y cell lines, primary patient fibroblasts with a FBXO7 mutation, and MEFs and tissues from a Fbxo7 KO mouse. My analysis of fibroblasts from a patient without FBXO7 expression revealed several interesting phenotypes. Briefly, the patient fibroblasts proliferated slower due to increased apoptosis and lower CDK6 and cyclin D1 expression, which led to fewer cells progressing through the G1 phase of the cell cycle. My experiments showed that these cells also had mitochondrial respiration defects, exhibiting lower basal respiration, ATP production, maximal respiration and spare capacity, in addition to complex I, III and IV deficiencies. Patient fibroblasts also had significantly lower levels of 12S and 16S ribosomal mRNA transcripts, which are necessary for the translation of mitochondrially encoded subunits of complexes I, III, and IV. Similar phenotypes were also observed in MEFs from a Fbxo7 KO mouse model, indicating conservation between human and mouse FBXO7 in regulating mitochondria, cell death and proliferation. In a tissue-specific KO mouse model of PD, where FBXO7 expression was ablated in the dopaminergic neurons, I analysed proteins regulated by FBXO7 which might be responsible for cell loss in the substantia nigra. I discovered that RPL23, a regulator of MDM2, was ubiquitinated by SCFFbxo7 using K48 chain linkages, promoting its degradation by the proteasome. This suggests that misregulation of the MDM2:p53 axis may underlie the cell loss observed in this conditional Fbxo7 KO mouse model. In conclusion, these results elaborate on the role of FBXO7 in mitochondrial biology, and identify a new ubiquitination substrate of FBXO7 in a mouse model of PD. It is hoped that by elucidating the potential pathogenic mechanisms of FBXO7 in rare familial forms of the disease, it will be possible to translate findings to the more prevalent sporadic forms of Parkinson's disease as well.
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Sammler, Esther. « Signalling pathway of FBXO7 and its role in hereditary Parkinsonism ». Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/2a2889b3-20b5-4353-af11-72782c07ef3a.
Texte intégralRésumé :
Parkinson’s Disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s and old age is the strongest risk factor for developing PD. PD has traditionally been seen as a motor disorder, but its non-motor symptoms such as dysautonomia, sensory dysfunction, sleeping problems and neuropsychiatric features equally add to the disease burden. There is no cure for PD and this is probably a reflection of our poor understanding of the disease pathogenesis. One way of tackling this is to focus on the small, but significant number of PD patients with a family history compatible with Mendelian autosomal inheritance (10-15%). Hereditary and sporadic PD share important clinical and neuropathological features, and there is reasonable hope that dissecting molecular pathways of PD gene products will have more general implications for the pathophysiology of PD associated neurodegeneration and help device new treatment strategies. Mutations in the FBXO7 gene have recently been shown to cause an autosomal recessive early onset Parkinsonian-pyramidal syndrome and FBXO7 has been designated as PARK 15 (Di Fonzo et al., 2009). FBXO7 is a member of the F-box protein family, which functions as the variable subunit of Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complexes and as such dictate substrate specificity. The canonical outcome of ubiquitylation is proteasomal degradation and my working hypothesis is that FBXO7 may be involved in protein quality control in the brain. A perturbation thereof may be a first step towards FBXO7 dependent disease. At the time of starting with my PhD project, little was known about the molecular function of FBXO7 and how mutations in FBXO7 result in neurodegeneration. In order to learn more and dissect the signalling pathway of FBXO7 I have used tagged stable overexpression cell lines of the FBXO7 wildtype as well as human disease mutant proteins for tag-pulldowns followed by mass-spectrometry to identify interacting partners and possible substrates. With this approach I have been able to confirm the interaction between FBXO7 and its core SCF E3 ligase partners as well as some of the previously reported interacting partners. I have been able to show that not only the FBXO7 wildytpe protein, but also all of the so far reported human disease mutants are able to assemble into an SCF complex. Hence, my fist conclusion is that the human disease mutants do not exert their pathogenicity by SCF complex disruption. Next, a knock-in (KI) mouse model of one of the pathogenic FBXO7 mutations (R378G) was generated and evaluated by molecular and biochemical approaches as well as motor and behaviour phenotyping. In particular, I have used the Fbxo7 mouse model for extensive proteomic screens to identify wildtype (wt) and KI Fbxo7 interactors: endogenous Fbxo7 immunoprecipitations from mouse brain lysates and subsequent fingerprint mass-spectrometry; differential whole proteome: ex vivo differential dimethyl labelling of wt and KI brain samples, and Fbxo7-dependent ubiquitinome analysis: quantitative di-GLY capture proteomics combining in vivo SILAC labelling with antibody-based affinity enrichment of “di-GLY remnant motifs”- containing peptides prior to proteomic profiling of the wild-type in comparison to the homozygous R379G Fbxo7 KI ubiquitinome in MEF lysates. The di-GLY remnant motif is the signature peptide of ubiquitinylated protein sites at peptide level after tryptic digestions. Some of my findings are: • For the first time I show that endogenous Fbxo7 actually assembles into an Skp1-Cullin1-Fbxo7 complex and that the pathogenic R378G does not disrupt SCFFbxo7-KI complex formation in vivo. This is true for the Fbxo7 KI mouse model, but also for patient derived immortalized cell lines carrying the R378G FBXO7 mutation.• Endogenous Fbxo7 interacts with the Sumo E3 ligase complex RanBP2/ RanGAP1*Sumo1/Ubc9 complex. • In the differential enrichment of ubiquitylated protein species in SILAC labelled wild-type and homozygous R379G Fbxo7 KI MEFs, I have clearly identifies 2 highly conserved lysine residues, which are conserved amongst VDAC 1, 2, and 3 in mouse as well as human homologous, to be preferentially ubiquitinylated in a Fbxo7 wild-type background (in collaboration with Dr. Patrick Pedrioli, MRC Programme leader).• There is a significant difference in motor performance between wildtype and homozygous R379G KI Fbxo7 mice at 10 months of age (in collaboration with Dr. Steve Martin, Neuroscience Division, Dundee). • Furthermore, I have successfully set up an in vitro FBXO7 dependent ubiquitinylation assays.
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Liu, Jia, et 劉佳. « Role of FBXO31 in regulating MAPK-mediated genotoxic stress response and cancer cell survival ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205657.
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Esophageal cancer is the third most common digestive tract malignancy. Along with surgery, genotoxic drugs (e.g. cisplatin) and radiotherapy are the mainstays of treatment for this disease. Environmental factors and environmental stress-induced responses contribute to esophageal tumorigenesis and chemoresistance. Studying key molecules in stress-induced signal pathway can help unravel the underlying mechanisms and discover rational therapeutic targets.
Cyclin D1 is DNA damage response protein. Genotoxic stress induces rapid cyclin D1 degradation and the molecules mediating this response are cell-type dependent. The first part of this study investigated the changes of cyclin D1 expression in response to genotoxic stress in immortalized esophageal epithelial cells, which are experimental models commonly used to study the early events of cancer development. The results showed that cyclin D1 underwent rapid proteasomal degradation before p53-induced p21 accumulation, which substantiates that cyclin D1 plays a role in eliciting cell cycle arrest very early in the DNA damage response. FBXO31 and FBX4, two F-box proteins previously reported to mediate cyclin D1 degradation, were found to be accumulated and unchanged, respectively, after ionizing irradiation in immortalized esophageal epithelial cells and esophageal squamous cell carcinoma (ESCC) cell lines. Yet, knockdown of FBXO31 did not rescue rapid cyclin D1 degradation upon UV or ionizing irradiation. This led to the hypothesis that accumulation of FBXO31 may have novel functions beyond mediating cyclin D1 degradation in cells responding to genotoxic stress.
The second part of this study explored the function of FBXO31 in genotoxic stress response. The accumulation of FBXO31 in cancer cells after exposure to various genotoxic stresses was found to coincide with p38 deactivation, giving the clue that FBXO31 may negatively regulate this important pathway. Further studies revealed that knockdown of FBXO31 resulted in sustained activation of stress-activated MAPKs (SAPKs) p38 and JNK, as well as increase in UV-induced cell apoptosis, whereas overexpression of FBXO31 had opposite effects. The inhibitory role of FBXO31 on SAPK activation and apoptosis was confirmed by shRNA rescue experiments. Consistent with the observed anti-apoptotic effect, soft agar, colony formation and in vivo xenograft experiments showed that FBXO31 had oncogenic function in ESCC. Moreover, in vitro and in vivo results showed that knockdown of FBXO31 could sensitize ESCC cells to cisplatin treatment.
The mechanism underlying the inhibition of SAPKs by FBXO31 was investigated in the third part of this study. Co-immunoprecipitation results showed that FBXO31 could interact with MKK6 (a p38 activator), but not p38, JNK1, or other MAP2Ks. FBXO31 was found to be co-localized with MKK6 in the cytoplasm. Mapping of interaction domains of FBXO31 revealed that aa 115-240 and aa 351-475 were responsible for binding to MKK6. Further study found that binding of FBXO31 to MKK6 could facilitate the K48-linked polyubiquitination and degradation of MKK6.
Taken together, the results of this study showed that FBXO31 accumulation upon genotoxic stress can promote the degradation of MKK6 via K48-linked ubiquitination, thereby inhibiting SAPK activation and protecting cancer cells from genotoxic stress-induced apoptosis. FBXO31 may be a potentially useful therapeutic target to overcome chemoresistance in cancer therapy.published_or_final_version
Anatomy
Doctoral
Doctor of Philosophy
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Kleppa, Marc-Jens [Verfasser]. « Charakterisierung des Gens Fbxl22 und seiner Funktion während der Muskelentwicklung der Maus / Marc-Jens Kleppa ». Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover (TIB), 2011. http://d-nb.info/1019235071/34.
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Shang, Jinsai. « STRUCTURAL AND FUNCTIONAL STUDIES OF F-BOX-ONLY PROTEIN FBXO7 AND ITS INTERACTIONS WITH PROTEASOME INHIBITOR PI31 ». OpenSIUC, 2015. https://opensiuc.lib.siu.edu/dissertations/1053.
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F-box only protein 7 (Fbxo7), a member of the F-box-only subfamily of FBPs, is a biologically and pathophysiologically important human protein that assumes many critical functions. The different functions of Fbxo7 depend on the formation of various multi-protein complexes. Possible interplay between different Fbxo7 functions further complicate the protein-protein interaction networks involved in Fbxo7 biology. Although significant progresses have been made to understand the functions, regulation, specificity, and protein interaction network of Fbxo7, a myriad of questions remain to be answered. The objectives of the work presented in this dissertation are to elucidate the molecular structures underlying the functions of Fbxo7 and the interaction with its protein partners, such as proteasome inhibitor PI31. The best known biological function of Fbxo7 is its role as the substrate-recognition subunit of the SCFFbxo7 (Skp1-Cul1-F-box protein) E3 ubiquitin ligase that catalyzes the ubiquitination of hepatoma up-regulated protein (HURP) and inhibitor of apoptosis protein (IAP). Fbxo7 also assumes various SCF-independent functions through interact with its protein partners that are not the substrates of the ubiquitin proteasome system, such as PI31, Cdk6, p27, PINK1 (PTEN-induced kinase 1), and Parkin. PI31 is a known proteasome regulator which was initially characterized as a proteasome inhibitor in vitro. The binding affinity between Fbxo7 and PI31 is very strong, and The Fbxo7-PI31 interaction is mediated by heterodimerization of the FP domains of the two proteins. This work is focus on study the protein structure of the two FP domains in Fbxo7 and PI3. Chapter 1 reviewed the F-box-only protein Fbxo7 biology including the function of Fbxo7 protein in ubiquitination proteasome pathway and some SCF-independent functions which are relate to human disease. Chapter 2 discussed the function of proteasome inhibitor PI31. With the many important biological functions, Fbxo7 is clearly an extraordinary important protein, but the lack of structural knowledge has hampered efforts to achieve a better understanding of Fbxo7 biology. In this work, we have determined the crystal structure of Fbxo7 FP domain (residues 181-335) and the crystal structure of the PI31 FP domain (residues 1-161) using a longer protein construct both at 2.0Å resolution. The Fbxo7 FP domain adopts an α/β-fold similar to that of the PI31 FP domain and the secondary structure elements of the two FP domains are comparable including the C-terminal helix, indicating that the two FP domains share the same overall global fold. However, an α helix and three β strands in the Fbxo7 are longer than their counterparts in the PI31 FP domain. The two FP domains also differ substantially in the length and conformation of the longest connecting loop. More importantly, structural differences between the two FP domains lead to drastically different modes of inter-domain protein–protein interaction: the PI31 FP domain utilizes either an α interface or β interface for homodimeric interaction, whereas the Fbxo7 FP domain utilizes an αβ interface. We have note that the inter-domain interaction of the Fbxo7 FP domain is much more extensive, featuring a larger contact surface area, better shape complementarity and more hydrophobic and hydrogen-bonding interactions. The results of this structural study provide critical insights into how Fbxo7 may dimerize (or multimerize) and interact with PI31 via the FP domain. Chapter 4 and Chapter 5 discussed the structure determinations, structure features and detail of protein-protein interactions of Fbxo7 and PI31 FP domains. Chapter 2 reviewed the corresponding fundamental biochemical techniques that been used in this study. Chapter 3 discussed protein structure determination by X-ray crystallography in structural biology studies. It was believed that the FP domains of Fbxo7 and PI31 mediate homodimerization and heterodimerization of the proteins and the FP domain is not present in other human proteins. In order to study the Fbxo7-PI31 heterodimerization protein-protein interactions, we performed modeling studies. Chapter 6 discussed the model building and binding studies. Based on the result of model building studies, we propose that an interaction between the two FP domains of Fbxo7 and PI31 should be mediated by a αβ interface using the α-helical surface of the Fbxo7 FP domain and the β-sheet surface of the PI31 FP domain. According to the result of pull down assay, the PI31 FP domain may complete with Skp1 for the binding with Fbxo7. It is possible that the formation of heterodimer between the Fbxo7 and PI31 mediate by FP domains may lead to the Fbxo7 dissociation from SCFFbxo7 complex which might reveal a new regulation mechanism.
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Horn, Moritz [Verfasser], Adam [Akademischer Betreuer] Antebi, Thorsten [Akademischer Betreuer] Hoppe et Günter [Akademischer Betreuer] Schwarz. « Coordination of Developmental Timing and Maturation by the F-box Protein DRE-1/FBXO11 / Moritz Horn. Gutachter : Adam Antebi ; Thorsten Hoppe ; Günter Schwarz ». Köln : Universitäts- und Stadtbibliothek Köln, 2014. http://d-nb.info/1055038620/34.
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Mukherjee, Chaitali [Verfasser], Judith [Akademischer Betreuer] Stegmüller et Mikael [Akademischer Betreuer] Simons. « Functional analysis of the CNS-specific F-box protein FBXO41 in cerebellar development / Chaitali Mukherjee. Betreuer : Judith Stegmüller. Gutachter : Judith Stegmüller ; Mikael Simons ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2015. http://d-nb.info/1077913818/34.
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Simon-Kayser, Barbara. « Identification d'un gène humain localisé en 17q12, codant pour un membre de la famille F-box (Fbxo47) : étude des caractéristiques de la protéine ». Nantes, 2006. http://archive.bu.univ-nantes.fr/pollux/show.action?id=9ed39bb9-3443-422a-a221-ce1ddba667f4.
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Les altérations chromosomiques dans la région 17q surviennent dans de nombreux cancers, incluant les tumeurs papillaires rénales (pRCC), suggérant la présence d'un gène impliqué dans l'oncogenèse. Une analyse de perte d'hétérozygotie sur 15 cas de pRCC nous a permis de définir une zone minimale de délétion autour du marqueur D17S250 (17q12), dans laquelle nous avons isolé un nouveau gène, FBXO47. Ce transcrit apparaît fortement exprimé dans le testicule. La recherche de domaines protéiques caractéristiques a permis de montrer la présence: d'un domaine F-box, dont nous avons démontré la fonctionnalité; d'un motif Leucine-zipper ; d'une séquence d'adressage mitochondrial. Le motif F-box définit une famille de protéines dont la majorité des membres appartient à la voie de dégradation ubiquitine-protéasome dépendante. Afin de déterminer le rôle de Fbxo47 au sein de la cellule, nous avons cherché à identifier ses protéines partenaires. La technique de double-hybride nous a permis d'identifier Gfm1, facteur d'élongation principal de la traduction mitochondriale. Ce travail de thèse représente donc la première description de la présence du système F-box dans la matrice mitochondriale chez l'hommeGenetic alterations of chromosome arm 17q occur in numerous tumor types, including papillary renal cell carcinoma (pRCC). It suggests the presence of a tumor suppressor gene on the long arm of chromosome 17, which is critical for carcinogenesis. In this study, we analyzed 15 cases of pRCC for LOH. We identified a minimal deleted region in which the D17S250 marker (17q12). We isolated the cDNA of a novel gene named FBXO47. FBXO47 cDNA is preferentially expressed in normal tissue, particularly in the testis. The search of characteristic protein domains showed the presence of: a F-box domain, that we showed the functionality in vitro and in vivo; a Leucine-zipper; and a sequence of addressing mitochondrial. Most proteins of the family defined by the F-box motif belong to the ubiquitine-proteasome pathway. In order to determine the cellular function of Fbxo47, we sought to identify its protein partners. A screening in two- hybrid system enabled us to identify the protein Gfm1, the principal elongation factor of the mitochondrial translation. This thesis work represents indeed the first description of the presence of F-box system in mitochondrial matrix in human
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Simon-Kayser, Barbara Bezieau Stéphane. « Identification d'un gène humain localisé en 17q12, codant pour un membre de la famille F-box (Fbxo47) étude des caractéristiques de la protéine / ». [S.l.] : [s.n.], 2006. http://theses.univ-nantes.fr/thesemed/DOCsimon.pdf.
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Vadhvani, Mayur [Verfasser], Judith [Akademischer Betreuer] Stegmüller, Klaus-Armin [Akademischer Betreuer] Nave et Till [Akademischer Betreuer] Marquardt. « The role of E3 ubiquitin ligase FBXO31-SCF in neuronal morphogenesis / Mayur Vadhvani. Gutachter : Judith Stegmüller ; Klaus-Armin Nave ; Till Marquardt. Betreuer : Judith Stegmüller ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://d-nb.info/1044047453/34.
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Slimani, Samira. « Rôle de la protéine FBXW4 dans le complexe SCF et dans le développement du split hand/split foot malformation de type 3 (SHFM3) ». Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66675.
Texte intégralRésumé :
La dégradation des protéines, appelée protéolyse, est un mécanisme essentiel pour le fonctionnement et la survie cellulaire. Elle se fait en grande partie grâce à l’ubiquitination des protéines qui permet au protéasome de les reconnaître et de les cliver. Dans le cadre de ce projet, et ce, à partir de deux cas cliniques, j’ai étudié le rôle la protéine F-box/WD repeat-containing protein 4 (FBXW4) dans ce processus de dégradation. Les patients étaient tous deux atteints d’un syndrome polymalformatif caractérisé par une ectrodactylie appelé split hand/split foot malformation de type 3 (SHFM3) et par une insuffisance rénale chronique. Ils étaient aussi tous deux porteurs d’une mutation P376Q dans FBXW4. Comme on suspectait déjà que FBXW4 appartienne à un complexe d’ubiquitination, nous avons émis l’hypothèse que la mutation affectait l’assemblage de ce complexe et causait ainsi les désordres cliniques identifiés. J’ai donc reproduit cette mutation in vitro ainsi que d’autres à cette position pour en étudier les effets dans le système d’expression des ovocytes de Xenopus laevis. J’ai constaté que FBXW4 était organisé en homomères et que la nature du résidu 376 jouait un rôle dans cet assemblage. J’ai aussi observé que la nature du résidu 376 affectait aussi la liaison de FBXW4 avec Skp1, une autre protéine qui se retrouve dans le complexe. Ces travaux ont ainsi permis d’en arriver aux conclusions suivantes : 1) la mutation des patients affecte l’assemblage oligomérique de FBXW4, 2) elle est donc fort possiblement causale, et 3) elle entraînerait la maladie dû à un désordre de l’ubiquitination de certaines protéines durant le développement.Protein degradation, also known as proteolysis, is essential for cell function and survival. It is most often achieved through the ubiquitination of proteins, a process that allows the proteasome to recognize and cleave such proteins. In this project, I studied two clinical cases in which the protein F-box/WD repeat-containing protein 4 (FBXW4) was believed to play a role. Both patients suffered from a polymalformative syndrome characterized by an ectrodactyly called type 3 split hand/split foot malformation (SHFM3) and chronic renal failure. Both patients also bore a P376Q mutation in FBXW4. As previous studies was consistent with the possibility that FBXW4 was part of an ubiquitination complex, we hypothesized that the mutation affected the assembly of this complex and resulted in the observed clinical disorders. I therefore reproduced the mutation in vitro among others at this location and characterized the effects of such mutations in Xenopus laevis oocyte expression system. I found that FBXW4 was organized in homooligomers and that the nature of the residue of position 376 played a role in assembly of the FBXW4 containing complex. I also found that the nature of residue 376 affected the binding of FBXW4 to another protein in the complex, that is, to Skp1. These results allow us to draw the following conclusions: 1) the mutation identified affects the oligomeric assembly of FBXW4, 2) it is thus very likely to be causative, and 3) it could cause an ubiquitination disorder in which certain proteins are not properly degraded during development
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Schwarz, Tobias. « Charakterisierung von humanem PI31 und neuen alternativen Spleißvarianten des PI31 Gens PSMF1 ». Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15919.
Texte intégralRésumé :
Das Ubiquitin-Proteasom-System eukaryotischer Zellen spielt eine zentrale Rolle beim Abbau von fehlgefalteten und nicht mehr benötigten Proteinen. Damit erfüllt es regulatorische Funktionen bei zellulären Prozessen wie z.B. dem Zellzyklus und der Transkription. Das Protein Proteasominhibitor 31 (PI31) wurde als Inhibitor des Proteasoms in vitro charakterisiert. Des weiteren wurde gezeigt, daß überexprimiertes PI31 im murinen System ein Modulator der Assemblierung des Immunoproteasoms (i20S) ist. Über die Funktion und Regulation von PI31 im humanen System war bisher nichts bekannt und wurde deshalb in dieser Arbeit untersucht. Es konnte gezeigt werden, daß neben dem PI31-Transkript mindestens neun weitere alternative Spleißvarianten des humanen PI31 Gens PSMF1 existieren. Die PI31-Isoformen V2 bis V10 unterscheiden sich von PI31 (V1) teils durch eine fehlende N-terminale Domäne oder einen veränderten C-Terminus. Die Isoform V5 wird als einzige gewebespezifisch in Testikeln exprimiert und ist im Zellkern lokalisiert. Ausschließlich die Überexpression der Isoform V3 führt zur Inhibition der proteasomalen Aktivität in vivo. Ein modulatorischer Einfluß von PI31 oder einer der Isoformen auf die Assemblierung des humanen i20S bestätigte sich dagegen nicht. Die Überexpression von PI31 und V3 in humanen Zellen führte indes zu einer Akkumulation und verzögerten Degradation von proteasomalen Substraten. Es wurde außerdem gezeigt, daß die Expression von humanem PI31 durch virusassoziierte Stimuli wie dsRNA und Typ I-Interferone induziert werden kann. Für die 3kb lange 3’UTR der PI31-mRNA konnte zusätzlich nachgewiesen werden, daß sie inhibitorisch auf die Expression wirkt und somit eine regulatorische Funktion besitzt. In Zusammenhang mit der von Kirk et al. (2008) gezeigten Heterodimerisierung von PI31 mit dem F-Box Protein Fbxo7, weisen die hier vorgestellten Ergebnisse auf eine Funktion von PI31 und dessen Isoformen bei der Ubiquitinierung von proteasomalen Substraten hin.The ubiquitin–proteasome pathway is the major intracellular system for protein degradation. It plays an important role in the regulation of cellular processes like cell cycle control, signal transduction and gene transcription. The protein proteasome inhibitor 31 (PI31) was initially characterized as a potent inhibitor of proteasomal activity in vitro. Furthermore it was shown that PI31 modulates the assembly of the murine immunoproteasome (i20S). The function and regulation of PI31 in the human system is so far unexplored and therefore the topic of this study. It was shown that at least nine alternatively spliced variants of the PI31 gene PSMF1 exist additionally to the PI31 transcript. The PI31 isoforms V2 to V10 differ from PI31 (V1) in parts of the N-terminus and in a modified C-terminus. Only the isoform V5 is tissue specific expressed in testis and localized in the nucleus. After overexpression only the isoform V3 has the ability to inhibit the proteasomal activity in vivo. In contrast to the murine system neither PI31 nor the isoforms showed a modulatory effect on the assembly of the i20S. The overexpression of PI31 and V3 in human cells results instead in the accumulation and delayed degradation of proteasomal substrates. Furthermore the expression of human PI31 can be induced by virus associated stimuli like dsRNA and type I interferones. In addition, for the 3kb long 3’UTR of the PI31-mRNA an inhibitory effect on the expression and therefore a regulatory role was shown. Together with data from Kirk et al. (2008), who show the heterodimerization of PI31 with the F-box protein Fbxo7, the presented results suggest a function of PI31 and its isoforms in the process of ubiquitination of proteasomal substrates.
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Dontcheva, Guergana Ivanova [Verfasser], Judith [Akademischer Betreuer] Stegmüller, Nils [Gutachter] Brose, Anastassia [Gutachter] Stoykova et Tiago Fleming [Gutachter] Outeiro. « Functional analysis of the parkinsonism-associated protein FBXO7 (PARK15) in neurons / Guergana Ivanova Dontcheva ; Gutachter : Nils Brose, Anastassia Stoykova, Tiago Fleming Outeiro ; Betreuer : Judith Stegmüller ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://d-nb.info/1139491571/34.
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Joseph, Sabitha Lis [Verfasser], Judith [Akademischer Betreuer] Stegmüller, Judith [Gutachter] Stegmüller et Klaus-Armin [Gutachter] Nave. « A novel role for the E3 ubiquitin ligase FBXO7 in axonb-myelin interaction / Sabitha Lis Joseph ; Gutachter : Judith Stegmüller, Klaus-Armin Nave ; Betreuer : Judith Stegmüller ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://d-nb.info/1160753474/34.
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Brockelt, David [Verfasser], Judith [Akademischer Betreuer] [Gutachter] Stegmüller et Tiago Fleming [Gutachter] Outeiro. « The role of the E3 ubiquitin ligase FBXO7-SCF in early-onset Parkinson's disease / David Brockelt. Betreuer : Judith Stegmüller. Gutachter : Judith Stegmüller ; Tiago Fleming Outeiro ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1112736522/34.
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Holubowska, Anna [Verfasser], Judith [Akademischer Betreuer] Stegmüller, Hannelore [Akademischer Betreuer] Ehrenreich, André [Akademischer Betreuer] Fischer, Anastassia [Akademischer Betreuer] Stoykova, Andreas [Akademischer Betreuer] Wodarz et Ralf [Akademischer Betreuer] Heinrich. « Characterization of the CNS-specific F-box protein FBXO41 in cerebellar development / Anna Holubowska. Gutachter : Judith Stegmüller ; Hannelore Ehrenreich ; André Fischer ; Anastassia Stoykova ; Andreas Wodarz ; Ralf Heinrich. Betreuer : Judith Stegmüller ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2014. http://d-nb.info/1051740568/34.
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Baumann, Ursula [Verfasser], Florian [Akademischer Betreuer] [Gutachter] Bassermann, Bernhard [Gutachter] Küster et Claus [Gutachter] Belka. « The role of the ubiquitin-proteasome system in the pathology and treatment of B-cell lymphoma : Characterization of the PRKCD-FBXO25-HAX1 axis in lymphomagenesis and treatment resistance of B-cell lymphoma / Ursula Baumann ; Gutachter : Bernhard Küster, Claus Belka, Florian Bassermann ; Betreuer : Florian Bassermann ». München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1137010452/34.
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Kirk, Rebecca Jane. « Structural and functional analysis of the proteasome inhibitor PI31 and its interaction with the F-box protein Fbxo 7 ». Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445730/.
Texte intégralRésumé :
This thesis describes the structural and functional analysis of two related proteins, PI31 and Fbxo7, both of which act within the ubiquitin-proteasome system. This system is involved in a wide variety of cellular processes. Proteins modified with ubiquitin are often targeted for degradation by the proteasome, an ATP-dependent multi-subunit complex. Specificity for ubiquitin transfer is controlled by the E3 ubiquitin ligases. The multi-subunit SCF E3 ubiquitin ligases use their F-box domain protein to engage substrates. Analysis of possible binding partners of the novel F-box protein Fbxo7 using an affinity pull-down in Jurkat cell lysates identified PI31, a putative proteasome inhibitor. Fbxo7 was also shown to bind Skpl, Cullinl and Rbxl inferring that it forms part of a functional E3 ubiquitin ligase. Crystallisation of the Fbxo7-Skpl complex yielded poorly diffracting crystals with a maximum resolution of 8A. The PI31 N-terminal domain (NTD) shows significant sequence similarity to a globular domain of Fbxo7. The PI31-NTD structure was obtained at 2.64A by MAD phasing after introducing an additional methionine to engineer a non-centrosymmetric selenium substructure. The structure reveals a homodimer of novel a/p topology, which we define as the FP (Fbxo7 - PI31) domain since its distribution is limited to Fbxo7 and PI31 proteins in higher eukaryotes. Biophysical analysis of structure-based mutations identified the relevant residues in the homodimer interface by confirming the production of a monomeric form of PI31. Further mutations also revealed the binding surface between Fbxo7 and PI31 by using isothermal calorimetry. Fbxo7 and PI31 were shown to interact in vivo by co-immunoprecipitation and yeast two-hybrid screens using either PI31 or Fbxo7 as bait. Fbxo7 was shown to ubiquitinate FLAG-tagged PI31 in vivo. Abolishing the interaction between Fbxo7 and PI31 by mutations in PI31 prevents this ubiquitination. A model for the interaction between PI31 and Fbxo7 is presented.
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Vingill, Siv [Verfasser], Judith [Akademischer Betreuer] Stegmüller, Thomas A. [Gutachter] Bayer, Tiago Fleming [Gutachter] Outeiro, Nils [Gutachter] Brose, Ralf [Gutachter] Heinrich et Thomas [Gutachter] Dresbach. « Characterization of FBXO7 (PARK15) knockout mice modeling Parkinsonian-Pyramidal Syndrome / Siv Vingill ; Gutachter : Thomas A. Bayer, Tiago Fleming Outeiro, Nils Brose, Ralf Heinrich, Thomas Dresbach ; Betreuer : Judith Stegmüller ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://d-nb.info/1130400816/34.
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Targosz, Bianca-Sabrina [Verfasser], Florian C. [Akademischer Betreuer] Bassermann et Claus [Akademischer Betreuer] Schwechheimer. « The role of the SCF-Fbxo9 in the pathogenesis and therapy of Multiple Myeloma / Bianca-Sabrina Yvonne Targosz. Gutachter : Claus Schwechheimer ; Florian C. Bassermann. Betreuer : Florian C. Bassermann ». München : Universitätsbibliothek der TU München, 2013. http://d-nb.info/1036495167/34.
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Viñas, Castells Rosa. « Ubiquitin ligases involved in the regulation of Snail1 ». Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/145483.
Texte intégralRésumé :
Epithelial to mesenchymal transition (EMT) is a process by which epithelial cells acquire a mesenchymal phenotype. It is characterized by the down-regulation of the adherens junction protein E-cadherin, and it is important during embryonic development. Snail1 expression is sufficient to trigger EMT in cultured cells and is found up-regulated in some cancers. Snail1 is stabilized both at mRNA and protein levels and in this project we analyzed the action of ubiquitin ligases affecting protein half-life. Apart from the already described β-Trcp1, that degrades Snail1 in a GSK-3β phosphorylation-dependent manner, we found the F-box proteins FBXL14 and FBXL5 as novel E3 ubiquitin ligases for Snail1. FBXL14 is a cytoplasmic ubiquitin ligase that is down-regulated in hypoxia through a transcriptional mechanism. FBXL5 is nuclear and modulates Snail1 binding to the DNA and nuclear ubiquitination. FBXL5 protein is destabilized after γ-irradiation, inducing high levels of Snail1. Together, these ligases keep a tight control of Snail1 cellular levels, maintaining them low in normal conditions.La transició epiteli-mesènquima (per l’acrònim en anglès de: “epithelial to mesenchymal transition”, EMT) és un procés durant el qual cèl•lules epitelials adquireixen un fenotip mesenquimal. Està caracteritzat per la baixada de l’E-caderina, una proteïna de les unions adherents, i és important en el desenvolupament embrionari. L’expressió de Snail1 és suficient per desencadenar la EMT en cèl•lules en cultiu i s’ha trobat sobre-expressada en alguns càncers. Snail1 s’estabilitza tant a nivell de mRNA com de proteïna i en aquest projecte hem analitzat l’acció de les lligases d’ubiquitina que afecten els nivells de la proteïna. Apart de la ja descrita β-Trcp1, que degrada Snail1 de manera depenent a la fosforilació de Snail1 per GSK-3β, hem trobat les proteïnes F-box FBXL14 i FBXL5 con a noves lligases d’ubiquitina E3 que degraden Snail1. La FBXL14 és citoplasmàtica i els seus nivells disminueixen en hipòxia a través d’un mecanisme transcripcional. La FBXL5 és nuclear i modula tant la unió de Snail1 al DNA com la seva ubiquitinació nuclear. La proteïna FBXL5 es desestabilitza degut a la radiació gamma (γ) induint els nivells de Snail1.
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陳映如. « A Study on the Institution of Working Time in Taiwan : Focusing on Working besides Regular Working Hours ». Thesis, 2019. http://ndltd.ncl.edu.tw/handle/fbxe2q.
Texte intégralRésumé :
碩士國立政治大學
勞工研究所
107
As we view the revisal of the Labor Standard Act for the past few years, surely the issue of cutting down working time has become something that draws quite a few attentions. Even so, as confronting the actual need when it comes to operating a company, some exceptions are made besides the principles of regular working hours.However, while the Act has been revised, it seems like nothing has changed, people still work besides regular working hours, people still dispute about how to have their regular leave, and people still work overtime. In this article, the concept of working besides regular working hours has divided into two parts, which is a part that includes working besides regular hours and working on a rest day, and a part that includes working on a regular leave and working on a holiday. Due to the affection of the Act, these two parts will have different situation. The purpose of the article is to study the requirements base on the Act, and the affection and issue they cause. By using document analysis, with the assistance of comparative law, after the analysis, it is found that even though it shouldn’t be normal to work besides regular working hours, it is quite common for three reasons. First of all, the Act set the employer’s necessity as a reason, but the definition of necessity is questionable. Secondary, the Act makes a consent made by the labor union or a lobor-management conference as the approval of extending working hours, however, it may not occur restriction for individual labor, which may be favorable for employers. The third reason, which should be review and make improvement as soon as possible, is that there is no cleary specification for the requirement of working on a rest day. In addition, since it is possible to adjust regular leave or holiday, it opens up many disturbing situaions. Finally, it is found that when dealing with issues that contain extending working time by voluntary, the judicial authourities doesn’t have indentical views for the determination standard. Moreover, due to the calculation stardard which doesn’t indentical views for that as well, it causes issues of working exceed more than two calendar days.
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Chen, Wan-Rou, et 陳婉柔. « Genetic Study of Two Candidate Genes, FBXO25 and ARHGEF10, in Autism Spectrum Disorders ». Thesis, 2012. http://ndltd.ncl.edu.tw/handle/26818068096871531634.
Texte intégralRésumé :
碩士慈濟大學
分子生物暨人類遺傳學系碩士班
100
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopment disorders, it can be diagnosed before three years of age, the syndromes of ASD are defined by the damage of social interaction, abnormal development of speech and language, and highly restricted interests and stereotyped behavior. Previous studies showed that ASD are highly heritable, however, the disease causing genes are poorly known. We recently reported that using Array Comparative Genomic Hybridization analysis (array CGH), a boy with ASD who had a terminal deletion at the short arm of chromosome 8, was detected.The deletion region contains 23 genes. To further elucidate which genes might be associated with ASD, we investigated two genes in this study, i.e. F-box protein 25 (FBXO25) and the Rho guanine nucleotide exchange factor 10 (ARHGEF10). To investigate whether the FBXO25 and the ARHGEF10 are associated with ASD, we set out to screen mutations of these two genes in ASD. We used PCR-based direct sequencing to screen mutations at all the exonic regions of these two genes in 360 ASD patients and 400 controls. We identified a missense mutation R38H in the FBXO25 in one patient. In ARHGEF10 gene, we identified several missense mutations, including D96N, G118C, G187S, E189V, R275H, V700I, T970M, T1173S, I1241F, Y1282C, and R1320S. Five mutations, G118C, G187S, E189V, T970M and Y1282C, were only found in patients, but not in controls. Computer programs of PolyPhen and SIFT predict that G118C, R275H and T1173S mutations of ARHGEF10 gene are probably damaging. And only in SIFT, E189V was probably damaging. In ARHGEF10, E189V mutation had significant difference of genotype frequency and allele frequency of case-control analysis (genotype frequency, p=0.03, allele frequency, p=0.04). These mutations might be result in increased risk to ASD.
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Vadhvani, Mayur. « The role of E3 ubiquitin ligase FBXO31-SCF in neuronal morphogenesis ». Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-F0CA-7.
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Holubowska, Anna. « Characterization of the CNS-specific F-box protein FBXO41 in cerebellar development ». Doctoral thesis, 2013. http://hdl.handle.net/11858/00-1735-0000-0022-5ECB-7.
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Huang, Ting-Wei, et 黃廷瑋. « Interaction of FBXL14 and a Schizophrenia Associated Gene DISC1 in Mouse Embryonic Brain ». Thesis, 2014. http://ndltd.ncl.edu.tw/handle/95791312336805945594.
Texte intégralRésumé :
碩士國立臺灣大學
腦與心智科學研究所
103
Disrupted in Schizophrenia 1 (DISC1), first identified in human (Homo sapiens), is a disease-related gene that is associated with schizophrenia and other psychiatric disorders including bipolar disorder and autism spectrum disorders (Soares et al, 2011). DISC1 protein is known to be involved in neurodevelopment processes such as neuronal migration (Ishizuka et al, 2011) and neuronal progenitor proliferation (Singh et al, 2010). F-box and leucine-rich repeat protein 14 (FBXL14) is a subunit of E3 ubiquitin ligase complex involved in proteasome-mediated protein degradation (Cardozo et al, 2004). Preliminary data from our lab showed that mouse DISC1 (mDISC1) co-immunoprecipitates (co-IP) with mouse FBXL14 (mFBXL14), suggesting that these two proteins together may play a role in regulating neurodevelopment. To characterize the interaction of mDISC1 and mFBXL14, the deletion constructs of these two genes were prepared to define their respective interaction domains by co-IP assays. GST pull-down assay was also performed to address whether the interactions are via direct binding. Using in utero electroporation (IUEP), we found knock-down of mFbxl14 caused mouse embryonic cortical neurons gathering in the intermediate zone while knock-down of mDisc1 were reported to cause cortical neuron migration defects (Kamiya et al, 2005). How the interaction of mDISC1 and mFBXL14 may affect embryonic cortical neuronal migration and proliferation in vivo was also explored. Through these studies, the molecular basis of the interaction of mDISC1 and mFBXL14 was characterized, which provides insight into the developmental role of mDISC1 and mFBXL14 in the embryonic corticogenesis.
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Mukherjee, Chaitali. « Functional analysis of the CNS-specific F-box protein FBXO41 in cerebellar development ». Doctoral thesis, 2015. http://hdl.handle.net/11858/00-1735-0000-0023-9648-1.
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Vingill, Siv. « Characterization of FBXO7 (PARK15) knockout mice modeling Parkinsonian-Pyramidal Syndrome ». Doctoral thesis, 2016. http://hdl.handle.net/11858/00-1735-0000-0023-3E1B-6.
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Dontcheva, Guergana Ivanova. « Functional analysis of the parkinsonism-associated protein FBXO7 (PARK15) in neurons ». Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3EF5-7.
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Chen, Ying-Lin, et 陳映伶. « Investigating up-regulating FBXO7 expression as a preventive strategy for Parkinson's disease ». Thesis, 2014. http://ndltd.ncl.edu.tw/handle/92758321094666163111.
Texte intégralRésumé :
碩士國立臺灣師範大學
生命科學研究所
102
Parkinson’s disease (PD), the second most common neurodegenerative disorder, is pathologically characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain. Mutations in the F-box only protein 7 gene (FBXO7), the substrate-specifying subunit of Skp1-Cullin-F-Box (SCF) E3 ubiquitin ligase complex, cause PD-15 (PARK15). Previously we identified an amino acid changed variant Y52C in association with decreased risk of developing PD. Upon expression in cells, Y52C variant displayed significantly reduced rate of decay in cycloheximide chase experiment. The human FBXO7 gene promoter has not been analyzed. To investigate cis elements controlling FBXO7 expression, we cloned FBXO7 promoter fragments from -1240, -694, -538, -438, -202 and -56 to +261 by PCR amplification and placed in front of GFP reporter for transfection assay in HEK-293T cells. The expression of GFP was monitored by both high content analysis and flow cytometry. When the expressed GFP level of the -56~+261 promoter fragment was set as 100%, significantly increased FBXO7 promoter activity was observed with the -202~+261 and -694~+261 fragments by both methods. As the protective role of increased FBXO7 level in PD was implicated, Flp-In 293 cell line expressing GFP reporter driven by FBXO7 -694~+261 promoter fragment was constructed and used as a platform to screen herbal extracts provided by Industrial Technology Research Institute for enhancing FBXO7 expression. Herbal extracts NTNU-319, 379, 395 and 439 were found to increase endogenous FBXO7 protein expression in both Flp-In 293 and SH-SY5Y cells. Treatment of the above herbal extracts protected SH-SY5Y cells against MPP+-induced cell death. In addition, herbal extracts NTNU-319, 395 and 439 significantly alleviated MPP+-induced loss of mitochondrial membrane potential. As lack of treatment to prevent or slow PD progression, the proposed study may provide new insights into the therapeutic approach to PD.
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Joseph, Sabitha Lis. « A novel role for the E3 ubiquitin ligase FBXO7 in axon-myelin interaction ». Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-002E-E414-8.
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Chou, Jian-Liang, et 周建良. « The Role of Aberrant Epigenetic Alteration of the TGF-β Targets FBXO32 and ABCA1 In Ovarian Cancer ». Thesis, 2013. http://ndltd.ncl.edu.tw/handle/19886517080024773013.
Texte intégralRésumé :
博士國立中正大學
分子生物研究所
101
The Dysregulation of TGF-β signaling plays a key role in ovarian carcinogenesis and maintaining cancer stem cell properties. In this study, we utilized previous ChIP-chip, mDIP-chip, and expression array data to identify TGF-β/SMAD4 relative genes: FBXO32 and ABCA1. In the first part of study, we found that expression of FBXO32 was observed in normal ovarian surface epithelium but not in ovarian cancer cell lines. FBXO32 methylation was seen in ovarian cancer cell lines, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines, suggesting that epigenetic modifications regulate the expression of this gene in ovarian cancer. In advanced stage ovarian tumors, significant (29.3%; p<0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression free survival was significant (Kaplan-Meier, p<0.05). Re-expression of FBXO32 markedly reduced proliferation of ovarian cancer line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In the second part of the study, we identified ABCA1 by mDIP-Chip which was methylated in ovarian cancer cell line, A2780 and CP70. ABCA1 was expressed not only in IOSE, but in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines. In A2780 and CP70 ovarian cancer cell line, ABCA1 was down-regulated and was associated with promoter hypermethylation as demonstrated by bisulfite pyro-sequencing. Analysis of ABCA1 methylation in 8 normal OSE and 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation is associated with high stage and high grade (p=0.0169 vs. p=0.0024). Importantly, patients with higher methylation of ABCA1 have shorter progression free survival (p=0.09) and overall survival (p=0.016). In conclusion, both of FBXO32 and ABCA1 were repressed by DNA methylation in ovarian cancer, and hypermethylation of them was associated with poor prognosis in cancer patients.
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Brockelt, David. « The role of the E3 ubiquitin ligase FBXO7-SCF in early-onset Parkinson's disease ». Doctoral thesis, 2015. http://hdl.handle.net/11858/00-1735-0000-0028-881A-3.
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Hagens, Olivier [Verfasser]. « Search for genes involved in human cognition : molecular characterisation of two novel genes, FBXO25 and KIAA1202, disrupted by a translocation in a mentally retarded patient / vorgelegt Olivier Hagens ». 2007. http://d-nb.info/985002883/34.
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Neilsen, Paul Matthew. « Functional analysis of ANKRD11 and FBXO31 : two candidate tumour suppressor genes from the 16q24.3 breast cancer loss of heterozygosity region ». 2008. http://hdl.handle.net/2440/59014.
Texte intégralRésumé :
Loss of heterozygosity (LOH) on the long arm of chromosome 16 is frequently observed during the onset of breast cancer. Our laboratory has recently identified both ANKRD11 and FBXO31 as candidate tumour suppressor genes in the chromosome band 16q24.3, which is the smallest region of overlap for breast cancer LOH. This thesis focuses on the functional analysis of these two novel genes and implicates a role for them as breast cancer tumour suppressors. ANKRD11: a novel p53 coactivator involved in the rescue of mutant p53. The ability of p53 to act as a transcription factor is critical for its function as a tumour suppressor. Ankyrin repeat domain 11 (ANKRD11) was found to be a novel p53-interacting protein which enhanced the transcriptional activity of p53. ANKRD11 expression in breast cancer cell lines was shown to be down-regulated when compared to ANKRD11 expression in finite life-span HMECs and non-malignant immortalized breast epithelial cells. Restoration of ANKRD11 expression in MCF-7 (p53 wild-type) and MDA-MB-468 (p53[superscript R273H] mutant) cells suppressed the oncogenic properties of these breast cancer cell lines through enhancement of p21[superscript waf1] expression. ShRNA-mediated silencing of ANKRD11 reduced the ability of p53 to activate p21[superscript waf1] expression in response to DNA damage. ANKRD11 was shown to associate with the p53 acetyltransferase, P/CAF, and exogenous ANKRD11 expression increased the levels of acetylated p53. Exogenous ANKRD11 expression enhanced the DNA-binding properties of the p53[superscript R273H] mutant to the CDKN1A promoter, implicating a role for ANKRD11 in the restoration of mutant p53[superscript R273H] function. These findings demonstrate a role for ANKRD11 as a p53 coactivator and illustrate the potential of ANKRD11 in the restoration of mutant p53[superscript R273H] function. ANKRD11 has roles beyond that of p53 coactivation. This thesis also presents preliminary findings to suggest that ANKRD11 may be involved in the regulation of eukaryotic cell division. Furthermore, ANKRD11 was shown to function as an estrogen receptor coactivator. Taken together, these finding suggest that ANKRD11 is a multi-functional cancer-related protein. FBXO31: the 16q24.3 senescence gene. A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumour cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. Exogenous FBXO31 expression inhibited the oncogenic properties of the MCF-7 breast cancer cell line. In addition, compared to the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumour cell lines and primary tumours. FBXO31 protein levels were cell cycle regulated, with maximal expression from late G2 to early G1 phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G1 phase of the cell cycle. FBXO31 was also shown to be a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumour suppressor by generating SCF[superscript FBXO31] complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1325445
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, Discipline of Medicine, 2008
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Neilsen, Paul Matthew. « Functional analysis of ANKRD11 and FBXO31 : two candidate tumour suppressor genes from the 16q24.3 breast cancer loss of heterozygosity region ». Thesis, 2008. http://hdl.handle.net/2440/59014.
Texte intégralRésumé :
Loss of heterozygosity (LOH) on the long arm of chromosome 16 is frequently observed during the onset of breast cancer. Our laboratory has recently identified both ANKRD11 and FBXO31 as candidate tumour suppressor genes in the chromosome band 16q24.3, which is the smallest region of overlap for breast cancer LOH. This thesis focuses on the functional analysis of these two novel genes and implicates a role for them as breast cancer tumour suppressors.
ANKRD11: a novel p53 coactivator involved in the rescue of mutant p53.
The ability of p53 to act as a transcription factor is critical for its function as a tumour suppressor. Ankyrin repeat domain 11 (ANKRD11) was found to be a novel p53-interacting protein which enhanced the transcriptional activity of p53. ANKRD11 expression in breast cancer cell lines was shown to be down-regulated when compared to ANKRD11 expression in finite life-span HMECs and non-malignant immortalized breast epithelial cells. Restoration of ANKRD11 expression in MCF-7 (p53 wild-type) and MDA-MB-468 (p53[superscript R273H] mutant) cells suppressed the oncogenic properties of these breast cancer cell lines through enhancement of p21[superscript waf1] expression. ShRNA-mediated silencing of ANKRD11 reduced the ability of p53 to activate p21[superscript waf1] expression in response to DNA damage. ANKRD11 was shown to associate with the p53 acetyltransferase, P/CAF, and exogenous ANKRD11 expression increased the levels of acetylated p53. Exogenous ANKRD11 expression enhanced the DNA-binding properties of the p53[superscript R273H] mutant to the CDKN1A promoter, implicating a role for ANKRD11 in the restoration of mutant p53[superscript R273H] function. These findings demonstrate a role for ANKRD11 as a p53 coactivator and illustrate the potential of ANKRD11 in the restoration of mutant p53[superscript R273H] function.
ANKRD11 has roles beyond that of p53 coactivation. This thesis also presents preliminary findings to suggest that ANKRD11 may be involved in the regulation of eukaryotic cell division. Furthermore, ANKRD11 was shown to function as an estrogen receptor coactivator. Taken together, these finding suggest that ANKRD11 is a multi-functional cancer-related protein.
FBXO31: the 16q24.3 senescence gene.
A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumour cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. Exogenous FBXO31 expression inhibited the oncogenic properties of the MCF-7 breast cancer cell line. In addition, compared to the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumour cell lines and primary tumours. FBXO31 protein levels were cell cycle regulated, with maximal expression from late G2 to early G1 phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G1 phase of the cell cycle. FBXO31 was also shown to be a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumour suppressor by generating SCF[superscript FBXO31] complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, Discipline of Medicine, 2008
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Rizk, Rana. « Analyzing KDM4A protein interaction network using proximity-dependent biotin identification assay ». Thesis, 2020. http://hdl.handle.net/1866/24711.
Texte intégralRésumé :
Cette étude a été conçue pour identifier les protéines qui interagissent potentiellement avec Déméthylase 4A spécifique de la lysine (KDM4A) dans le contexte du cancer en utilisant l’essai d'identification de la biotine dépendante de la proximité 2 (BioID2). KDM4A est une lysine déméthylase et un régulateur épigénétique qui joue un rôle dans la carcinogenèse en favorisant la prolifération. Nous avons cherché à identifier l'interactome protéique de KDM4A dans la lignée cellulaire du cancer du col de l'utérus HeLa. Ces interactions protéiques ont été caractérisées en fonction de leur dépendance à l’activité catalytique de KDM4A et / ou au domaine Tandem Tudor. De nouveaux interactants de KDM4A ont été détectés, tout en observant des partenaires protéiques précédemment identifiés, comme FBXO22. KDM4A semble interagir avec certains membres du complexe de remodelage de la chromatine pBAF, en particulier, ARID2, BRD7 et SMARCA2. Le complexe pBAF facilite ou empêche l'accessibilité à l'ADN en restructurant le nucléosome. Une analyse plus approfondie est nécessaire pour valider si l'interaction complexe KDM4A-pBAF est directe ou indirecte. Cette étude suggère également l’importance du domaine Tandem Tudor dans le rôle de KDM4A dans la réparation de bris double brin. Enfin, nous proposons également une implication potentielle de KDM4A dans l'épissage de l'ARNm et le transport d'anions organiques. Cette étude fournit de nouvelles informations sur le rôle de KDM4A dans le développement du cancer.This study was designed to identify potential interacting proteins of Lysine-specific demethylase 4A (KDM4A) in the context of cancer using proximity-dependent biotin identification 2 (BioID2) assay. KDM4A is a lysine demethylase and an epigenetic regulator that plays a role in carcinogenesis by promoting proliferation. Herein, we sought out to identify the protein interactome of KDM4A in cervical cancer cell line HeLa. These protein interactions were characterized by their dependency on KDM4A’s catalytic activity and/or Tandem Tudor domain. It succeeded at detecting novel interactors of KDM4A as well as previously studied interactions, such as FBXO22. KDM4A seems to be interacting with some members of the pBAF chromatin remodeling complex, specifically, ARID2, BRD7, and SMARCA2. The pBAF complex facilitates or prevents accessibility to DNA by restructuring the nucleosome. Further analysis is required to validate whether the KDM4A-pBAF complex interaction is direct or indirect. This study also implied the importance of the Tandem Tudor domain in KDM4A’s role in the double stranded break repair. Finally, we also propose the potential involvement of KDM4A in mRNA splicing and organic anion transport. This study provides new insights into KDM4A’s role in cancer development.
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Haydu, Julie Erika M. « The Roles of F-box and Leucine-Rich Repeat Protein 4 (FBXL4) in Mitochondrial Encephalopathy and T-cell Acute Lymphoblastic Leukemia ». Thesis, 2015. https://doi.org/10.7916/D8028Q64.
Texte intégralRésumé :
The F-box and leucine-rich repeat factor (FBXL4) locus is altered in two distinct diseases, a pediatric mitochondrial encephalopathy associated with early death, and the highly aggressive hematological malignancy T-cell Acute Lymphoblastic Leukemia (T-ALL). As an F-box protein, FBXL4 is predicted to target specific protein substrates for proteasomal degradation. Notably, not much is known about the roles of FBXL4 in homeostasis or disease, and thus I generated conditional Fbxl4 knockout mice to characterize the contributions of Fbxl4 to mitochondrial encephalopathy and to T-ALL. Homozygous mutations in FBXL4 are associated with pediatric-onset mitochondrial encephalopathy, but the molecular and cellular mechanisms driving disease pathogenesis are unknown. Here, I show that constitutive loss of Fbxl4 recapitulates key features of human mitochondrial encephalopathy, including microcephaly, failure to thrive, and perinatal lethality. Moreover, Fbxl4 inactivation drives profound metabolic alterations in the perinatal period. On the cellular level, loss of Fbxl4 results in mitochondria DNA depletion and disrupts oxidative phosphorylation and mitochondria membrane potential. Isolation of the FBXL4 protein complex reveals that FBXL4 interacts with a diverse set of mitochondrial factors crucial for normal mitochondrial function. Overall, these findings underscore the importance of FBXL4 in development, metabolism, and mitochondrial dynamics, and may be used to develop novel therapies for patients with mitochondrial encephalopathy associated with FBXL4 mutations and for patients with 6q- T-ALL.
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Magalhães, Ana Luísa Dos Santos. « Identificação de Novos Genes de Susceptibilidade para o Cancro do Cólon e Recto do Tipo X ». Master's thesis, 2017. http://hdl.handle.net/10362/63366.
Texte intégralRésumé :
O cancro do cólon e recto familiar do tipo X (FCCTX) descreve as famílias HNPCC que preenchem
os CA mas não apresentam mutações germinais nos genes MMR e cujos tumores são microssatélites
estáveis. Não são ainda conhecidas causas moleculares que expliquem a susceptibilidade para o
desenvolvimento de cancro do cólon na grande maioria das famílias FCCTX. Assim, o presente
projecto pretendeu identificar genes candidatos/variantes específicas em genes candidatos que possam
estar envolvidos na susceptibilidade para o cancro do cólon e recto familiar do tipo X (FCCTX).
Foram incluídas neste estudo e foco principal das várias análises, 15 famílias FCCTX. Com base
em resultados prévios do grupo e numa possível interacção com o gene MSH6, foi estudada a
contribuição de alterações genéticas germinais no gene FBXO11 para a susceptibilidade para o
FCCTX, por sequenciação de Sanger, análise de copy-number e de expressão na linha germinal. Para
as mesmas famílias foi efectuada uma caracterização a nível germinal de dois subgrupos de famílias
FCCTX, correspondentes a duas entidades moleculares previamente identificadas pelo grupo (TSG+ e
TSG-), através de sequenciação de nova geração utilizando um painel multigénico de 94 genes que
conferem risco aumentado para cancro. Com base nos resultados desta análise foi seleccionado um
sub-grupo de genes, que foram analisados para 78 indivíduos índex adicionais de potenciais famílias
FCCTX. Para uma família, mais informativa, do grupo TSG-, foi avaliado o potencial carácter
patogénico de variantes genéticas específicas em genes candidatos para a susceptibilidade para o
FCCTX, obtidas através de whole exome sequencing (WES), de modo a identificar mutações que
possam predispor para esta condição hereditária. Com esta finalidade foi efectuada análise
bioinformática e análise in silico para selecção de variantes candidatas seguida de análise de
segregação com a doença na família em 9 de indivíduos afectados e 3 não afectados.
Os resultados obtidos da análise mutacional, de expressão e de copy-number não revelaram
qualquer contribuição do gene FBXO11 para o FCCTX. A análise do painel multigénico para as
famílias FCCTX identificou mutações em genes que codificam para proteínas associadas a vias de
reparação do DNA associadas à recombinação homóloga em 7/17 (47%), mas apenas em famílias com
tumores com assinatura molecular TSG+. Mutações nestes genes foram também identificadas num
subgrupo de potenciais famílias FCCTX (29/78, 37%), o que poderá vir a ser importante para o
manejo clínico destas famílias. A análise das variantes provenientes da sequenciação do exoma numa
família FCCTX, permitiu a selecção de 43 variantes, das quais, após completa análise in silico e de
segregação, se seleccionaram 6 variantes nos genes MTMR3,DUSP12,LGR6,SMG7,TAS1R1 e NEK7,
como contribuindo possivelmente para o FCCTX. A identificação de mais do que uma variante
genética em algumas famílias parece estar de acordo com um modelo do FCCTX como uma doença
poligénica.
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Rostosky, Christine Melina. « Onset and Progression of Neurodegeneration in Mouse Models for Defective Endocytosis ». Doctoral thesis, 2018. http://hdl.handle.net/21.11130/00-1735-0000-0005-1286-F.
Texte intégral