Relevant bibliographies by topics / Mutant FUS

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  2. Dissertations / Theses
  3. Books
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  5. Conference papers

Academic literature on the topic 'Mutant FUS'

Author: Grafiati
Published: 4 June 2021
Last updated: 10 February 2022

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Journal articles on the topic "Mutant FUS"

1

Humphrey, Jack, Nicol Birsa, Carmelo Milioto, Martha McLaughlin, Agnieszka M. Ule, David Robaldo, Andrea B. Eberle, et al. "FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention." Nucleic Acids Research 48, no. 12 (June 1, 2020): 6889–905. http://dx.doi.org/10.1093/nar/gkaa410.

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Abstract Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.
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Schwartz, Jacob C., Elaine R. Podell, Steve S. W. Han, James D. Berry, Kevin C. Eggan, and Thomas R. Cech. "FUS is sequestered in nuclear aggregates in ALS patient fibroblasts." Molecular Biology of the Cell 25, no. 17 (September 2014): 2571–78. http://dx.doi.org/10.1091/mbc.e14-05-1007.

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Mutations in the RNA-binding protein FUS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigate whether mutant FUS protein in ALS patient–derived fibroblasts affects normal FUS functions in the nucleus. We investigated fibroblasts from two ALS patients possessing different FUS mutations and a normal control. Fibroblasts from these patients have their nuclear FUS protein trapped in SDS-resistant aggregates. Genome-wide analysis reveals an inappropriate accumulation of Ser-2 phosphorylation on RNA polymerase II (RNA Pol II) near the transcription start sites of 625 genes for ALS patient cells and after small interfering RNA (siRNA) knockdown of FUS in normal fibroblasts. Furthermore, both the presence of mutant FUS protein and siRNA knockdown of wild-type FUS correlate with altered distribution of RNA Pol II within fibroblast nuclei. A loss of FUS function in orchestrating Ser-2 phosphorylation of the CTD of RNA Pol II is detectable in ALS patient–derived fibroblasts expressing mutant FUS protein, even when the FUS protein remains largely nuclear. A likely explanation for this loss of function is the aggregation of FUS protein in nuclei. Thus our results suggest a specific mechanism by which mutant FUS can have biological consequences other than by the formation of cytoplasmic aggregates.
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Kamelgarn, Marisa, Jing Chen, Lisha Kuang, Huan Jin, Edward J. Kasarskis, and Haining Zhu. "ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay." Proceedings of the National Academy of Sciences 115, no. 51 (November 19, 2018): E11904—E11913. http://dx.doi.org/10.1073/pnas.1810413115.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed a protocol to isolate the dynamic mutant FUS-positive cytoplasmic granules. Proteomic identification of the protein composition and subsequent pathway analysis led us to hypothesize that mutant FUS can interfere with protein translation. We demonstrated that the ALS mutations in FUS indeed suppressed protein translation in N2a cells expressing mutant FUS and fibroblast cells derived from FUS ALS cases. In addition, the nonsense-mediated decay (NMD) pathway, which is closely related to protein translation, was altered by mutant FUS. Specifically, NMD-promoting factors UPF1 and UPF3b increased, whereas a negative NMD regulator, UPF3a, decreased, leading to the disruption of NMD autoregulation and the hyperactivation of NMD. Alterations in NMD factors and elevated activity were also observed in the fibroblast cells of FUS ALS cases. We conclude that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation, both of which likely contribute to motor neuron death.
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Mallik, Moushami, Marica Catinozzi, Clemens B. Hug, Li Zhang, Marina Wagner, Julia Bussmann, Jonas Bittern, et al. "Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity." Journal of Cell Biology 217, no. 11 (September 12, 2018): 3947–64. http://dx.doi.org/10.1083/jcb.201802151.

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Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.
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Rhine, Kevin, Jaya Sarkar, Amirhossein Ghanbari Niaki, Xinyi Cai, Gabby Vidaurre, and Sua Myong. "Wild-Type Fus Rescues Altered RNA Binding of ALS-Linked FUS Mutant." Biophysical Journal 116, no. 3 (February 2019): 213a. http://dx.doi.org/10.1016/j.bpj.2018.11.1177.

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6

Perrotti, Danilo, Angela Iervolino, Vincenzo Cesi, Maria Cirinná, Silvia Lombardini, Emanuela Grassilli, Silvia Bonatti, Pier Paolo Claudio, and Bruno Calabretta. "BCR-ABL Prevents c-Jun-Mediated and Proteasome-Dependent FUS (TLS) Proteolysis through a Protein Kinase CβII-Dependent Pathway." Molecular and Cellular Biology 20, no. 16 (August 15, 2000): 6159–69. http://dx.doi.org/10.1128/mcb.20.16.6159-6169.2000.

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ABSTRACT The DNA binding activity of FUS (also known as TLS), a nuclear pro-oncogene involved in multiple translocations, is regulated by BCR-ABL in a protein kinase CβII (PKCβII)-dependent manner. We show here that in normal myeloid progenitor cells FUS, although not visibly ubiquitinated, undergoes proteasome-dependent degradation, whereas in BCR-ABL-expressing cells, degradation is suppressed by PKCβII phosphorylation. Replacement of serine 256 with the phosphomimetic aspartic acid prevents proteasome-dependent proteolysis of FUS, while the serine-256-to-alanine FUS mutant is unstable and susceptible to degradation. Ectopic expression of the phosphomimetic S256D FUS mutant in granulocyte colony-stimulating factor-treated 32Dcl3 cells induces massive apoptosis and inhibits the differentiation of the cells escaping cell death, while the degradation-prone S256A mutant has no effect on either survival or differentiation. FUS proteolysis is induced by c-Jun, is suppressed by BCR-ABL or Jun kinase 1, and does not depend on c-Jun transactivation potential, ubiquitination, or its interaction with Jun kinase 1. In addition, c-Jun-induced FUS proteasome-dependent degradation is enhanced by heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and depends on the formation of a FUS-Jun-hnRNP A1-containing complex and on lack of PKCβII phosphorylation at serine 256 but not on FUS ubiquitination. Thus, novel mechanisms appear to be involved in the degradation of FUS in normal myeloid cells; moreover, the ability of the BCR-ABL oncoprotein to suppress FUS degradation by the induction of posttranslational modifications might contribute to the phenotype of BCR-ABL-expressing hematopoietic cells.
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Brizzio, V., A. E. Gammie, G. Nijbroek, S. Michaelis, and M. D. Rose. "Cell fusion during yeast mating requires high levels of a-factor mating pheromone." Journal of Cell Biology 135, no. 6 (December 15, 1996): 1727–39. http://dx.doi.org/10.1083/jcb.135.6.1727.

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During conjugation, two yeast cells fuse to form a single zygote. Cell fusion requires extensive remodeling of the cell wall, both to form a seal between the two cells and to remove the intervening material. The two plasma membranes then fuse to produce a continuous cytoplasm. We report the characterization of two cell fusion defective (Fus-) mutants, fus5 and fus8, isolated previously in our laboratory. Fluorescence and electron microscopy demonstrated that the fus5 and fus8 mutant zygotes were defective for cell wall remodeling/removal but not plasma membrane fusion. Strikingly, fus5 and fus8 were a specific; both mutations caused the mutant phenotype when present in the MATa parent but not in the MAT alpha parent. Consistent with an a-specific defect, the fus5 and fus8 mutants produced less a-factor than the isogenic wild-type strain. FUS5 and FUS8 were determined to be allelic to AXL1 and RAM1, respectively, two genes known to be required for biogenesis of a-factor. Several experiments demonstrated that the partial defect in a-factor production resulted in the Fus- phenotype. First, overexpression of a-factor in the fus mutants suppressed the Fus- defect. Second, matings to an MAT alpha partner supersensitive to mating pheromone (sst2 delta) suppressed the Fus- defect in trans. Finally, the gene encoding a-factor, MFA1, was placed under the control of a repressible promoter; reduced levels of wild-type a-factor caused an identical cell fusion defect during mating. We conclude that high levels of pheromone are required as one component of the signal for prezygotes to initiate cell fusion.
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Ichikawa, Hitoshi, Kimiko Shimizu, Rieko Katsu, and Misao Ohki. "Dual Transforming Activities of the FUS (TLS)-ERG Leukemia Fusion Protein Conferred by Two N-Terminal Domains of FUS (TLS)." Molecular and Cellular Biology 19, no. 11 (November 1, 1999): 7639–50. http://dx.doi.org/10.1128/mcb.19.11.7639.

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ABSTRACT The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing’s sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing’s sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.
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Kuang, Lisha, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, and Haining Zhu. "Clinical and experimental studies of a novel P525R FUS mutation in amyotrophic lateral sclerosis." Neurology Genetics 3, no. 4 (July 20, 2017): e172. http://dx.doi.org/10.1212/nxg.0000000000000172.

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Objective:To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.Methods:We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position.Results:A novel mutation c.1574C>G (p.525P>R) in the FUS gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule–like cytoplasmic inclusions in multiple cellular models.Conclusions:The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance.
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Zhang, Xue, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Jisong Guan, and Yichang Jia. "In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model." Brain 143, no. 5 (May 1, 2020): 1350–67. http://dx.doi.org/10.1093/brain/awaa076.

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Abstract Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
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Dissertations / Theses on the topic "Mutant FUS"

1

Kaushansky, Laura J. "Investigating the Effects of Mutant FUS on Stress Response in Amyotrophic Lateral Sclerosis: A Thesis." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/792.

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During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress. The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is an RNA-binding protein mutated in ALS with roles in RNA and DNA processing. Most ALS-associated FUS mutations cause FUS to aberrantly localize in the cytoplasm due to a disruption in the nuclear localization sequence. Intriguingly, pathological inclusions in human FUSALS cases contain aggregated FUS as well as several SG-associated proteins. Further, cytoplasmic mutant FUS incorporates into SGs, which increases SG volume and number, delays SG assembly, accelerates SG disassembly, and alters SG dynamics. I posit that mutant FUS association with stress granules is a toxic gain-of-function in ALS that alters the function of SGs by interaction with SG components. Here, I show that mutant FUS incorporates in to SGs via its Cterminal RGG motifs, the methylation of which is not required for this localization. Further, I identify protein interactions specific to full-length mutant FUS under stress conditions that are potentially capable of interacting with FUS in SGs. Finally, I demonstrate a potential change in the protein composition of SGs upon incorporation of mutant FUS. These findings advance the field of ALS and SG biology, thereby providing groundwork for future investigation.
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Kaushansky, Laura J. "Investigating the Effects of Mutant FUS on Stress Response in Amyotrophic Lateral Sclerosis: A Thesis." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/792.

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During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress. The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is an RNA-binding protein mutated in ALS with roles in RNA and DNA processing. Most ALS-associated FUS mutations cause FUS to aberrantly localize in the cytoplasm due to a disruption in the nuclear localization sequence. Intriguingly, pathological inclusions in human FUSALS cases contain aggregated FUS as well as several SG-associated proteins. Further, cytoplasmic mutant FUS incorporates into SGs, which increases SG volume and number, delays SG assembly, accelerates SG disassembly, and alters SG dynamics. I posit that mutant FUS association with stress granules is a toxic gain-of-function in ALS that alters the function of SGs by interaction with SG components. Here, I show that mutant FUS incorporates in to SGs via its Cterminal RGG motifs, the methylation of which is not required for this localization. Further, I identify protein interactions specific to full-length mutant FUS under stress conditions that are potentially capable of interacting with FUS in SGs. Finally, I demonstrate a potential change in the protein composition of SGs upon incorporation of mutant FUS. These findings advance the field of ALS and SG biology, thereby providing groundwork for future investigation.
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3

Boucher, Aurélie. "Intéractions entre les cannabinoïdes et le gène de la neuréguline 1 comme modèle animal de vulnérabilité à la schizophrénie." Thesis, Bordeaux 1, 2008. http://www.theses.fr/2008BOR13668/document.

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L’utilisation du cannabis peut précipiter la schizophrénie, en particulier chez les individus qui présentent une vulnérabilité génétique aux désordres mentaux. Des recherches humaines et animales indiquent que la neuréguline 1 (Nrg1) est un gène de susceptibilité à la schizophrénie. L’objectif de cette thèse est d’examiner si une modification du gène Nrg1 chez des souris mutante module les effets neuronaux et comportementaux des cannabinoïdes après traitement aiguë et chronique. De plus cette thèse examine les effets d'un pré-traitement au delta9-tétrahydrocannabinol, le principal composant psychotropique du cannabis, sur un modèle de flexibilité cognitive chez la souris
Cannabis use may precipitate schizophrenia, especially in individuals who have a genetic vulnerability to the disorder. Human and animal researches indicate that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. This thesis aim at investigating if partial deletion of Nrg1 in mutant mice modulate the neuronal and behavioural effects cannabinoids after acute or chronic treatment. In addition, this thesis examine the effects of a pre-treatment with delta9-tetrahydrocannabinol, the main psychoactive constituent of cannabis, in a model of cognitive flexibility in the mice
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Zhao, Yuming. "Phenotypic analysis of osteoclast lineage in c-fos mutant mice." Thesis, King's College London (University of London), 2003. https://kclpure.kcl.ac.uk/portal/en/theses/phenotypic-analysis-of-osteoclast-lineage-in-cfos-mutant-mice(fafcec7f-6480-4f8c-87b6-3cca60a475fb).html.

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Fumoto, Naohiro. "Evaluation of seizure foci and genes in the Lgi1(L385R/+) mutant rat." Kyoto University, 2014. http://hdl.handle.net/2433/189657.

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Ko, Hae Kyung. "Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/799.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade. FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown. The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock. However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits. These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.
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Ko, Hae Kyung. "Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/799.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade. FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown. The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock. However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits. These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.
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8

Porte, Dominique. "Utilisation du represseur lexa pour l'identification de mutants de la proteine c-fos capables d'homodimeriser." Université Louis Pasteur (Strasbourg) (1971-2008), 1996. http://www.theses.fr/1996STR13125.

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La fixation sur l'adn et la dimerisation sont deux mecanismes essentiels a l'activite transcriptionnelle d'un facteur de transcription dimerique. Lexa est le represseur du systeme sos chez e. Coli. Des mutations ponctuelles dans le domaine n-terminal de liaison a l'adn, rendent lexa deficient dans la fixation de l'adn et dans son activite de represseur. Des mutations de reversion intrageniques restaurant l'activite represseur ont ete localisees dans le domaine n-terminal. Ces mutations de reversion ont ete isolees et introduites dans la sequence sauvage de lexa et conferent aux variants de lexa une activite represseur generalement superieure a celle de lexa sauvage. Le mutant de lexa portant la reversion ek71 isolee a ete purifie pour une etude in vitro de ses proprietes de liaison a l'adn. Les affinites pour une sequence d'adn non specifique et une sequence specifique sont augmentees pour ce mutant. C-fos est un composant du facteur ap1. C-fos ne peut lier l'adn qu'en formant un heterodimere avec c-jun grace a un motif leucine zipper. Fos ne peut pas homodimeriser car la proteine possede dans son interface de dimerisation, en plus de residus polaires, des residus charges qui exercent entre eux des repulsions electrostatiques. Dans une construction hybride contenant le domaine de liaison a l'adn de lexa fusionne au leucine zipper de c-fos, lorsqu'on remplace les residus des positions a du leucine zipper par des residus hydrophobes, i,l,v,m,f, c-fos est alors capable d'homodimeriser. En outre la substitution d'un seul residu a par i permet a c-fos d'homodimeriser. Certaines mutations parmi les plus interessantes ont ete introduites dans la proteine c-fos entiere. Ces mutants de c-fos capable de former des homodimeres ne possedent qu'une faible activite transactivatrice
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Habif, Guillaume. "Identification des évènements de signalisation associés à la prolifération autonome induite par le récepteur mutant FLT3-ITD dans les cellules myéloïdes." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10327.

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Le récepteur tyrosine kinase FLT3 est impliqué dans le maintien et le renouvellement des cellules souches et des progéniteurs hématopoïétiques. Dans environ 30% des cas de leucémies aiguës myéloïdes, il est activé constitutivement par des mutations, dont les plus fréquentes impliquent une duplication de séquence dans le domaine juxtamembranaire (Internal Tandem Duplication, ou ITD). Des inhibiteurs chimiques de FLT3 ont été développés dans le cadre de thérapies anti-cancéreuses, mais leurs essais cliniques se sont révélés assez décevants avec des effets essentiellement transitoires. Par ailleurs, certaines études ont mis en évidence une signalisation intracellulaire spécifique au mutant FLT3-ITD, comme l’activation spécifique de STAT5a. Ces données soulignent la nécessité d’étudier exhaustivement et en détail la signalisation intracellulaire induite par le récepteur FLT3 et ses mutants oncogéniques dans des modèles pertinents, avec l’espoir d’identifier de nouvelles cibles thérapeutiques. Nous avons surexprimé FLT3 et sa forme mutante ITD dans la lignée murine de progéniteurs myéloïdes FDCP-1/Fms. Ce modèle s’est avéré représentatif des processus observés in vivo en termes de survie, de prolifération et de différenciation monocytaire. Nous l’avons alors utilisé dans une approche protéomique pour identifier des protéines différemment phosphorylées et/ou exprimées entre les deux cas. L’utilisation d’ARN interférant et la surexpression des protéines candidates ou de leurs mutants a permis de révéler l’implication fonctionnelle de plusieurs d’entre elles dans la signalisation FLT3, telles que Hcls1, Ezrin, et PAK1 qui sont toutes des régulateurs du cytosquelette
The FLT3 receptor is involved in stem cells and myeloid progenitors self renewal processes. In about 30% of the acute myeloid leukemia cases, this receptor is mutated and constitutively active, the most common mutation being duplication of sequences in the juxtamembrane domain (Internal Tandem Duplication, ITD). Many chemical inhibitors of FLT3 have been developed for anti-cancer therapies but the clinical trials were a bit disappointing, showing mainly transient effect on blast reduction. Several studies have shown that FLT3-ITD triggers a different signaling from the wild-type receptor, like the specific activation of STAT5a. These data show the necessity of the exhaustive and detailed study of the intracellular signaling induced by FLT3 and its oncogenic mutants, to identify new therapeutic targets. We have overexpressed wild-type and ITD mutant forms of FLT3 in the murine myeloid progenitors cell line FDCP-1/Fms. This model proved it-self representative of the in vivo processes described in the literature in terms of survival, proliferation and monocytic differentiation. Consequently, we have used it for a proteomic approach to identify differentially expressed and/or phosphorylated proteins depending on FLT3 status. Using RAN interference and overexpression of these identified candidate proteins, we have demonstrated the functional involvement of several of them in FLT3 signaling, including Hcls1, Ezrin, and PAK1, which all regulate the cytoskeleton
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Chung, Maureen. "Expression of the c-fos proto-oncogene, mutant p53 anti-oncogene and statin in colorectal carcinoma and adjacent mucosa." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=56961.

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The purpose of this study was to provide evidence for a field defect around colorectal carcinomas using c-fos, mutant p53 and statin markers. Tissue from ten colorectal carcinomas and mucosa at 1, 5 and 10 cm from the primary lesion was obtained from surgical specimens and frozen in liquid nitrogen. Detergent-extracted protein was separated by electrophoresis through polyacrylamide gells and western blots performed using monoclonal antibodies against c-fos, mutant p53 and statin. Expression of c-fos within the carcinoma was increased relative to its expression at 1 cm, which was increased relative to 5 or 10 cm. The reverse results were obtained for statin with the lowest expression detected in the carcinoma, intermediate expression at 1 cm, and highest values at 5 and 10 cm. Increased mutant p53 expression was detected only within the carcinoma. These results indicate that c-fos gain and statin loss may occur before p53 mutation and be initial steps in oncogenesis.
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Books on the topic "Mutant FUS"

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Arnold, J. Douglas. Awesome Super Nintendo Secrets. Maui, USA: Sandwich Islands Publishing, 1992.

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Compute's Nintendo Tips & Tricks. Greensboro, N.C: Compute Books, 1991.

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Publishing, RH Value. Super Strategies for Nintendo. Lincolnwood, IL: Publications International, Ltd., 1991.

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Tom, Badgett, ed. Ultimate Unauthorized Nintendo Classic Game Strategies. 2nd ed. New York: Bantam Books, 1992.

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Tom, Badgett, ed. Ultimate Unauthorized Nintendo Classic Game Strategies. New York, N.Y.: Bantam Books, 1991.

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Mcdermott, Leeanne. GamePro Presents: Sega Genesis Games Secrets: Greatest Tips. Rocklin: Prima Publishing, 1992.

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Nick, Roberts. Super NES Games: Unauthorized Power Tips Book. Rocklin, CA: Prima Publishing, 1993.

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Awesome Super Nintendo Secrets 4. Lahaina, HI: Sandwich Islands Publishing, 1995.

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Perotti, Giovanni, ed. Sega Mega Drive Game Secrets: Strategie e Segreti, Volume 2. Via Rosellini, Milano, Italy: Jackson Libri, 1993.

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Arnold, J. Douglas. Awesome Sega Genesis Secrets II. Lahaina, HI: Sandwich Islands Publishing, 1993.

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Book chapters on the topic "Mutant FUS"

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Stone, James C., Michael F. Moran, and Tony Pawson. "[56] Construction and expression of linker insertion and site-directed mutants of v-fps protein-tyrosine kinase." In Methods in Enzymology, 673–92. Elsevier, 1991. http://dx.doi.org/10.1016/0076-6879(91)00180-5.

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Conference papers on the topic "Mutant FUS"

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Meng, Jieru, Humberto Lara-Guerra, Lin Ji, and Jack A. Roth. "Abstract 870: Synergistic antitumor activity of AKT inhibitor MK2206 and FUS1-nanoparticles in LKB1 mutant NSCLC." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-870.

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Hellwig, Sabine, Nathanael S. Gray, and Thomas E. Smithgall. "Abstract A234: Identification and characterization of inhibitor-resistant mutants of the protein-tyrosine kinase c-Fes." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a234.

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Weir, Mark, Sabine Hellwig, Nathanael S. Gray, and Thomas E. Smithgall. "Abstract A25: Dual inhibition of Flt3 and Fes tyrosine kinases potently blocks proliferation of AML cells expressing an active Flt3 mutant." In Abstracts: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.hemmal14-a25.

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Ma, Cynthia X., Jingqin Luo, Rachel A. Freedman, Timothy Pluard, Julie Nangia, Janice Lu, Frances Valdez-Albini, et al. "Abstract CT026: A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-ct026.

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Fang, Douglas D., Hengrui Zhu, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Ping Min, Guangfeng Wang, Dajun Yang, and Yifan Zhai. "Abstract 1096: FMS-like tyrosine kinase 3 (FLT3) inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 in preclinical models of FLT3-mutant acute myeloid leukemia (AML)." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1096.

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Martínez Arroyo, Emilio José, Trinidad Gracia Bensa, Francisco Giner Martínez, and Carlos García Miragall. "Producción de sentido y proceso de trabajo en el videomapping kavafisVives." In III Congreso Internacional de Investigación en Artes Visuales :: ANIAV 2017 :: GLOCAL. Valencia: Universitat Politècnica València, 2017. http://dx.doi.org/10.4995/aniav.2017.6339.

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KavafisVives es una producción audiovisual que fue proyectada en octubre de 2016 en el Claustro del Centro Cultural La Nau, en Valencia, con motivo de las actividades paralelas realizadas en el evento Mostra viva del Mediterrani 2016: cultura i conflictes del Mediterrani. Realizado por el grupo de investigación Laboratorio de Luz de la UPV dentro del proyecto de investigación “Pantallas mutantes” financiado por MINECO HAR2103-47778R. El proyecto parte de una interpretación del tema “cultura i conflictes del Mediterrani”, que intenta conectar las raíces de la cultura del Mediterráneo, con la emergencia del momento actual y el propio lugar físico sobre el que se proyectará este audiovisual. A partir de la obra poética de Constantino Kavafis que aborda el viaje y el mar como lugar de encuentro, separación, perdida y vida, desde de la subjetividad vital, intentamos generar un discurso de las recientes crisis de refugiados que intentan cruzar ese mismo mar hasta Europa, huyendo de la barbarie hacia un futuro posible. La proyección se realiza en el Claustro del Centro Cultural La Nau, en Valencia, en cuyo centro se encuentra la estatura de Lluis Vives, humanista cuya integridad intelectual y obra están vinculadas a los mejores virtudes del espíritu europeísta. KavafisVives es un vídeo mapping realizado por un grupo de artistas interdisciplinar cuya premisa inicial era la de crear una narrativa alejada del tono espectacular de algunas producciones de vídeo mapping, que mantenga un tono de sobriedad que permita aproximarse con respeto a la situación actual, desde la reflexión del discurso europeísta de Lluis Vives y de la subjetividad poética de Constantino Kavafis.http://dx.doi.org/10.4995/ANIAV.2017.6339
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