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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Etude de la protéine CIRP et sa fonction dans le métabolime de l'ARNm

De Leeuw, Frederic 15 January 2008 (has links)
La protéine CIRP (Cold Induced RNA binding Protein) est une petite protéine de liaison à l’ARN de 172 acides aminés, qui est constituée du côté amino-terminal d’un domaine de liaison à l’ARN de type RRM (RNA recognition motif), et d’une partie carboxy-terminale riche en glycine et arginine qui comprend plusieurs motifs RGG. Elle a été identifiée comme étant inductible par hypothermie mais aussi par irradiation aux UV et par hypoxie. Nous avons analysé son expression et sa localisation en réponse à différents stress cellulaires. Nous avons montré qu’un traitement à l’arsénite qui induit un stress oxydant n’altère pas l’expression de CIRP provoque sa localisation dans les granules de stress (SG). Les SG sont des structures ribonucléoprotéiques cytoplasmiques contenant des complexes de pré-initiation incompétents pour la traduction, et qui s’accumulent dans les cellules exposées à un stress. Ces structures constituent des sites de triages des ARNm, dans lesquels les ARNm sont soit stockés en attente d’une réinitiation de la traduction une fois le stress surmonté, soit destinés à être dégradés. La protéine CIRP se localise dans les SG que ce soit suite à un stress cytoplasmique ou du réticulum endoplasmique. Nous avons montré également que la localisation de la protéine CIRP dans les SG se déroule indépendamment de la présence de la protéine TIA-1 qui a été décrite comme responsable de l’assemblage des SG. De plus la surexpression de la protéine CIRP conduit à la formation de SG. Nous suggérons donc qu’il existe plusieurs voies qui mènent à l’assemblage de ces structures. En outre, nous avons analysé la localisation de mutants par délétion de la protéine CIRP et avons montré que le domaine RRM et le domaine RGG peuvent indépendamment localiser la protéine dans les SG. Par contre, la méthylation des résidus arginine du domaine RGG est une modification nécessaire à la localisation de CIRP dans les SG. Ensuite, nous avons étudié la fonction de la protéine CIRP dans le métabolisme des ARN messagers. Nous avons montré par une méthode d’adressage, que CIRP est un répresseur de la traduction des ARNm et que le domaine carboxy-terminal est nécessaire et suffisant à cette fonction.
2

REGULATION OF STRESS-ACTIVATED MAP KINASE PATHWAYS DURING CELL FATE DECISIONS

ICHIKAWA, KENJI, NAKAMURA, TAKANORI, KUBOTA, YUJI, TAKEKAWA, MUTSUHIRO 02 1900 (has links)
No description available.
3

Modulation of neuroinflammation and tauopathy by RNA-binding protein TIA1 in the P301S mouse model of tauopathy

LeBlang, Chelsey Jenna 29 May 2020 (has links)
Tauopathies are a class of neurodegenerative diseases characterized by aggregation of hyperphosphorylated microtubule associated protein tau (phospho-tau), resulting in neuroinflammation and neurodegeneration. Neuroinflammatory processes play an integral role in the exacerbation and progression of pathology in these disorders, leading to increased levels of neurodegeneration. The RNA binding protein (RBP) T-cell Intracellular Antigen 1 (TIA1) is an important regulator of the innate immune response in the periphery, dampening cytotoxic inflammation and apoptosis during cellular stress, however its role in central neuroinflammation is unclear. We have recently shown that TIA1 regulates tau pathophysiology and toxicity in part through the binding of phospho-tau oligomers into pathological stress granules. Haploinsufficiency of TIA1 in the P301S mouse model of tauopathy results in reduced accumulation of toxic tau oligomers, pathologic stress granules, and the development of downstream pathological features of tauopathy. The putative role of TIA1 as a regulator of the peripheral immune response led us to characterize the role of TIA1 in neuroinflammation, and determine its relationship with neurodegeneration in the context of tauopathy, a chronic stressor in the neural environment. Here, we evaluated indicators of neuroinflammation (reactive microgliosis and phagocytosis, pro-inflammatory cytokine release, and oxidative stress), and neurodegeneration (gross hippocampal atrophy, neuronal loss, synapse loss, and phospho-tau load) in wildtype and P301S transgenic mice expressing TIA1+/+, TIA1+/-, and TIA1-/- in both early (5 month) and advanced (9 month) disease states through biochemical, ultrastructural, and histological analyses. Our data show that both TIA1 haploinsufficiency and TIA1 knockout exacerbate neuroinflammatory processes in advanced stages of tauopathy, suggesting that TIA1 dampens the immune response in the central nervous system during chronic stress. TIA1 haploinsufficiency and knockout do not reduce neurodegeneration in advanced disease, and importantly, TIA1 knockout exacerbates neuron and synapse loss in hippocampal regions. With both increased levels of neuroinflammation and neurodegeneration, P301S animals with TIA1 knockout are distinct from age-matched P301S and wildtype mice. This study demonstrates that TIA1 plays an important role in the regulation of innate immune response in neurodegenerative disease, and its expression significantly impacts the progression of tauopathy.
4

Dysregulation of Stress Granules in Amyotrophic Lateral Sclerosis

Dudman, Jessica 27 January 2023 (has links)
No description available.
5

Assembly of mRNP Complexes During Stress and Nonsense-Mediated mRNA Decay Quality Control in Saccharomyces cerevisiae

Swisher, Kylie January 2011 (has links)
In eukaryotes, mRNA is in constant flux between an actively translating state and translationally repressed states. Specifically, mRNA degradation and repression factors compete with translation factors to direct mRNAs out of translation for storage or decay. This process often leads to formation of cytoplasmic aggregates. P-bodies are granules that contain mRNA and degradation factors, suggesting they are sites of mRNA decay or storage. Stress granules form in response to stress conditions and contain mRNAs and translation factors.P-bodies and stress granules consist of mRNPs of different compositions, believed to mature and transition between the states. It is proposed that mRNAs transition between the two granules. In the work described below, we use <italic>Saccharomyces cerevisiae</italic> to demonstrate that a decay factor, Dhh1 is capable of existing in both P-body and stress granule mRNPs. This suggests that a decay factor can be part of two different mRNP complexes. Additionally, we identify two novel components of the stress granule mRNPs, Pbp4 and Lsm12, and determine that they are not essential for stress granule formation. Lastly, we show that the stress granule mRNP factor, Pab1, is not absolutely required for stress granule formation.An important aspect of cytoplasmic mRNA regulation is mRNA quality control. One example of this is nonsense-mediated mRNA decay (NMD), whereby aberrant mRNAs containing premature termination codons are targeted for decay, and can be localized to P-bodies. Upf1-3 and the mRNA decapping complex, Dcp2/Dcp1 are essential for NMD, which requires Upf1 interaction with stalled ribosomal/mRNA complexes to target aberrant mRNA for decapping and degradation. How Dcp2/Dcp1 is recruited to aberrant mRNA is poorly understood.Here, we show by yeast two-hybrid assays that an interaction between Dcp2 and Upf1 is mediated by the decapping stimulator Edc3. Interestingly, Edc3 and Upf2 share overlapping binding sites on the Upf1 N-terminal domain. The decapping stimulator, Pat1, also interacts on the Upf1 N-terminus, but Edc3 and Pat1 are not essential for NMD. Surprisingly, the Upf1-Edc3 interaction does not promote or negatively regulate NMD. Thus, the Upf1-Edc3 and Upf1-Pat1 interactions likely regulate a subset of mRNA transcripts, or are essential for proper NMD under different environmental conditions.
6

PHOSHOLIPASE Cβ INTERACTS WITH ARGONAUTE 2 IN STRESS GRANULES TO CHANGE THE MICRORNAs POPULATION IN RESPONSE TO OSMOTIC STRESS

Singla, Ashima 04 December 2017 (has links)
"When cells are exposed to environmental stress, they respond by compartmentalizing mRNA and translation proteins in stress granulates to protect mRNA. However, the mechanism through which external stress is communicated into the cell to form stress granules is unknown. Phospholipase Cβ (PLCβ) is activated by Gq on the plasma membrane in response to sensory stimuli to initiate calcium signals resulting in a variety of cellular responses. Here, we show that PLCβ binds to major proteins that organize stress granules as well as the main component of the RNA-induced silencing machinery, Argonaute-2 (Ago2). Under stress, PLCβ moves from the plasma membrane to the cytosol to escort Ago2 into stress granules and potentially inhibit mRNA degradation by regulating microRNAs (miRs) expression. Using a model muscle cell line functionally adapted to handle stress, we find that upon osmotic stress, the movement of PLCβ into the cytosol to move Ago2 into stress granules changes the population and distribution of miRs, and in particular, members of the let family. The impact of changes in let is to acutely affect glucose metabolism allowing cells to adapt to stress conditions. Our studies present a model in which PLCβ relays information about external stress to promote stress granule formation and protect mRNAs."
7

Analysis of the Cellular Proteins, TIA-1 and TIAR, and their Interaction with the West Nile Virus (WNV) 3' SL Minus-Strand RNA

Emara, Mohamed Maged 23 April 2007 (has links)
The 3' terminal stem loop of the WNV minus-strand [WNV3'(-) SL] RNA was previously shown to bind the cell protein, T-cell intracellular antigen-1 (TIA-1), and the related protein, TIAR. These two proteins are known to bind AU-rich sequences in the 3' UTRs of some cellular mRNAs. AU stretches are located in three single-stranded loops (L1, L2, and L3) of the WNV3'(-) SL RNA. The RNA binding activity of both proteins was reduced when L1 or L2, but not L3, AU sequences were deleted or substituted with Cs. Deletion or substitution with Cs of the entire AU-rich sequence in either L1 or L2 in a WNV infectious clone was lethal for the virus while mutation of some of these nt decreased the efficiency of virus replication. Mutant viral RNAs with small plaque or lethal phenotypes had similar translational efficiencies to wildtype RNA, but showed decreased levels of plus-strand RNA synthesis. These results correlated well with the efficiency of TIA-1 and/or TIAR binding in in vitro assays. In normal cells, TIA-1 and TIAR are evenly distributed in the cytoplasm and nucleus. Between 6 and 24 hr after WNV infection, TIAR concentrated in the perinuclear region and TIA-1 localization to this region began by 24 hr. Similar observations were made in DV2 infected cells but at later times after infection. In infected cells, both proteins colocalized with dsRNA, a marker for viral replication complexes, and with viral non-structural proteins. Anti-TIAR or anti-TIA-1 antibody coimmunoprecipitated viral NS3 and possibly other viral nonstructural proteins. In response to different types stress, TIA-1 and TIAR recruit cell mRNA poly(A)+ into cytoplasmic stress granules (SG) leading to general translational arrest in these cells. SG were not induced by flavivirus infection and cells became increasingly resistant to arsenite induction of SG with time after infection. Processing Body (PB) assembly was also decreased beginning at 24 hr. These data suggest that the sequestration of first TIAR and then TIA-1 via their interaction with viral components in flavivirus infected cells inhibits SG formation and prevents the shutoff of host translation.
8

Functional Analysis of Host Cell Proteins and Stress Responses that Inhibit West Nile Virus Infection

Courtney, Sean C 14 December 2011 (has links)
Resistance to flavivirus-induced disease is conferred by a single gene that encodes oligoadenylate synthetase (Oas) 1b (Oas1b). Oas1b is not a functional synthetase suggesting its anti-flavivirus mechanism is RNase L-independent and that it may be mediated by interactions with other host cell protein(s). A yeast two-hybrid screen was used to identify host cell binding partners of Oas1b. Candidate partners were confirmed by yeast co-transformation and co-immunoprecipitation analyses. Oxysterol binding protein-related 1L (ORP1L) and ATP binding cassette subfamily F 3 (ABCF3) were found to interact with Oas1b. RNAi knockdown studies suggested that ORP1L and ABCF3 form a tripartite complex with Oas1b that is critical for the flavivirus-induced disease resistance mechanism. Stresses including oxidation, nutrient starvation, and viral infections often induce the formation of stress granules (SGs) in eukaryotic cells. In response to stress, eIF2α kinases phosphorylate eIF2α leading to stalled 48S pre-initiation complexes and SG formation. West Nile virus (WNV) Eg101 infections were previously shown not to induce the formation of SGs. Infections with viruses of other natural WNV strains, as well as a WNV lineage 1/2-based infectious clone (W956IC) were analyzed and only W956IC infections were found to induce SGs. eIF2α kinase knockout MEFs were used to show that the W956IC-induced SGs were PKR-dependent. WNV chimeras were made by inserting Eg101 genes into the W956IC backbone. Chimeras replacing NS5 or NS1 and NS5 or NS1 and NS3 and NS4a reduced SG formation as well as early viral RNA synthesis similar to Eg101 infections. W956IC infections but not Eg101 infections were shown to produce exposed viral dsRNA at early times after infection. The data suggest that natural WNV infections evade the cell SG response by suppressing the amplification of viral RNA until cytoplasmic membranes have been remodeled to protect replication complexes from detection. It was previously reported that WNV Eg101 infections inhibited the formation of arsenite-induced SGs. The ability of other natural WNV strain infections to inhibit SG formation by arsenite (HRI), DTT (PERK), W956IC co-infection (PKR), and heat shock treatments was assessed. WNV infections only inhibited arsenite-induced SG formation suggesting that WNV infections specifically suppress the response to oxidative intermediates.
9

Hsp90 and its co-chaperones regulate the activity of human Argonaute2 in RNA-mediated silencing pathways

Pare, Justin Mathew Unknown Date
No description available.
10

Characterizing the Role of Protein Arginine Methyltransferase 7 (PRMT7) in Breast Cancer

Haghandish, Nasim 09 January 2019 (has links)
The development of more efficient therapeutic strategies in the treatment of breast cancer relies on understanding the biological events that promote its progression. Protein arginine methyltransferases (PRMTs) are enzymes that catalyze the methylation of arginine residues within proteins resulting in changes in several biological processes. PRMTs have been shown to be aberrantly expressed in many cancers and promote tumourigenesis and cancer progression. Specifically, PRMT7 mRNA expression correlates with breast cancer aggressiveness and invasiveness. Thus, we sought to determine whether PRMT7 promotes breast cancer progression/tumourigenesis and to further identify the functional mechanisms through which this is possible. We have shown that PRMT7 is upregulated in both breast cancer tissues and cell lines. Moreover, we have shown both in vitro and in vivo that PRMT7 enhances breast cancer cell invasion and metastasis. Using biochemical experimentation, we demonstrated that PRMT7 induces the expression of matrix metalloproteinase 9 to promote invasion and subsequent metastasis. Furthermore, using proteomic experiments, we discovered many novel PRMT7-interacting proteins. Further biochemical experimentation identified eukaryotic translation initiation factor eIF2α as an interacting protein and substrate of PRMT7. We demonstrated a regulatory interplay between eIF2α methylation and phosphorylation upon cellular stress: methylation is required for S51 phosphorylation. Accordingly, we have shown that stress granule formation, in the face of cellular stresses, was significantly diminished in PRMT7-knockdown cells. We additionally found that PRMT7 plays a regulatory role in protein translation. Overall, these findings suggest that PRMT7 plays a critical role in promoting breast cancer cell invasion, metastasis, stress regulation, and protein translation.

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