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Showing 1 to 20 of 36 for “"proteotoxic stress"”.
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Aneuploidy causes proteotoxic stress in Saccharomyces cerevisiae
… that aneuploid budding yeast cells are under proteotoxic stress. I show that aneuploid strains are prone to aggregation of endogenous proteins as well as of ectopically expressed hard to fold proteins such as polyQ stretch-containing proteins. Prion conversion rates are also increased in most …
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Compromising the 20S Proteasome Activates a Quality Control Pathway to Mitigate Proteotoxic Stress
… complexed and multi-phased assembly adapts to proteotoxic stress. In this thesis I used a proteasome impaired genetic background to screen for suppressors of proteotoxic stress which modify proteasomes adaptive tress response. To my surprise I identified a core 20S subunit of the proteasome, α1 …
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MOLECULAR MECHANISMS ORCHESTRATING LYSOSOME-MEDIATED DEGRADATION OF RIBOSOMES IN ANEUPLOID CELLS
… cell physiology, causing a plethora of cellular stresses. One of the most prominent effects of abnormal karyotypes is the development of proteotoxic stress, which is characterised by the aggregation of aberrant proteins in the cytoplasm. The disruption of protein homeostasis correlates with and …
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Structural and Functional Evolution of Human Heat Shock Transcription Factors
<p>Proteotoxic stress is implicated in numerous human diseases including neurodegeneration, cancer, and diabetes. Unfortunately, our mechanistic understanding of the cellular response to proteotoxic stress is limited. A critical feature of the cellular stress response is the activation of Heat …
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Severely Stressed Astrocytes Adapt to Injury and Still Protect Neighboring Neurons
… diseases are characterized by protein-misfolding stress, or proteotoxicity, in both neurons and glia. However, the impact of proteotoxicity on glia is less well understood than in neurons. Astrocytes are an abundant type of glia and play an essential role in brain homeostasis by supporting …
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TRPML1 Promotes Protein Homeostasis in Melanoma Cells by Negatively Regulating MAPK and mTORC1 Signaling
… macropinocytosis as well as serine depletion and proteotoxic stress. All of these phenotypes were partially or completely rescued by mTORC1 inhibition. Melanoma cells thus increase TRPML1 expression relative to melanocytes to attenuate MAPK and mTORC1 signaling. This helps melanoma cells prevent …
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Polyubiquitin chain editing by UCH37 promotes degradation of a subset of proteasome substrates
… substrates is affected by UCH37, and proteotoxic stress enhances that dependence. In cells, loss of UCH37 activity leads to an enrichment of polyubiquitin and proteostasis factors on the proteasome and in the detergent-insoluble fraction of lysate as well as impaired degradation of the …
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Biophysical methods to study the ubiquitination of amyloidogenic proteins and proteasomal responses to protein aggregates
… of the cellular proteome in response to a proteotoxic stress induced by protein aggregates, two cell models were generated to visualise the proteasome and ubiquitin (Ub) in live cells. Proteasomes were observed to form transient foci with distinct characteristics under the proteolytic …
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The Role of ATF5 in Mitochondrial Maintenance, Biogenesis and UPRmt Signaling Following Acute Exercise in Skeletal Muscle
… control mechanism that relieves intraorganellar proteotoxic stress in a manner dependent on activating transcription factor 5 (ATF5) during mitochondrial dysfunction. Protein homeostasis can temporarily be disrupted by acute exercise, inducing the UPRmt. Using WT and whole-body ATF5 KO animals, …
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Chemical Biology Approaches to Interrogate Heat Shock Transcription Factor 1 Regulation in Cancer
… and signal integrator in the eukaryotic proteotoxic stress response. Revealed by recent discoveries in cancer, the functions of HSF1 have extended far beyond its canonical role in protein folding, further encompassing critical functions in anti-apoptosis, invasion and metastasis, energy …
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Mechanisms Underlying The Heterogeneous Sensitivities of Cancer Cells to Proteasome Inhibitors
… the ability of a cell to manage the amount of proteotoxic stress following proteasome inhibition dictates survival. In this study using the FDA-approved proteasome inhibitor bortezomib (Velcade®) in solid tumor cells, we demonstrated that perhaps the most critical response to proteasome …
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Hsp70-Mediated Regulation of Hsf1 Transcriptional Activity In Saccharomyces Cerevisiae
… heat shock factor 1 (HSF1) during exposure to proteotoxic stress. HSF1 controls the basal and stress-induced expression of molecular chaperones and other protective targets. Dynamic regulation of HSF1 involves the major heat shock proteins Hsp70 and Hsp90. Recent advances in the understanding …
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Global identification of SUMO modification sites
… and 8262 sites from the same fraction of heat-stressed cells. Exposure to proteotoxic stress increased the extent of substrate sumoylation, and targeted proteins with similar functions or found within the same macromolecular complexes. These data provide a comprehensive resource for future …
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Aneuploidy reveals insights into control of protein complex stoichiometry
… of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits. This work informs both our comprehension of …
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Investigating dysregulation in protein quality control mechanisms in senescent cells
… carcinoma epithelial A549s, following proteotoxic stress. Our findings reveal a generally highly-conserved stress response to proteotoxic insult between all three distinct cell-states, suggesting that senescent cells do not mount a particularly dysregulated response to external stress. …
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Novel Aspects of the Response to Cellular Stress and Intracellular Bacterial Pathogens
The cellular stress response represents an essential mechanism that enables cells to adapt to an array of environmental and physiological conditions. Given the importance of these adaptive responses, it comes as no surprise that dysregulation of the stress response has been strongly implicated in …
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Altered Responses to Endoplasmic Reticulum Stress In Pancreatic Cancer
… progress has been made in understanding how proteotoxic stress affects rapidly proliferating pancreatic tumor cells. Endoplasmic reticulum (ER) stress occurs when protein homeostasis in the ER lumen is perturbed. ER stress activates the unfolded protein response (UPR) to reduce the protein …
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The Discovery of p62-dependent Processing Bodies
… bodies. Ribonucleoprotein (RNP) granules such as stress granules and <br/>processing-bodies (PBs) also form through LLPS. Persistent RNP granules have been <br/>associated with neurodegenerative diseases, in particular amyotrophic lateral sclerosis and <br/>frontotemporal lobar degeneration. This …
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Identifying a common cause of the loser cell status in Drosophila melanogaster.
… Nrf2, that typically co-ordinates an oxidative stress response, is sufficient to instruct the elimination of cells by their neighbors. Given the importance of Nrf2, I have sought to identify events occurring both upstream and downstream of the pathway in the loser context. Here, I have shown how …
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Leveraging HSF1 chemical-genetic tools to elucidate mechanisms of proteostasis
… of cytosolic chaperones in response to proteotoxic stressors. Previous work in our lab enabled precision regulation of HSF1 activity through constitutively active or constitutively dominant-negative variants. My graduate work has focused on applying these HSF1 chemical-genetic tools to …
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