The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Nikoletta A Gkatza - One of the best experts on this subject based on the ideXlab platform.
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cytosine 5 rna methylation links Protein Synthesis to cell metabolism
PLOS Biology, 2019Co-Authors: Nikoletta A Gkatza, Robert Harvey, Matthias Heis, Martyna C Popis, Susanne Bornelov, Cecilia Castro, Abdulrahim A Sajini, Sandra Blanco, Joseph G Gleeson, Julian L GriffinAbstract:Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt Protein Synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of Protein Synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global Protein Synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt Protein Synthesis rates to cell stress.
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stem cell function and stress response are controlled by Protein Synthesis
Nature, 2016Co-Authors: Sandra Blanco, Martyna C Popis, Abdulrahim A Sajini, Roberto Bandiera, Shobbir Hussain, Patrick Lombard, Jelena Aleksic, Hinal Tanna, Rosana Cortesgarrido, Nikoletta A GkatzaAbstract:Whether Protein Synthesis and cellular stress response pathways interact to control stem cell function is currently unknown. Here we show that mouse skin stem cells synthesize less Protein than their immediate progenitors in vivo, even when forced to proliferate. Our analyses reveal that activation of stress response pathways drives both a global reduction of Protein Synthesis and altered translational programmes that together promote stem cell functions and tumorigenesis. Mechanistically, we show that inhibition of post-transcriptional cytosine-5 methylation locks tumour-initiating cells in this distinct translational inhibition programme. Paradoxically, this inhibition renders stem cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour.
Sandra Blanco - One of the best experts on this subject based on the ideXlab platform.
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cytosine 5 rna methylation links Protein Synthesis to cell metabolism
PLOS Biology, 2019Co-Authors: Nikoletta A Gkatza, Robert Harvey, Matthias Heis, Martyna C Popis, Susanne Bornelov, Cecilia Castro, Abdulrahim A Sajini, Sandra Blanco, Joseph G Gleeson, Julian L GriffinAbstract:Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt Protein Synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of Protein Synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global Protein Synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt Protein Synthesis rates to cell stress.
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stem cell function and stress response are controlled by Protein Synthesis
Nature, 2016Co-Authors: Sandra Blanco, Martyna C Popis, Abdulrahim A Sajini, Roberto Bandiera, Shobbir Hussain, Patrick Lombard, Jelena Aleksic, Hinal Tanna, Rosana Cortesgarrido, Nikoletta A GkatzaAbstract:Whether Protein Synthesis and cellular stress response pathways interact to control stem cell function is currently unknown. Here we show that mouse skin stem cells synthesize less Protein than their immediate progenitors in vivo, even when forced to proliferate. Our analyses reveal that activation of stress response pathways drives both a global reduction of Protein Synthesis and altered translational programmes that together promote stem cell functions and tumorigenesis. Mechanistically, we show that inhibition of post-transcriptional cytosine-5 methylation locks tumour-initiating cells in this distinct translational inhibition programme. Paradoxically, this inhibition renders stem cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour.
Ian R. Falconer - One of the best experts on this subject based on the ideXlab platform.
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cylindrospermopsin induced Protein Synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes
Environmental Toxicology, 2003Co-Authors: Suzanne Froscio, Philip Burcham, Andrew R. Humpage, Ian R. FalconerAbstract:The toxicology of the cyanobacterial alkaloid cylindrospermopsin (CYN), a potent inhibitor of Protein Synthesis, appears complex and is not well understood. In exposed mice the liver is the main target for the toxic effects of CYN. In this study primary mouse hepatocyte cultures were used to investigate the mechanisms involved in CYN toxicity. The results show that 1–5 μM CYN caused significant concentration-dependent cytotoxicity (52%–82% cell death) at 18 h. Protein Synthesis inhibition was a sensitive, early indicator of cellular responses to CYN. Following removal of the toxin, the inhibition of Protein Synthesis could not be reversed, showing behavior similar to that of the irreversible inhibitor emetine. In contrast to the LDH leakage, Protein Synthesis was maximally inhibited by 0.5 μM CYN. No Protein Synthesis occurred over 4–18 h at or above this concentration. Inhibition of cytochrome P450 (CYP450) activity with 50 μM proadifen or 50 μM ketoconazole diminished the toxicity of CYN but not the effects on Protein Synthesis. These findings imply a dissociation of the two events and implicate the involvement of CYP450-derived metabolites in the toxicity process, but not in the impairment of Protein Synthesis. Thus, the total abolition of Protein Synthesis may exaggerate the metabolite effects but cannot be considered a primary cause of cell death in hepatocytes over an acute time frame. In cell types deficient in CYP450 enzymes, Protein Synthesis inhibition may play a more crucial role in the development of cytotoxicity. © 2003 Wiley Periodicals, Inc. Environ Toxicol 18: 243–251, 2003.
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cell free Protein Synthesis inhibition assay for the cyanobacterial toxin cylindrospermopsin
Environmental Toxicology, 2001Co-Authors: Suzanne Froscio, Philip Burcham, Andrew R. Humpage, Ian R. FalconerAbstract:The cyanobacterial toxin cylindrospermopsin (CYN) is known to be a potent inhibitor of Protein Synthesis. This paper describes the use of a rabbit reticulocyte lysate translation system as a Protein Synthesis inhibition assay for CYN. A dose response curve for Protein Synthesis inhibition by CYN was constructed and was modeled to a sigmoidal dose response curve with variable slope (R2=0.98). In this assay, CYN has an IC50 of 120 nM [95% chemical interaction (CI)=111−130 nM] with a detection limit in the region of 50 nM in the assay solution. Application of the assay allows quantification of toxin samples within the range 0.5–3.0 μM (200–1200 μg/L) CYN. To assess the usefulness of this assay, a range of toxic and nontoxic Cylindrospermopsis raciborskii extracts, including both laboratory strains and environmental samples, were assayed by Protein Synthesis inhibition. These CYN quantifications were then compared to quantifications obtained by high performance liquid chromatography (HPLC) and HPLC-tandem mass spectrometry (HPLCMS–MS). The results demonstrate that the Protein Synthesis inhibition assay correlates well with both HPLCMS–MS (r2=0.99) and HPLC (r2=0.97) quantifications. We conclude that this is an accurate and rapid assay for the measurement of cylindrospermopsin in cyanobacterial extracts. © 2001 John Wiley & Sons, Inc. Environ Toxicol 16: 408–412, 2001
Blake B Rasmussen - One of the best experts on this subject based on the ideXlab platform.
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resistance exercise increases leg muscle Protein Synthesis and mtor signalling independent of sex
Acta Physiologica, 2010Co-Authors: Hans C Dreyer, Satoshi Fujita, Erin L Glynn, Micah J Drummond, Elena Volpi, Blake B RasmussenAbstract:Aim Sex differences are evident in human skeletal muscle as the cross-sectional area of individual muscle fibres is greater in men as compared to women. We have recently shown that resistance exercise stimulates mTOR signalling and muscle Protein Synthesis in humans during early post-exercise recovery. Therefore, the aim of this study was to determine if sex influences the muscle Protein Synthesis response during recovery from resistance exercise.
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resistance exercise increases ampk activity and reduces 4e bp1 phosphorylation and Protein Synthesis in human skeletal muscle
The Journal of Physiology, 2006Co-Authors: Hans C Dreyer, Satoshi Fujita, Elena Volpi, Blake B Rasmussen, Jerson G Cadenas, David L ChinkesAbstract:Resistance exercise is a potent stimulator of muscle Protein Synthesis and muscle cell growth, with the increase in Protein Synthesis being detected within 2–3 h post-exercise and remaining elevated for up to 48 h. However, during exercise, muscle Protein Synthesis is inhibited. An increase in AMP-activated Protein kinase (AMPK) activity has recently been shown to decrease mammalian target of rapamycin (mTOR) signalling to key regulators of translation initiation. We hypothesized that the cellular mechanism for the inhibition of muscle Protein Synthesis during an acute bout of resistance exercise in humans would be associated with an activation of AMPK and an inhibition of downstream components of the mTOR pathway (4E-BP1 and S6K1). We studied 11 subjects (seven men, four women) before, during, and for 2 h following a bout of resistance exercise. Muscle biopsy specimens were collected at each time point from the vastus lateralis. We utilized immunoprecipitation and immunoblotting methods to measure muscle AMPKα2 activity, and mTOR-associated upstream and downstream signalling Proteins, and stable isotope techniques to measure muscle fractional Protein synthetic rate (FSR). AMPKα2 activity (pmol min−1 (mg Protein)−1) at baseline was 1.7 ± 0.3, increased immediately post-exercise (3.0 ± 0.6), and remained elevated at 1 h post-exercise (P < 0.05). Muscle FSR decreased during exercise and was significantly increased at 1 and 2 h post-exercise (P < 0.05). Phosphorylation of 4E-BP1 at Thr37/46 was significantly reduced immediately post-exercise (P < 0.05). We conclude that AMPK activation and a reduced phosphorylation of 4E-BP1 may contribute to the inhibition of muscle Protein Synthesis during resistance exercise. However, by 1–2 h post-exercise, muscle Protein Synthesis increased in association with an activation of Protein kinase B, mTOR, S6K1 and eEF2.
Martyna C Popis - One of the best experts on this subject based on the ideXlab platform.
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cytosine 5 rna methylation links Protein Synthesis to cell metabolism
PLOS Biology, 2019Co-Authors: Nikoletta A Gkatza, Robert Harvey, Matthias Heis, Martyna C Popis, Susanne Bornelov, Cecilia Castro, Abdulrahim A Sajini, Sandra Blanco, Joseph G Gleeson, Julian L GriffinAbstract:Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt Protein Synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of Protein Synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global Protein Synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt Protein Synthesis rates to cell stress.
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stem cell function and stress response are controlled by Protein Synthesis
Nature, 2016Co-Authors: Sandra Blanco, Martyna C Popis, Abdulrahim A Sajini, Roberto Bandiera, Shobbir Hussain, Patrick Lombard, Jelena Aleksic, Hinal Tanna, Rosana Cortesgarrido, Nikoletta A GkatzaAbstract:Whether Protein Synthesis and cellular stress response pathways interact to control stem cell function is currently unknown. Here we show that mouse skin stem cells synthesize less Protein than their immediate progenitors in vivo, even when forced to proliferate. Our analyses reveal that activation of stress response pathways drives both a global reduction of Protein Synthesis and altered translational programmes that together promote stem cell functions and tumorigenesis. Mechanistically, we show that inhibition of post-transcriptional cytosine-5 methylation locks tumour-initiating cells in this distinct translational inhibition programme. Paradoxically, this inhibition renders stem cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour.
