The Experts below are selected from a list of 132708 Experts worldwide ranked by ideXlab platform
Stephen E. Girardin - One of the best experts on this subject based on the ideXlab platform.
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Nutrient sensing and Metabolic Stress pathways in innate immunity.
Cellular microbiology, 2013Co-Authors: Jessica Tsalikis, David O. Croitoru, Dana J. Philpott, Stephen E. GirardinAbstract:Summary Cells monitor nutrient availability through several highly conserved pathways that include the mTOR signalling axis regulated by AKT/PI3K, HIF and AMPK, as well as the GCN2/eIF2α integrated Stress response pathway that provides cellular adaptation to amino acid starvation. Recent evidence has identified a critical interplay between these nutrient sensing pathways and innate immunity to bacterial pathogens, viruses and parasites. These observations suggest that, in addition to the well-characterized pro-inflammatory signalling mediated by pattern recognition molecules, a Metabolic Stress programme contributes to shape the global response to pathogens.
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Translation inhibition and Metabolic Stress pathways in the host response to bacterial pathogens
Nature Reviews Microbiology, 2013Co-Authors: Bruno Lemaitre, Stephen E. GirardinAbstract:Activation of most major innate immune signalling cascades relies on the detection of microorganisms or their associated danger signals by host pattern recognition molecules. A flurry of recent studies has now uncovered a role for host translation inhibition in innate immune surveillance and the detection of bacterial pathogens. Here, we present the main findings from these studies and discuss whether translation inhibition is an alarm signal that directly drives innate immune responses to bacterial pathogens, or rather one component of a more general Metabolic Stress response to infection. Recent studies have revealed a role for host translation inhibition in the innate immune surveillance and detection of bacterial pathogens. Lemaitre and Girardin review these findings and discuss whether translation inhibition is a direct innate immune signal or rather part of a more general Metabolic Stress response to infection.
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translation inhibition and Metabolic Stress pathways in the host response to bacterial pathogens
Nature Reviews Microbiology, 2013Co-Authors: Bruno Lemaitre, Stephen E. GirardinAbstract:Recent studies have revealed a role for host translation inhibition in the innate immune surveillance and detection of bacterial pathogens. Lemaitre and Girardin review these findings and discuss whether translation inhibition is a direct innate immune signal or rather part of a more general Metabolic Stress response to infection.
Hakkolajukka - One of the best experts on this subject based on the ideXlab platform.
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Extranuclear Sirtuins and Metabolic Stress
Antioxidants & Redox Signaling, 2017Co-Authors: Elkhwankymahmoud-sobhy, HakkolajukkaAbstract:Abstract Significance: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of Metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of Metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications. Critical Issues: Sensing of the Metabolic state and regulation of the sirtuin function and expression are critical components of the machinery, optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity, and Metabolic diseases cause Metabolic Stress that dysregulates the sirtuins, which may play a role in the pathogenesis and complications of metaboli...
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Extranuclear Sirtuins and Metabolic Stress
Antioxidants & Redox Signaling, 2017Co-Authors: Elkhwankymahmoud-sobhy, HakkolajukkaAbstract:Abstract Significance: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of Metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of Metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications. Critical Issues: Sensing of the Metabolic state and regulation of the sirtuin function and expression are critical components of the machinery, optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity, and Metabolic diseases cause Metabolic Stress that dysregulates the sirtuins, which may play a role in the pathogenesis and complications of metaboli...
Nerea Allende-vega - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
Scientific Reports, 2019Co-Authors: Martin Villalba, Nerea Allende-vegaAbstract:Eliminating mutant p53 (mt p53) protein could be a useful strategy to treat mt p53 tumors and potentially improve the prognosis of cancer patients. In this study, we unveil different mechanisms that eliminate p53-R248Q, one of the most frequent mutants found in human cancers. We show that the Hsp90 inhibitor 17-AAG eliminates R248Q by stimulating macroautophagy under normal growth conditions. Metabolic Stress induced by the pyruvate dehydrogenase kinase-1 (PDK1) inhibitor dichloroacetate (DCA) inhibits the macroautophagy pathway. This induces the accumulation of R248Q, which in addition further inhibits macroautophagy. Combination of DCA and 17-AAG further decreases the autophagy flux compared to DCA alone. Despite this, this co-treatment strongly decreases R248Q levels. In this situation of Metabolic Stress, 17-AAG induces the binding of p53-R248Q to Hsc70 and the activation of Chaperone-Mediated Autophagy (CMA), leading to higher R248Q degradation than in non-Stress conditions. Thus, different Metabolic contexts induce diverse autophagy mechanisms that degrade p53-R248Q, and under Metabolic Stress, its degradation is CMA-mediated. Hence, we present different strategies to eliminate this mutant and provide new evidence of the crosstalk between macroautophagy and CMA and their potential use to target mutant p53.
Guanghua Chen - One of the best experts on this subject based on the ideXlab platform.
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autophagy mitigates Metabolic Stress and genome damage in mammary tumorigenesis
Genes & Development, 2007Co-Authors: Vassiliki Karantzawadsworth, Shyam Patel, Olga Kravchuk, Guanghua Chen, Robin Mathew, Shengkan Jin, Eileen WhiteAbstract:Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to Metabolic Stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits Metabolic Stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.
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autophagy promotes tumor cell survival and restricts necrosis inflammation and tumorigenesis
Cancer Cell, 2006Co-Authors: Guanghua Chen, Robin Mathew, Kurt Degenhardt, Brian Beaudoin, Kevin Bray, Diana AndersonAbstract:Summary Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to Metabolic Stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer Metabolic Stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating Metabolic Stress and, in concert with apoptosis, by preventing death by necrosis.
Lee A Witters - One of the best experts on this subject based on the ideXlab platform.
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ampk β subunit targets Metabolic Stress sensing to glycogen
Current Biology, 2003Co-Authors: Galina Polekhina, Bryce J W Van Denderen, Ian G. Jennings, Sid Murthy, Susanne C. Feil, Duncan J Campbell, Belinda J. Michell, Lee A WittersAbstract:Abstract AMP-activated protein kinase (AMPK) is a multisubstrate enzyme activated by increases in AMP during Metabolic Stress caused by exercise, hypoxia, lack of cell nutrients [1], as well as hormones, including adiponectin and leptin [2, 3]. Furthermore, metformin and rosiglitazone, frontline drugs used for the treatment of type II diabetes, activate AMPK [4]. Mammalian AMPK is an αβγ heterotrimer with multiple isoforms of each subunit comprising α1, α2, β1, β2, γ1, γ2, and γ3, which have varying tissue and subcellular expression [5, 6]. Mutations in the AMPK γ subunit cause glycogen storage disease in humans [7], but the molecular relationship between glycogen and the AMPK/Snf1p kinase subfamily has not been apparent. We show that the AMPK β subunit contains a functional glycogen binding domain (β-GBD) that is most closely related to isoamylase domains found in glycogen and starch branching enzymes. Mutation of key glycogen binding residues, predicted by molecular modeling, completely abolished β-GBD binding to glycogen. AMPK binds to glycogen but retains full activity. Overexpressed AMPK β1 localized to specific mammalian subcellular structures that corresponded with the expression pattern of glycogen phosphorylase. Glycogen binding provides an architectural link between AMPK and a major cellular energy store and juxtaposes AMPK to glycogen bound phosphatases.
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Metabolic Stress and altered glucose transport activation of amp activated protein kinase as a unifying coupling mechanism
Diabetes, 2000Co-Authors: Tatsuya Hayashi, Lee A Witters, Michael F Hirshman, Nobuharu Fujii, Susan A Habinowski, Laurie J GoodyearAbstract:5'AMP-activated protein kinase (AMPK) can be activated in response to cellular fuel depletion and leads to switching off ATP-consuming pathways and switching on ATP-regenerating pathways in many cell types. We have hypothesized that AMPK is a central mediator of insulin-independent glucose transport, which enables fuel-depleted muscle cells to take up glucose for ATP regeneration under conditions of Metabolic Stress. To test this hypothesis, rat epitrochlearis muscles were isolated and incubated in vitro under several conditions that evoke Metabolic Stress accompanied by intracellular fuel depletion. Rates of glucose transport in the isolated muscles were increased by all of these conditions, including contraction (5-fold above basal), hypoxia (8-fold), 2,4-dinotrophenol (11-fold), rotenone (7-fold), and hyperosmolarity (8-fold). All of these stimuli simultaneously increased both alpha1 and alpha2 isoform-specific AMPK activity. There was close correlation between alpha1 (r2 = 0.72) and alpha2 (r2 = 0.67) AMPK activities and the rate of glucose transport, irrespective of the Metabolic Stress used, all of which compromised muscle fuel status as judged by ATP, phosphocreatine, and glycogen content. 5-Aminoimidazole-4-carboxamide ribonucleoside, a pharmacological AMPK activator that is metabolized to an AMP-mimetic ZMP, also increased both glucose transport and AMPK activity but did not change fuel status. Insulin stimulated glucose transport by 6.5-fold above basal but did not affect AMPK activity. These results suggest that the activation of AMPK may be a common mechanism leading to insulin-independent glucose transport in skeletal muscle under conditions of Metabolic Stress.