Leucobacter chromiiresistens JG 31 strain:JG 31
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PROVIDER: PRJNA72623 | ENA |
REPOSITORIES: ENA
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Project description:Leucobacter chromiiresistens overview
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Project description:Chromate is one of the major anthropogenic contaminants on Earth. Leucobacter chromiiresistens is a highly chromate-resistant strain, tolerating chromate concentrations in LB medium of up to 400 mM. In response to chromate stress, L. chromiiresistens forms biofilms, which are held together via extracellular DNA. Inhibition of biofilm formation leads to drastically decreased chromate tolerance. Moreover, chromate is reduced intracellularly to the less-toxic Cr(III). The oxidation status and localization of chromium in cell aggregates were analyzed by energy-dispersive X-ray spectroscopy coupled to scanning transmission electron microscopy and X-ray absorption spectroscopy measurements. Most of the heavy metal is localized as Cr(III) at the cytoplasmic membrane. As a new cellular response to chromate stress, we observed an increased production of the carotenoid lutein. Carotenoid production could increase membrane stability and reduce the concentration of reactive oxygen species. Bioinformatic analysis of the L. chromiiresistens genome revealed several gene clusters that could enable heavy-metal resistance. The extreme chromate tolerance and the unique set of resistance factors suggest the use of L. chromiiresistens as a new model organism to study microbial chromate resistance.IMPORTANCE Chromate is a highly toxic oxyanion. Extensive industrial use and inadequate waste management has caused the toxic pollution of several field sites. Understanding the chromate resistance mechanisms that enable organisms to thrive under these conditions is fundamental to develop (micro)biological strategies and applications aiming at bioremediation of contaminated soils or waters. Potential detoxifying microorganisms are often not sufficient in their resistance characteristics to effectively perform, e.g., chromate reduction or biosorption. In this study, we describe the manifold strategies of L. chromiiresistens to establish an extremely high level of chromate resistance. The multitude of mechanisms conferring it make this organism suitable for consideration as a new model organism to study chromate resistance.
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Project description:Hsp70 inhibition affects many signaling pathways. We established how these effects are translated into changes in gene expression. Hsp70 is a promising anti-cancer target, and several inhibitors of Hsp70 have been recently developed. Interest to Hsp70 inhibitors as drug prototypes is, however, somewhat hampered by potential similarity of their physiological effects to effects of already well-developed Hsp90 inhibitors. JG-98 series of inhibitors is unique in its ability to target an allosteric site in the ATPase domain of Hsp70, which disrupts its interaction with a co-chaperone Bag3 and affects a variety of signaling pathways important for cancer development and survival. Here, we used the Broad Institute Connectivity Map platform to evaluate physiological effects of JG-98, and found that these effects are dissimilar from effects of Hsp90 inhibitors, thus justifying further development of this compound series. Further, using gene expression data and ActivSignal IPAD platform, we identified pathways modulated by JG-98. Some of these pathways were affected by JG-98 in Bag3-dependent and some pathways in Bag3-independent manner, indicating multiple mechanisms of JG-98 action. Using pooled shRNA genetic screen, we established gene sets that modulate the response of cancer cells to JG-98. Based on genetic and gene expression information, we developed approaches to predict potent combinations of JG-98 with known drugs. These predictions were validated by demonstrating that proteasome, RNApol II, Akt and RTK inhibitors synergize with anti-cancer effects of JG-98. Overall, in this study we analyze unique effects of Hsp70 inhibitors of JG-98 series on cell physiology and define potential drug combinations for clinical use of these inhibitors.
2018-01-11 | GSE93542 | GEO
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