Combining chemical genomics screens in yeast to reveal spectrum of effects of chemical inhibition of sphingolipid biosynthesis

Kemmer, Danielle; McHardy, Lianne M.; Hoon, Shawn; Reberioux, Delphine; Giaever, Guri; Nislow, Corey; Roskelley, Calvin D.; Roberge, Michel

doi:10.1186/1471-2180-9-9

Cited by 40 publications

(37 citation statements)

References 50 publications

(61 reference statements)

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“…Upregulation of multidrug resistance genes is a common response of yeast to xenobiotics. The resistance of yeast to ϳ25% of all compounds tested (19,22) is dependent on the upregulation of these genes. Although several multidrug resistance transporters are upregulated after diclofenac exposure, a single ABC transporter, Pdr5p, is crucial in diclofenac resistance (Fig.…”

Section: Vol 77 2011mentioning

confidence: 98%

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Leeuwen

Vermeulen

Vos

2011

Appl Environ Microbiol

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Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p.

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Section: Vol 77 2011mentioning

confidence: 98%

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Leeuwen

Vermeulen

Vos

2011

Appl Environ Microbiol

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“…29, 30 Recent studies have also found the production of EVs aid in the development of biofilms by some strains. 31, 32 Despite the widespread production and activity of EVs, much still remains to be learned about the mechanisms controlling their biogenesis. 25, 28, 30 …”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureusextracellular vesicles (EVs): surface-binding antagonists of biofilm formation

Mitchell

2017

Mol. BioSyst.

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The prevalence of Staphylococcus aureus worldwide as a nosocomial infectious agent is recognized but the reason behind the spread of this bacterium has remained elusive. Here, we hypothesized that the communication of S. aureus might benefit from it blocking other bacteria from establishing themselves on the surface. This was found to be the case for several pathogens as the S. aureus supernatant curtailed their ability to form biofilms. Subsequent analyses using Acinetobacter baumannii as a model found this effect is primarily mediated by S. aureus’ extracellular vesicles (EVs), which bound to the polystyrene surface. We found the EV-treated surfaces were significantly more hydrophilic after EV treatment, a condition that made it difficult for A. baumannii to initially adhere to the polystyrene surface and reduced its resulting biofilm by up to 93%. Subsequent tests found this also extended to several other bacterial pathogens, with a 40-70% decrease in their biofilm mass. The S. aureus EVs and their activity still remained after the surface was washed with 10% bleach, while the use of ethylenediaminetetraacetic acid (EDTA) removed both the EVs from the surface and their activity.

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“…Mathematical modeling can be used in order to simulate the perturbation of ceramide and S1P levels, generating in silico disease models in yeast. The predictions of these models can be validated easily in yeast and then translated to complex mammalian systems [188]. …”

Section: Future Perspective: Exploiting Yeast To Elucidate Sphingolipmentioning

confidence: 99%

“…The effects of this perturbation can be analyzed in the context of the available yeast metabolome, transcriptome, proteome and interactome data [189–193]. Lipidomic analyses may identify specific (and unexpected) metabolites that are important in maintaining homeostasis and that may be altered in disease conditions [188]. Recent advances with mass spectrometric tools in the field of lipidomics have made it possible to identify and quantify many species of sphingolipids.…”

Section: Future Perspective: Exploiting Yeast To Elucidate Sphingolipmentioning

confidence: 99%

Harnessing the power of yeast to elucidate the role of sphingolipids in metabolic and signaling processes pertinent to psychiatric disorders

Jadhav

Greenberg

2014

Clinical Lipidology

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The development of therapies for neuropsychiatric disorders is hampered by the lack of understanding of the mechanisms underlying their pathologies. While aberrant sphingolipid metabolism is associated with psychiatric illness, the role of sphingolipids in these disorders is not understood. The genetically tractable yeast model can be exploited in order to elucidate the cellular consequences of sphingolipid perturbation. Hypotheses generated from studies in yeast and tested in mammalian cells may contribute to our understanding of the role of sphingolipids in psychiatric disorders and to the development of new treatments. Here, we compare sphingolipid metabolism in yeast and mammalian cells, discuss studies implicating sphingolipids in psychiatric disorders and propose approaches that utilize yeast in order to elucidate sphingolipid function and identify drugs that target sphingolipid synthesis.

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Combining chemical genomics screens in yeast to reveal spectrum of effects of chemical inhibition of sphingolipid biosynthesis

Cited by 40 publications

References 50 publications

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Staphylococcus aureusextracellular vesicles (EVs): surface-binding antagonists of biofilm formation

Harnessing the power of yeast to elucidate the role of sphingolipids in metabolic and signaling processes pertinent to psychiatric disorders

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