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Arsenic toxicity to Saccharomyces cerevisiae is a consequence of inhibition of the TORC1 kinase combined with a chronic stress response

Hosiner, Dagmar
Reiter, Wolfgang
Ammerer, Gustav
Schweyen, Rudolf
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Published in Molecular biology of the cell. 2009, vol. 20, no. 3, p. 1048-57
Abstract The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity.
Keywords Arsenic/toxicityBase SequenceChromatin/metabolismCytosol/drug effects/metabolismGene Expression Regulation, Fungal/drug effectsModels, BiologicalMolecular Sequence DataPhosphorylation/drug effectsProtein Kinases/genetics/metabolismProtein Transport/drug effectsRNA, Messenger/genetics/metabolismRegulatory Sequences, Nucleic Acid/geneticsSaccharomyces cerevisiae/cytology/drug effects/enzymology/geneticsSaccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics/metabolismStress, Physiological/drug effectsTranscription, Genetic/drug effects
PMID: 19073887
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HOSINER, Dagmar et al. Arsenic toxicity to Saccharomyces cerevisiae is a consequence of inhibition of the TORC1 kinase combined with a chronic stress response. In: Molecular biology of the cell, 2009, vol. 20, n° 3, p. 1048-57. doi: 10.1091/mbc.E08-04-0438 https://archive-ouverte.unige.ch/unige:18225

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Deposited on : 2012-01-30

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