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

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 ki...

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Veröffentlicht in:Molecular biology of the cell 2009-02, Vol.20 (3), p.1048-1057
Hauptverfasser: Hosiner, Dagmar, Lempiäinen, Harri, Reiter, Wolfgang, Urban, Joerg, Loewith, Robbie, Ammerer, Gustav, Schweyen, Rudolf, Shore, David, Schüller, Christoph
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container_end_page 1057
container_issue 3
container_start_page 1048
container_title Molecular biology of the cell
container_volume 20
creator Hosiner, Dagmar
Lempiäinen, Harri
Reiter, Wolfgang
Urban, Joerg
Loewith, Robbie
Ammerer, Gustav
Schweyen, Rudolf
Shore, David
Schüller, Christoph
description 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.
doi_str_mv 10.1091/mbc.E08-04-0438
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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. 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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.</description><subject>Arsenic - toxicity</subject><subject>Base Sequence</subject><subject>Chromatin - metabolism</subject><subject>Cytosol - drug effects</subject><subject>Cytosol - metabolism</subject><subject>Gene Expression Regulation, Fungal - drug effects</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Phosphorylation - drug effects</subject><subject>Protein Kinases - genetics</subject><subject>Protein Kinases - metabolism</subject><subject>Protein Transport - drug effects</subject><subject>Regulatory Sequences, Nucleic Acid - genetics</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Saccharomyces cerevisiae - cytology</subject><subject>Saccharomyces cerevisiae - drug effects</subject><subject>Saccharomyces cerevisiae - enzymology</subject><subject>Saccharomyces cerevisiae - genetics</subject><subject>Saccharomyces cerevisiae Proteins - antagonists &amp; 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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.</abstract><cop>United States</cop><pub>The American Society for Cell Biology</pub><pmid>19073887</pmid><doi>10.1091/mbc.E08-04-0438</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects Arsenic - toxicity
Base Sequence
Chromatin - metabolism
Cytosol - drug effects
Cytosol - metabolism
Gene Expression Regulation, Fungal - drug effects
Models, Biological
Molecular Sequence Data
Phosphorylation - drug effects
Protein Kinases - genetics
Protein Kinases - metabolism
Protein Transport - drug effects
Regulatory Sequences, Nucleic Acid - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae Proteins - antagonists & inhibitors
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Stress, Physiological - drug effects
Transcription, Genetic - drug effects
title Arsenic toxicity to Saccharomyces cerevisiae is a consequence of inhibition of the TORC1 kinase combined with a chronic stress response
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