Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae

The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH...

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Main Authors:	Desfossés-Baron, Kristelle, Hammond-Martel, Ian, Simoneau, Antoine, Sellam, Adnane, Roberts, Stephen, Wurtele, Hugo
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080547/

id	pubmed-5080547
recordtype	oai_dc
spelling	pubmed-50805472016-10-31 Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae Desfossés-Baron, Kristelle Hammond-Martel, Ian Simoneau, Antoine Sellam, Adnane Roberts, Stephen Wurtele, Hugo Article The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes. Nature Publishing Group 2016-10-26 /pmc/articles/PMC5080547/ /pubmed/27782169 http://dx.doi.org/10.1038/srep36013 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Desfossés-Baron, Kristelle Hammond-Martel, Ian Simoneau, Antoine Sellam, Adnane Roberts, Stephen Wurtele, Hugo
spellingShingle	Desfossés-Baron, Kristelle Hammond-Martel, Ian Simoneau, Antoine Sellam, Adnane Roberts, Stephen Wurtele, Hugo Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
author_facet	Desfossés-Baron, Kristelle Hammond-Martel, Ian Simoneau, Antoine Sellam, Adnane Roberts, Stephen Wurtele, Hugo
author_sort	Desfossés-Baron, Kristelle
title	Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
title_short	Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
title_full	Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
title_fullStr	Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
title_full_unstemmed	Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae
title_sort	valproate inhibits map kinase signalling and cell cycle progression in s. cerevisiae
description	The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080547/
_version_	1613698531564978176

Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae

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