title: Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae.
abstract: 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.
authors: Maisonneuve-Rosemont Hospital Research Center, 5415 L'Assomption Boulevard, Montreal, H1T 2M4, Canada.|Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors: Kristelle
authors: K
authors: Desfossés-Baron
authors: Maisonneuve-Rosemont Hospital Research Center, 5415 L'Assomption Boulevard, Montreal, H1T 2M4, Canada.|Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors: Ian
authors: I
authors: Hammond-Martel
authors: Maisonneuve-Rosemont Hospital Research Center, 5415 L'Assomption Boulevard, Montreal, H1T 2M4, Canada.|Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors: Antoine
authors: A
authors: Simoneau
authors: Infectious Diseases Research Centre-CRI, CHU de Québec Research Center (CHUQ), Université Laval, Québec, G1V 4G2, Canada.|Department of Microbiology-Infectious Disease and Immunology, Faculty of Medicine, Université Laval, Québec, G1V 0A6, Canada.
authors: Adnane
authors: A
authors: Sellam
authors: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
authors: Stephen
authors: S
authors: Roberts
authors: Maisonneuve-Rosemont Hospital Research Center, 5415 L'Assomption Boulevard, Montreal, H1T 2M4, Canada.|Department of Medicine, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors: Hugo
authors: H
authors: Wurtele
mesh_terms: D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D014635:Valproic Acid; C075580:FUS3 protein, S cerevisiae; C541984:KSS1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae