Valproate induces apoptosis by inducing accumulation of neutral lipids which was prevented by disruption of the <i>SIR2</i> gene in <i>Saccharomyces cerevisiae</i>

Sun, Qiang; Bi, Lijun; Su, Xiulan; Tsurugi, Kunio; Mitsui, Kazuhiro

doi:10.1016/j.febslet.2007.07.030

Cited by 18 publications

(16 citation statements)

References 28 publications

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“…We found that low pH strongly potentiated the growth-inhibiting properties of VPA, in accord with published studies documenting pH-dependent VPA-induced growth inhibition and apoptosis in S. pombe 53. VPA-induced apoptosis has also been reported in S. cerevisiae, although these data were generated using YPD medium (which is normally at higher pH than SC) over long time periods, i.e., 24 h or more1112. Yca1 (a caspase-like protease) and the class III HDAC Sir2 are required for apoptosis in response to VPA in budding yeast1112.…”

Section: Discussionsupporting

confidence: 90%

“…VPA-induced apoptosis has also been reported in S. cerevisiae, although these data were generated using YPD medium (which is normally at higher pH than SC) over long time periods, i.e., 24 h or more1112. Yca1 (a caspase-like protease) and the class III HDAC Sir2 are required for apoptosis in response to VPA in budding yeast1112. While we did not formally test whether VPA caused apoptosis under our conditions, deletion of YCA1 and SIR2, or other proapoptotic genes ( FIS1, BXI1, KEX1 ; Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…As for human cells, protracted VPA exposure causes apoptosis in the budding yeast Saccharomyces cerevisiae 1112. VPA-mediated HDAC inhibition also leads to hyperacetylation of certain DNA repair proteins in this organism, resulting in their autophagic degradation and consequent DNA repair defects13.…”

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

Desfossés-Baron

Hammond-Martel

Simoneau

et al. 2016

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Desfossés-Baron

Hammond-Martel

Simoneau

et al. 2016

Sci Rep

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“…This indicates that metacaspase did not play a role in the death of S. pombe cells induced by VPA. A defect in Sir2, which encodes a NAD-dependent histone deacetylase, 30) made S. cerevisiae cells resistant to VPA, 31) while the S. pombe strain with the sir2 mutation was as sensitive to VPA as the wild type both on plates and in liquid culture (Fig. 6B).…”

Section: Defects In Metacaspase and Sir2 Did Not Affect Sensitivity Tmentioning

confidence: 99%

Apoptotic Cell Death in the Fission YeastSchizosaccharomyces pombeInduced by Valproic Acid and Its Extreme Susceptibility to pH Change

Mutoh

Kitajima

Ichihara

2011

Bioscience, Biotechnology, and Biochemistry

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Schizosaccharomyces pombe treated with valproic acid died with apoptotic markers such as DNA fragmentation, loss of a mitochondrial electrochemial gradient and chromatin condensation, independently of metacaspase, a yeast homolog of metazoan caspase. Sensitivity to valproic acid was strongly dependent on growth phase. Cells in a later growth phase were much more sensitive to valproic acid than those in an earlier one. Altering the pH of the medium with HCl and with NaOH also caused remarkable changes in sensitivity. Cells in an acidic medium were more sensitive to valproic acid. This pH-dependent change in sensitivity did not require de novo protein synthesis, and a change in pH 60 min after the administration of valproic acid affected sensitivity. These results suggest that the intracellular cell death process was susceptible to extracellular pH. Although a sir2 mutant of Saccharomyces cerevisiae has been reported to be resistant to valproic acid, mutations in sir2 did not affect the sensitivity to valproic acid of S. pombe.

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“…39 Moreover, low doses of valproic acid, an inhibitor of histone deacetylases (HDACs) in mammalian cells, which displays antitumor activity and is extensively used to treat neuropsychiatric disorders, induces YCA1-dependent yeast apoptosis, 35 which is prevented upon deletion of the HDAC SIR2. 40 Treatment of yeast cells with amiodarone also triggers yeast cell death, in this case via the mitochondrial pathway and preceded by a Ca 2 þ boost. 36 The transcriptional response of yeast cells to amiodarone treatment includes two signatures: one that resembles a Ca 2 þ stress response that is accompanied by downregulation of genes involved in all stages of cell-cycle control, and another that is Ca 2 þ -independent and affects nutrient-responsive genes.…”

Section: Triggering Yeast Apoptosismentioning

confidence: 99%

Apoptosis in yeast: triggers, pathways, subroutines

et al. 2010

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A cell's decision to die is controlled by a sophisticated network whose deregulation contributes to the pathogenesis of multiple diseases including neoplastic and neurodegenerative disorders. The finding, more than a decade ago, that baker's yeast (Saccharomyces cerevisiae) can undergo apoptosis uncovered the possibility to investigate this mode of programmed cell death (PCD) in a model organism that combines both technical advantages and a eukaryotic 'cell room.' Since then, numerous exogenous and endogenous triggers have been found to induce yeast apoptosis and multiple yeast orthologs of crucial metazoan apoptotic regulators have been identified and characterized at the molecular level. Such apoptosis-relevant orthologs include proteases such as the yeast caspase as well as several mitochondrial and nuclear proteins that contribute to the execution of apoptosis in a caspase-independent manner. Additionally, physiological scenarios such as aging and failed mating have been discovered to trigger apoptosis in yeast, providing a teleological interpretation of PCD affecting a unicellular organism. Due to its methodological and logistic simplicity, yeast constitutes an ideal model organism that is efficiently helping to decipher the cell death regulatory network of higher organisms, including the switches between apoptotic, autophagic, and necrotic pathways of cellular catabolism. Here, we provide an overview of the current knowledge about the apoptotic subroutine of yeast PCD and its regulation.

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Valproate induces apoptosis by inducing accumulation of neutral lipids which was prevented by disruption of the SIR2 gene in Saccharomyces cerevisiae

Cited by 18 publications

References 28 publications

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

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

Apoptotic Cell Death in the Fission YeastSchizosaccharomyces pombeInduced by Valproic Acid and Its Extreme Susceptibility to pH Change

Apoptosis in yeast: triggers, pathways, subroutines

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