Valproic acid induces apoptosis dependent of Yca1p at concentrations that mildly affect the proliferation of yeast

Abstract

Valproic acid (VPA) inhibited the growth of yeast in a dose-dependent manner with complete inhibition attained at 100 mM. When cells were exposed to 25 mM VPA, the wild-type died showing apoptotic markers, while yca1D deleted of YCA1 encoding yeast caspase 1 survived. On the other hand, when cells were exposed to 50 mM VPA, both the wild-type and yca1D died showing morphological features similar to those of the autophagic death of cdc28 which was also independent of YCA1. Thus, these results suggested that yeast cells die via YCA1-dependent apoptosis when their proliferative activity is mildly impaired.

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

“…However, apoptotic death induced by VPA in S. pombe and S. cerevisiae showed several differences. In S. cerevisiae, apoptotic death induced by VPA is dependent on metacaspase 22) and the Sir2 mutation makes cells resistant to VPA, 30) but as shown in Fig. 6, a pca1 mutant and a sir2 mutant of S. pombe showed sensitivity similar to VPA as the wild type.…”

“…pombe treated with VPA died with apoptotic markers Since S. cerevisiae died apoptotically when treated with VPA, 22) it was inferred that S. pombe also died apoptotically with VPA. We tested several apoptotic markers in S. pombe cells treated with VPA.…”

“…Fungi have a homologous enzyme, metacaspase. Disruption of the metacaspase gene of S. cerevisiae abrogated the apoptotic death caused by VPA 22) and H 2 O 2 . 29) We tested the effects of disruption of the metacaspase gene on VPA-induced cell death in S. pombe.…”

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

“…Furthermore, we found [9] that a mutation in the ARL1 encoding ADP-ribosylation factorlike protein 1, which functions in vesicular transport in both exocytic and endocytic pathways, caused a defect in central vacuole formation and delayed the progress of autophagic death in cdc28 and also that Bax-induced cell death. We reported recently [10] that valproic acid (VPA, 2-propylpentanoic acid) induced apoptosis in an YCA1-dependent manner when the cell's proliferative activity is mildly impaired by low concentration of VPA, whereas they die via autophagic death when it is impaired severely or completely. The mechanism of apoptosis induced by low concentration of VPA in yeast has not been clarified so far.…”

Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast

“…Additionally, yeasts possess several orthologs of mammalian celldeath mediators . Metacaspase Yca1 in S. cerevisiae was shown to undergo caspase-like proteolytic processing and mediate apoptosis under a wide range of stimuli, including in conditions involving hydrogen peroxide, acetic acid, chronological aging, hyper-osmotic shock, viral killer toxins, valproic acid, deleterious mutations in mRNA decapping, DNA replication and protein deubiquitylation, and heterologous expression of α-synuclein (Bettiga et al, 2004;Flower et al, 2005;Madeo et al, 2002;Mazzoni et al, 2005;Mitsui et al, 2005;Reiter et al, 2005;Silva et al, 2005;Weinberger et al, 2005). Overexpression of Trypanosoma brucei metacaspase promotes mitochondrion-associated cell death in S. cerevisiae, and Leishmania major metacaspase can functionally replace S. cerevisiae Yca1, alluding to the functional conservation of metacaspases in lower eukaryotes (Gonzalez et al, 2007;Szallies et al, 2002).…”