Multiple signaling pathways regulate yeast cell death during the response to mating pheromones

Department of Biology and Whitaker Institute for Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Molecular Biology of the Cell (Impact Factor: 4.47). 09/2006; 17(8):3409-22. DOI: 10.1091/mbc.E06-03-0177
Source: PubMed

ABSTRACT Mating pheromones promote cellular differentiation and fusion of yeast cells with those of the opposite mating type. In the absence of a suitable partner, high concentrations of mating pheromones induced rapid cell death in approximately 25% of the population of clonal cultures independent of cell age. Rapid cell death required Fig1, a transmembrane protein homologous to PMP-22/EMP/MP20/Claudin proteins, but did not require its Ca2+ influx activity. Rapid cell death also required cell wall degradation, which was inhibited in some surviving cells by the activation of a negative feedback loop involving the MAP kinase Slt2/Mpk1. Mutants lacking Slt2/Mpk1 or its upstream regulators also underwent a second slower wave of cell death that was independent of Fig1 and dependent on much lower concentrations of pheromones. A third wave of cell death that was independent of Fig1 and Slt2/Mpk1 was observed in mutants and conditions that eliminate calcineurin signaling. All three waves of cell death appeared independent of the caspase-like protein Mca1 and lacked certain "hallmarks" of apoptosis. Though all three waves of cell death were preceded by accumulation of reactive oxygen species, mitochondrial respiration was only required for the slowest wave in calcineurin-deficient cells. These findings suggest that yeast cells can die by necrosis-like mechanisms during the response to mating pheromones if essential response pathways are lacking or if mating is attempted in the absence of a partner.

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    • "Upon failure of either one of these processes, triggering PCD cleans the population from infertile or damaged cells, thus ensuring fitness and survival. In this line, haploid cells undergo PCD upon long-term exposure to pheromones without subsequent mating (Severin and Hyman, 2002; Zhang et al., 2006). Moreover, during meiosis of diploids to generate long-lived spores, a fraction of cells undergoes apoptosis (Knorre et al., 2005). "
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    Yeast 08/2014; 31(8). DOI:10.1002/yea.3020 · 1.63 Impact Factor
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    • "Cytoplasmic TUNEL staining has been described, but RNA fragmentation is rarely suggested as a possible cause. Nevertheless, TUNEL protocols often advise the use of RNAse treatment to clear the so-called cytoplasmic background (Zhang et al., 2006). However, as RNA integrity has been analyzed in an indirect way, further experiments like mass spectrometry would be necessary to confirm the alteration of RNA in KO-Tau mice. "
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    ABSTRACT: Nucleic acid protection is a substantial challenge for neurons, which are continuously exposed to oxidative stress in the brain. Neurons require powerful mechanisms to protect DNA and RNA integrity and ensure their functionality and longevity. Beside its well known role in microtubule dynamics, we recently discovered that Tau is also a key nuclear player in the protection of neuronal genomic DNA integrity under reactive oxygen species (ROS)-inducing heat stress (HS) conditions in primary neuronal cultures. In this report, we analyzed the capacity of Tau to protect neuronal DNA integrity in vivo in adult mice under physiological and HS conditions. We designed an in vivo mouse model of hyperthermia/HS to induce a transient increase in ROS production in the brain. Comet and Terminal deoxyribonucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assays demonstrated that Tau protected genomic DNA in adult cortical and hippocampal neurons in vivo under physiological conditions in wild-type (WT) and Tau-deficient (KO-Tau) mice. HS increased DNA breaks in KO-Tau neurons. Notably, KO-Tau hippocampal neurons in the CA1 subfield restored DNA integrity after HS more weakly than the dentate gyrus (DG) neurons. The formation of phosphorylated histone H2AX foci, a double-strand break marker, was observed in KO-Tau neurons only after HS, indicating that Tau deletion did not trigger similar DNA damage under physiological or HS conditions. Moreover, genomic DNA and cytoplasmic and nuclear RNA integrity were altered under HS in hippocampal neurons exhibiting Tau deficiency, which suggests that Tau also modulates RNA metabolism. Our results suggest that Tau alterations lead to a loss of its nucleic acid safeguarding functions and participate in the accumulation of DNA and RNA oxidative damage observed in the Alzheimer's disease (AD) brain.
    Frontiers in Cellular Neuroscience 03/2014; 8:84. DOI:10.3389/fncel.2014.00084 · 4.29 Impact Factor
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    • "Significantly, one study has shown that S. cerevisiae cells undergo apoptotic cell death in acidic environments [34]. PCD has also been linked to intrinsic processes including colony differentiation, replicative and chronological aging, and failed mating events [35-39]. Finally, the process of yeast programmed cell death is mediated by genes that have orthologs that have been implicated in mammalian apoptosis [40]. "
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    ABSTRACT: Background Saccharomyces boulardii is a probiotic yeast routinely used to prevent and to treat gastrointestinal disorders, including the antibiotic-associated diarrhea caused by Clostridium difficile infections. However, only 1-3% of the yeast administered orally is recovered alive in the feces suggesting that this yeast is unable to survive the acidic environment of the gastrointestinal tract. Results We provide evidence that suggests that S. boulardii undergoes programmed cell death (PCD) in acidic environments, which is accompanied by the generation of reactive oxygen species and the appearance of caspase-like activity. To better understand the mechanism of cell death at the molecular level, we generated microarray gene expression profiles of S. boulardii cells cultured in an acidic environment. Significantly, functional annotation revealed that the up-regulated genes were significantly over-represented in cell death pathways Finally, we show that S-adenosyl-L-methionine (AdoMet), a commercially available, FDA-approved dietary supplement, enhances the viability of S. boulardii in acidic environments, most likely by preventing programmed cell death. Conclusions In toto, given the observation that many of the proven health benefits of S. boulardii are dependent on cell viability, our data suggests that taking S. boulardii and AdoMet together may be a more effective treatment for gastrointestinal disorders than taking the probiotic yeast alone.
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