Genome-wide identification of genes involved in the positive and negative regulation of acetic acid-induced programmed cell death in Saccharomyces cerevisiae

BMC Genomics

Research Article

Andreia Pacheco¹  Manuela Côrte-Real¹  Ana Marta Duarte¹  Tânia R Fernandes¹  Marlene Sousa¹  Maria João Sousa¹  Susana R Chaves¹  Cecília Leão² 

[1] Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Universidade do Minho, Campus de Gualtar, 4710-057, Braga, Portugal;Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057, Braga, Portugal;ICVS/3B’s - PT Government Associate Laboratory, Braga, Guimarães, Portugal;

关键词: Phenotypic screen;    Euroscarf knock-out mutant collection;    Yeast;    Apoptosis;    Tumour cells;    Alcoholic fermentation;   

DOI  :  10.1186/1471-2164-14-838

 received in 2013-06-28, accepted in 2013-11-14,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAcetic acid is mostly known as a toxic by-product of alcoholic fermentation carried out by Saccharomyces cerevisiae, which it frequently impairs. The more recent finding that acetic acid triggers apoptotic programmed cell death (PCD) in yeast sparked an interest to develop strategies to modulate this process, to improve several biotechnological applications, but also for biomedical research. Indeed, acetate can trigger apoptosis in cancer cells, suggesting its exploitation as an anticancer compound. Therefore, we aimed to identify genes involved in the positive and negative regulation of acetic acid-induced PCD by optimizing a functional analysis of a yeast Euroscarf knock-out mutant collection.ResultsThe screen consisted of exposing the mutant strains to acetic acid in YPD medium, pH 3.0, in 96-well plates, and subsequently evaluating the presence of culturable cells at different time points. Several functional categories emerged as greatly relevant for modulation of acetic acid-induced PCD (e.g.: mitochondrial function, transcription of glucose-repressed genes, protein synthesis and modifications, and vesicular traffic for protection, or amino acid transport and biosynthesis, oxidative stress response, cell growth and differentiation, protein phosphorylation and histone deacetylation for its execution). Known pro-apoptotic and anti-apoptotic genes were found, validating the approach developed. Metabolism stood out as a main regulator of this process, since impairment of major carbohydrate metabolic pathways conferred resistance to acetic acid-induced PCD. Among these, lipid catabolism arose as one of the most significant new functions identified. The results also showed that many of the cellular and metabolic features that constitute hallmarks of tumour cells (such as higher glycolytic energetic dependence, lower mitochondrial functionality, increased cell division and metabolite synthesis) confer sensitivity to acetic acid-induced PCD, potentially explaining why tumour cells are more susceptible to acetate than untransformed cells and reinforcing the interest in exploiting this acid in cancer therapy. Furthermore, our results clearly establish a connection between cell proliferation and cell death regulation, evidencing a conserved developmental role of programmed cell death in unicellular eukaryotes.ConclusionsThis work advanced the characterization of acetic acid-induced PCD, providing a wealth of new information on putative molecular targets for its control with impact both in biotechnology and biomedicine.

【 授权许可】

CC BY   
© Sousa et al.; licensee BioMed Central Ltd. 2013