A common need for microbial cells is the ability to respond to potentially toxic environmental insults. Here we review the progress in understanding the response of the yeast Saccharomyces cerevisiae to two important environmental stresses: heat shock and oxidative stress. Both of these stresses are fundamental challenges that microbes of all types will experience. The study of these environmental stress responses in S. cerevisiae has illuminated many of the features now viewed as central to our understanding of eukaryotic cell biology. Transcriptional activation plays an important role in driving the multifaceted reaction to elevated temperature and levels of reactive oxygen species. Advances provided by the development of whole genome analyses have led to an appreciation of the global reorganization of gene expression and its integration between different stress regimens. While the precise nature of the signal eliciting the heat shock response remains elusive, recent progress in the understanding of induction of the oxidative stress response is summarized here. Although these stress conditions represent ancient challenges to S. cerevisiae and other microbes, much remains to be learned about the mechanisms dedicated to dealing with these environmental parameters.
Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.
Saccharomyces cerevisiae cells possess the ability to simultaneously acquire resistance to an array of drugs with different cytotoxic activities. The genes involved in this acquisition are referred to as pleiotropic drug resistant (PDR) (14,20,22,25,30,49
The jun family of transcriptional activators includes mammalian AP-1 as well as the yeast regulatory protein GCN4. Recently, an additional transcriptional activator has been found in yeast that recognizes the TGACTCA sequence element common in GCN4/AP-1 sites. This factor was designated yAP-1. The structural gene for yAP-1 has now been isolated and characterized. The deduced amino acid sequence predicts a protein of 650 residues, considerably larger than GCN4 or c-Jun. The amino terminus of yAP-1 is homologous to the carboxyterminal DNA-binding domains of GCN4 and e-Jun. Disruption of the YAP1 gene demonstrates this gene is not essential but is required for AP-1 recognition element-dependent transcriptional activation. DNA-affinity blots of proteins from YAP1 cells suggest the presence of additional TGACTCA-binding proteins other than GCN4 and yAP-1. Furthermore, expression of at least one of these related DNA-binding proteins appears to be under control of yAP-1.
Multiple or pleiotropic drug resistance most often occurs in Saccharomyces cerevisiae due to substitution mutations within the Cys 6 -Zn(II) transcription factors Pdr1p and Pdr3p. These dominant transcriptional regulatory proteins cause elevated drug resistance and overexpression of the ATP-binding cassette transporterencoding gene, PDR5. We have carried out a genetic screen to identify negative regulators of PDR5 expression and found that loss of the mitochondrial genome ( o cells) causes up-regulation of Pdr3p but not Pdr1p function. Additionally, loss of the mitochondrial inner membrane protein Oxa1p generates a signal that results in increased Pdr3p activity. Both of these mitochondrial defects lead to increased expression of the PDR3 structural gene. Importantly, the signaling pathway used to enhance Pdr3p function in o cells is not the same as in oxa1 cells. Loss of previously described nuclear-mitochondrial signaling genes like RTG1 reduce the level of PDR5 expression and drug resistance seen in o cells but has no effect on oxa1-induced phenotypes. These data uncover a new regulatory pathway connecting expression of multidrug resistance genes with mitochondrial function.
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