Differentiating mechanisms of toxicity using global gene expression analysis in Saccharomyces cerevisiae

Caba, Ebru; Dickinson, Donna; Warnes, Gregory R.; Aubrecht, Jiri

doi:10.1016/j.mrfmmm.2005.02.005

Cited by 51 publications

(64 citation statements)

References 53 publications

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“…Two other proteins identified in our study that affect sulfide production, Sit4p and Iki3p, are also known to form a complex with Hht2p (15,23,37). SIT4 is involved in transcriptional regulation (9), and IKI3 encodes for a subunit of the elongator complex (7,22,23). The fact that deletion of all three of these genes leads to increased H 2 S suggests that the reported interaction of their gene products is of biological significance and this complex exerts some form of regulation on the reduction of sulfide, either directly or indirectly.…”

Section: Discussionmentioning

confidence: 77%

Identification of Genes Affecting Hydrogen Sulfide Formation inSaccharomyces cerevisiae

Linderholm

Findleton

Kumar

et al. 2008

Appl Environ Microbiol

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A screen of the Saccharomyces cerevisiae deletion strain set was performed to identify genes affecting hydrogen sulfide (H 2 S) production. Mutants were screened using two assays: colony color on BiGGY agar, which detects the basal level of sulfite reductase activity, and production of H 2 S in a synthetic juice medium using lead acetate detection of free sulfide in the headspace. A total of 88 mutants produced darker colony colors than the parental strain, and 4 produced colonies significantly lighter in color. There was no correlation between the appearance of a dark colony color on BiGGY agar and H 2 S production in synthetic juice media. Sixteen null mutations were identified as leading to the production of increased levels of H 2 S in synthetic juice using the headspace analysis assay. All 16 mutants also produced H 2 S in actual juices. Five of these genes encode proteins involved in sulfur containing amino acid or precursor biosynthesis and are directly associated with the sulfate assimilation pathway. The remaining genes encode proteins involved in a variety of cellular activities, including cell membrane integrity, cell energy regulation and balance, or other metabolic functions. The levels of hydrogen sulfide production of each of the 16 strains varied in response to nutritional conditions. In most cases, creation of multiple deletions of the 16 mutations in the same strain did not lead to a further increase in H 2 S production, instead often resulting in decreased levels.

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Section: Discussionmentioning

confidence: 77%

Identification of Genes Affecting Hydrogen Sulfide Formation inSaccharomyces cerevisiae

Linderholm

Findleton

Kumar

et al. 2008

Appl Environ Microbiol

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“…9). Thirty-three of the 64 genes have been implicated in DNA damage response from previous microarray studies (14,16,23,33). Of these 33 genes, all but one had inferred regulatory directions that were consistent with current knowledge about the DNA damage response.…”

Section: (See Si Materials and Methods)mentioning

confidence: 80%

A systems approach to delineate functions of paralogous transcription factors: Role of the Yap family in the DNA damage response

Tan

Feizi

Luo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Duplication of genes encoding transcription factors plays an essential role in driving phenotypic variation. Because regulation can occur at multiple levels, it is often difficult to discern how each duplicated factor achieves its regulatory specificity. In these cases, a ''systems approach'' may distinguish the role of each factor by integrating complementary large-scale measurements of the regulatory network. To explore such an approach, we integrate growth phenotypes, promoter binding profiles, and gene expression patterns to model the DNA damage response network controlled by the Yeast-specific AP-1 (YAP) family of transcription factors. This analysis reveals that YAP regulatory specificity is achieved by at least three mechanisms: (i) divergence of DNAbinding sequences into two subfamilies; (ii) condition-specific combinatorial regulation by multiple Yap factors; and (iii) interactions of Yap 1, 4, and 6 with chromatin remodeling proteins. Additional microarray experiments establish that Yap 4 and 6 regulate gene expression through interactions with the histone deacetylase, Hda1. The data further highlight differences among Yap paralogs in terms of their regulatory mode of action (activation vs. repression). This study suggests how other large TF families might be disentangled in the future.ChIP-chip ͉ evolution ͉ systems biology

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“…Based on these results, the 56MESS concentration of 0.45 mM (between 0.40 and 0.50 mM), which caused significant growth inhibition, yet not substantial cell death, was chosen for genome-wide expression profiling of yeast response to 56MESS. This level of dosage was previously used in gene expression profiling studies in yeast for cellular response to drug treatments and certain environmental conditions [9,22]. Changes in gene expression and identification of major biological processes in response to 56MESS treatment To uncover genes important to the cytotoxicity of 56MESS, cDNA microarray technology was used to measure the changes of genome-wide gene expression after treatment for 1 h with 0.45 mM 56MESS.…”

Section: Cytotoxicity Of 56mess In the Cisplatin-resistant L1210cisr mentioning

confidence: 99%

“…The model eukaryotic organism, yeast Saccharomyces cerevisiae, plays a significant role in this approach [68] due to its easy amendability with various experimental approaches and conservation of genes and essential cellular functions with humans [3]. Application of yeast transcriptomics has already yielded insights on the genes and molecular mechanisms of cisplatin [9,23]. We therefore employed yeast transcriptomics in this study to uncover the genes and molecular pathways underpinning the cytotoxicity of 56MESS following the assessment of 56MESS activity in a cisplatin-resistant cancer cell line L1210cisR.…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Differentiating mechanisms of toxicity using global gene expression analysis in Saccharomyces cerevisiae

Cited by 51 publications

References 53 publications

Identification of Genes Affecting Hydrogen Sulfide Formation inSaccharomyces cerevisiae

Identification of Genes Affecting Hydrogen Sulfide Formation inSaccharomyces cerevisiae

A systems approach to delineate functions of paralogous transcription factors: Role of the Yap family in the DNA damage response

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

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