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Selective inhibition of yeast regulons by daunorubicin: a transcriptome-wide analysis.

Rojas M, Casado M, Portugal J, Piña B - BMC Genomics (2008)

Bottom Line: Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin.The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks.This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut for Molecular Biology of Barcelona, IBMB-CSIC, Jordi Girona, 18, 08034 Barcelona, Spain. mrabmc@cid.csic.es <mrabmc@cid.csic.es>

ABSTRACT

Background: The antitumor drug daunorubicin exerts some of its cytotoxic effects by binding to DNA and inhibiting the transcription of different genes. We analysed this effect in vivo at the transcriptome level using the budding yeast Saccharomyces cerevisiae as a model and sublethal (IC40) concentrations of the drug to minimise general toxic effects.

Results: Daunorubicin affected a minor proportion (14%) of the yeast transcriptome, increasing the expression of 195 genes and reducing expression of 280 genes. Daunorubicin down-regulated genes included essentially all genes involved in the glycolytic pathway, the tricarboxylic acid cycle and alcohol metabolism, whereas transcription of ribosomal protein genes was not affected or even slightly increased. This pattern is consistent with a specific inhibition of glucose usage in treated cells, with only minor effects on proliferation or other basic cell functions. Analysis of promoters of down-regulated genes showed that they belong to a limited number of transcriptional regulatory units (regulons). Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin.

Conclusion: The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks. This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.

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Related in: MedlinePlus

Transcriptional rate changes for Ribosomal Protein genes (solid dots) and Glycolytic genes (diamonds) after 1 (Y-axis) and 4 h (X-axis) of daunorubicin treatment. Data are expressed as logarithmic values of expression ratios between treated and untreated cells.
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Figure 3: Transcriptional rate changes for Ribosomal Protein genes (solid dots) and Glycolytic genes (diamonds) after 1 (Y-axis) and 4 h (X-axis) of daunorubicin treatment. Data are expressed as logarithmic values of expression ratios between treated and untreated cells.

Mentions: Gene Ontology (GO) analysis of genes activated and repressed by daunorubicin treatment showed a very different distribution of GO categories for both groups. Up-regulated genes fell into three main functional categories: Genes related to ribosome assembly and metabolism, Ty transposition, and proteolytic processes (Table 2). Whereas the two last categories may indicate a certain level of stress, up regulation of ribosome assembling-related genes usually correlates with a positive effect in cell growth. In contrast, GO analysis of genes down regulated by daunorubicin showed a general decrease of energy-producing metabolism, including genes involved in fermentation and in the tricarboxylic acid cycle. A significant proportion of down-regulated genes appeared involved in the metabolism of nitrogen compounds, including amino acids (Table 3). The dissociation between expression of ribosomal and glycolytic genes upon daunorubicin treatment can be observed in Figure 3, which shows up-regulation of most ribosomal protein genes and down-regulation of sugar and alcohol-metabolism related genes at one and four hours of daunorubicin treatment. Figure 4 shows a scheme of the glycolytic pathway, highlighting genes down regulated by daunorubicin. These genes codify the enzymes responsible for no less than 9 consecutive steps of the pathway. Therefore, the data suggests that the fermentation capacity should be depressed in daunorubicin-treated yeast cells.


Selective inhibition of yeast regulons by daunorubicin: a transcriptome-wide analysis.

Rojas M, Casado M, Portugal J, Piña B - BMC Genomics (2008)

Transcriptional rate changes for Ribosomal Protein genes (solid dots) and Glycolytic genes (diamonds) after 1 (Y-axis) and 4 h (X-axis) of daunorubicin treatment. Data are expressed as logarithmic values of expression ratios between treated and untreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2536678&req=5

Figure 3: Transcriptional rate changes for Ribosomal Protein genes (solid dots) and Glycolytic genes (diamonds) after 1 (Y-axis) and 4 h (X-axis) of daunorubicin treatment. Data are expressed as logarithmic values of expression ratios between treated and untreated cells.
Mentions: Gene Ontology (GO) analysis of genes activated and repressed by daunorubicin treatment showed a very different distribution of GO categories for both groups. Up-regulated genes fell into three main functional categories: Genes related to ribosome assembly and metabolism, Ty transposition, and proteolytic processes (Table 2). Whereas the two last categories may indicate a certain level of stress, up regulation of ribosome assembling-related genes usually correlates with a positive effect in cell growth. In contrast, GO analysis of genes down regulated by daunorubicin showed a general decrease of energy-producing metabolism, including genes involved in fermentation and in the tricarboxylic acid cycle. A significant proportion of down-regulated genes appeared involved in the metabolism of nitrogen compounds, including amino acids (Table 3). The dissociation between expression of ribosomal and glycolytic genes upon daunorubicin treatment can be observed in Figure 3, which shows up-regulation of most ribosomal protein genes and down-regulation of sugar and alcohol-metabolism related genes at one and four hours of daunorubicin treatment. Figure 4 shows a scheme of the glycolytic pathway, highlighting genes down regulated by daunorubicin. These genes codify the enzymes responsible for no less than 9 consecutive steps of the pathway. Therefore, the data suggests that the fermentation capacity should be depressed in daunorubicin-treated yeast cells.

Bottom Line: Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin.The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks.This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut for Molecular Biology of Barcelona, IBMB-CSIC, Jordi Girona, 18, 08034 Barcelona, Spain. mrabmc@cid.csic.es <mrabmc@cid.csic.es>

ABSTRACT

Background: The antitumor drug daunorubicin exerts some of its cytotoxic effects by binding to DNA and inhibiting the transcription of different genes. We analysed this effect in vivo at the transcriptome level using the budding yeast Saccharomyces cerevisiae as a model and sublethal (IC40) concentrations of the drug to minimise general toxic effects.

Results: Daunorubicin affected a minor proportion (14%) of the yeast transcriptome, increasing the expression of 195 genes and reducing expression of 280 genes. Daunorubicin down-regulated genes included essentially all genes involved in the glycolytic pathway, the tricarboxylic acid cycle and alcohol metabolism, whereas transcription of ribosomal protein genes was not affected or even slightly increased. This pattern is consistent with a specific inhibition of glucose usage in treated cells, with only minor effects on proliferation or other basic cell functions. Analysis of promoters of down-regulated genes showed that they belong to a limited number of transcriptional regulatory units (regulons). Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin.

Conclusion: The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks. This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.

Show MeSH
Related in: MedlinePlus