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The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.

Calvo IA, García P, Ayté J, Hidalgo E - Nucleic Acids Res. (2012)

Bottom Line: Oxidation and nuclear accumulation of Pap1 can also be accomplished by genetic inhibition of thioredoxin reductase.Furthermore, genetic alteration of the nuclear export pathway, or mutations in Pap1 nuclear export signal trigger nuclear accumulation of reduced Pap1.We show here that a subset of Pap1-dependent genes, such as those coding for the efflux pump Caf5, the ubiquitin-like protein Obr1 or the dehydrogenase SPCC663.08c, only require nuclear Pap1 for activation, whereas another subset of genes, those coding for the antioxidants catalase, sulfiredoxin or thioredoxin reductase, do need oxidized Pap1 to form a heterodimer with the constitutively nuclear transcription factor Prr1.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress and Cell Cycle Group, Department de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Dr. Aiguader 88, E-08003 Barcelona, Spain.

ABSTRACT
In response to hydrogen peroxide (H(2)O(2)), the transcription factor Pap1 from Schizosaccharomyces pombe regulates transcription of genes required for adaptation to oxidative stress and for tolerance to toxic drugs. H(2)O(2) induces oxidation of Pap1, its nuclear accumulation and expression of more than fifty Pap1-dependent genes. Oxidation and nuclear accumulation of Pap1 can also be accomplished by genetic inhibition of thioredoxin reductase. Furthermore, genetic alteration of the nuclear export pathway, or mutations in Pap1 nuclear export signal trigger nuclear accumulation of reduced Pap1. We show here that a subset of Pap1-dependent genes, such as those coding for the efflux pump Caf5, the ubiquitin-like protein Obr1 or the dehydrogenase SPCC663.08c, only require nuclear Pap1 for activation, whereas another subset of genes, those coding for the antioxidants catalase, sulfiredoxin or thioredoxin reductase, do need oxidized Pap1 to form a heterodimer with the constitutively nuclear transcription factor Prr1. The ability of Pap1 to bind and activate drug tolerance promoters is independent on Prr1, whereas its affinity for the antioxidant promoters is significantly enhanced upon association with Prr1. This finding suggests that the activation of both antioxidant and drug resistance genes in response to oxidative stress share a common inducer, H(2)O(2), but alternative effectors.

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Association of oxidized Pap1 and Prr1 is required for the activation of the antioxidant, but not the drug resistance, genes. (A) In wild-type cells, oxidation of Pap1 upon H2O2 stress induces its nuclear accumulation and its association with Prr1. The heterodimer is then able to activate both sets of promoters, the antioxidant (trr1, srx1, ctt1) and the drug resistance (obr1, caf5, c663.08c) genes. (B) In cells defective in Pap1 export (such as cells lacking Hba1 or expressing Pap1.C523D), the transcription factor cannot be oxidized by H2O2, cannot associate with Prr1 and can only trigger transcription of the drug resistance genes. (C) Similarly, in cells lacking Prr1, H2O2-oxidized Pap1 will only be able to activate drug resistance genes.
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gks141-F6: Association of oxidized Pap1 and Prr1 is required for the activation of the antioxidant, but not the drug resistance, genes. (A) In wild-type cells, oxidation of Pap1 upon H2O2 stress induces its nuclear accumulation and its association with Prr1. The heterodimer is then able to activate both sets of promoters, the antioxidant (trr1, srx1, ctt1) and the drug resistance (obr1, caf5, c663.08c) genes. (B) In cells defective in Pap1 export (such as cells lacking Hba1 or expressing Pap1.C523D), the transcription factor cannot be oxidized by H2O2, cannot associate with Prr1 and can only trigger transcription of the drug resistance genes. (C) Similarly, in cells lacking Prr1, H2O2-oxidized Pap1 will only be able to activate drug resistance genes.

Mentions: Components of oxidative stress signalling pathways have often been isolated in screens of general drug resistance, since several of these regulons include genes reported to contribute to drug export or detoxification. Here, we show that the Pap1-dependent gene expression program can be classified into two different and not overlapping subsets. The first one codes for activities responsible for multidrug resistance, and are triggered by nuclear Pap1, irrespective of its oxidation state. The second one, which includes traditional antioxidant genes, is only engaged by oxidized Pap1, which then binds to Prr1 and recognizes these promoters (Figure 6).Figure 6.


The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.

Calvo IA, García P, Ayté J, Hidalgo E - Nucleic Acids Res. (2012)

Association of oxidized Pap1 and Prr1 is required for the activation of the antioxidant, but not the drug resistance, genes. (A) In wild-type cells, oxidation of Pap1 upon H2O2 stress induces its nuclear accumulation and its association with Prr1. The heterodimer is then able to activate both sets of promoters, the antioxidant (trr1, srx1, ctt1) and the drug resistance (obr1, caf5, c663.08c) genes. (B) In cells defective in Pap1 export (such as cells lacking Hba1 or expressing Pap1.C523D), the transcription factor cannot be oxidized by H2O2, cannot associate with Prr1 and can only trigger transcription of the drug resistance genes. (C) Similarly, in cells lacking Prr1, H2O2-oxidized Pap1 will only be able to activate drug resistance genes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367182&req=5

gks141-F6: Association of oxidized Pap1 and Prr1 is required for the activation of the antioxidant, but not the drug resistance, genes. (A) In wild-type cells, oxidation of Pap1 upon H2O2 stress induces its nuclear accumulation and its association with Prr1. The heterodimer is then able to activate both sets of promoters, the antioxidant (trr1, srx1, ctt1) and the drug resistance (obr1, caf5, c663.08c) genes. (B) In cells defective in Pap1 export (such as cells lacking Hba1 or expressing Pap1.C523D), the transcription factor cannot be oxidized by H2O2, cannot associate with Prr1 and can only trigger transcription of the drug resistance genes. (C) Similarly, in cells lacking Prr1, H2O2-oxidized Pap1 will only be able to activate drug resistance genes.
Mentions: Components of oxidative stress signalling pathways have often been isolated in screens of general drug resistance, since several of these regulons include genes reported to contribute to drug export or detoxification. Here, we show that the Pap1-dependent gene expression program can be classified into two different and not overlapping subsets. The first one codes for activities responsible for multidrug resistance, and are triggered by nuclear Pap1, irrespective of its oxidation state. The second one, which includes traditional antioxidant genes, is only engaged by oxidized Pap1, which then binds to Prr1 and recognizes these promoters (Figure 6).Figure 6.

Bottom Line: Oxidation and nuclear accumulation of Pap1 can also be accomplished by genetic inhibition of thioredoxin reductase.Furthermore, genetic alteration of the nuclear export pathway, or mutations in Pap1 nuclear export signal trigger nuclear accumulation of reduced Pap1.We show here that a subset of Pap1-dependent genes, such as those coding for the efflux pump Caf5, the ubiquitin-like protein Obr1 or the dehydrogenase SPCC663.08c, only require nuclear Pap1 for activation, whereas another subset of genes, those coding for the antioxidants catalase, sulfiredoxin or thioredoxin reductase, do need oxidized Pap1 to form a heterodimer with the constitutively nuclear transcription factor Prr1.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress and Cell Cycle Group, Department de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Dr. Aiguader 88, E-08003 Barcelona, Spain.

ABSTRACT
In response to hydrogen peroxide (H(2)O(2)), the transcription factor Pap1 from Schizosaccharomyces pombe regulates transcription of genes required for adaptation to oxidative stress and for tolerance to toxic drugs. H(2)O(2) induces oxidation of Pap1, its nuclear accumulation and expression of more than fifty Pap1-dependent genes. Oxidation and nuclear accumulation of Pap1 can also be accomplished by genetic inhibition of thioredoxin reductase. Furthermore, genetic alteration of the nuclear export pathway, or mutations in Pap1 nuclear export signal trigger nuclear accumulation of reduced Pap1. We show here that a subset of Pap1-dependent genes, such as those coding for the efflux pump Caf5, the ubiquitin-like protein Obr1 or the dehydrogenase SPCC663.08c, only require nuclear Pap1 for activation, whereas another subset of genes, those coding for the antioxidants catalase, sulfiredoxin or thioredoxin reductase, do need oxidized Pap1 to form a heterodimer with the constitutively nuclear transcription factor Prr1. The ability of Pap1 to bind and activate drug tolerance promoters is independent on Prr1, whereas its affinity for the antioxidant promoters is significantly enhanced upon association with Prr1. This finding suggests that the activation of both antioxidant and drug resistance genes in response to oxidative stress share a common inducer, H(2)O(2), but alternative effectors.

Show MeSH
Related in: MedlinePlus