The role of Pap1 in oxidative stress and drug resistance

The transcription factor Pap1 in fission yeast is the homologue of mammalian c-Jun, which is part of the AP-1 complex that regulates genes controlling cellular differentiation, proliferation and apoptosis. Pap1 was identified, because it confers resistance to several drugs and it was also seen that this phenomenon is associated with the activation of oxidative stress signaling pathways in several microbes. Surprisingly, recent research by the Oxidative Stress and Cell Cycle group of Elena Hidalgo from the CEXS-UPF demonstrates now that the gain of drug resistance does not correlate with enhanced tolerance to oxidative stress.

The article published in Nucleic Acid Research presents evidence that only oxidized nuclear Pap1, but not the reduced one, interacts with the transcription regulator Prr1 and activates antioxidant genes. The activities responsible for multidrug resistance, on the other hand, are triggered by nuclear Pap1 irrespective of its oxidation state. So it looks like there are two non-overlapping Pap1-dependent gene expression programs.

Furthermore it could be shown that the drug tolerance gene Caf5, an efflux pump, gets over-expressed, when non-oxidized Pap1 accumulates in the nucleus in the absence of Prr1. At present, Caf5 seems to be sufficient to explain the drug resistance phenotype.

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.


Calvo IA, García P, Ayté J, Hidalgo E
The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.
Nucleic Acids Res. 2012 Feb 16;


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