Regulation of the fission yeast transcription factor Pap1 by oxidative stress: requirement for the nuclear export factor Crm1 (Exportin) and the stress-activated MAP kinase Sty1/Spc1.
The fission yeast Sty1 stress-activated MAP kinase is crucial for the cellular response to a variety of stress conditions. Accordingly, sty1- cells are defective in their response to nutrient limitation, lose viability in stationary phase, and are hypersensitive to osmotic stress, oxidative stress, and UV treatment. Some of these phenotypes are caused by Sty1-dependent regulation of the Atf1 transcription factor, which controls both meiosis-specific and osmotic stress-responsive genes. However, in this report we demonstrate that the cellular response to oxidative stress and to treatment with a variety of cytotoxic agents is the result of Sty1 regulation of the Pap1 transcription factor, a bZip protein with structural and DNA binding similarities to the mammalian c-Jun protein. We show that both Sty1 and Pap1 are required for the expression of a number of genes involved in the oxidative stress response and for the expression of two genes, hba2+/bfr1+ and pmd1+, which encode energy-dependent transport proteins involved in multidrug resistance. Furthermore, we demonstrate that Pap1 is regulated by stress-dependent changes in subcellular localization. On imposition of oxidative stress, the Pap1 protein relocalizes from the cytoplasm to the nucleus in a process that is dependent on the Sty1 kinase. This relocalization is the result of regulated protein export, rather than import, and involves the Crm1 (exportin) nuclear export factor and the dcd1+/pim1+ gene that encodes an Ran nucleotide exchange factor.
Toone
W M
WM
Laboratory of Gene Regulation, Imperial Cancer Research Fund (ICRF), London WC2A 3PX, UK.jonesn@icrf.icnet.uk
Kuge
S
S
Samuels
M
M
Morgan
B A
BA
Toda
T
T
Jones
N
N
D051697:Activating Transcription Factor 1; D050976:Basic-Leucine Zipper Transcription Factors; D001692:Biological Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D002451:Cell Compartmentation; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D028884:Karyopherins; D016350:Leucine Zippers / Q000235:genetics / Q000502:physiology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D018384:Oxidative Stress; D000073718:Pancreatitis-Associated Proteins; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear; D012568:Schizosaccharomyces / Q000235:genetics* / Q000502:physiology; D029702:Schizosaccharomyces pombe Proteins; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014170:Transformation, Genetic; D000097606:Exportin 1 Protein
D051697:Activating Transcription Factor 1; D050976:Basic-Leucine Zipper Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D028884:Karyopherins; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D000073718:Pancreatitis-Associated Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D029702:Schizosaccharomyces pombe Proteins; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C105096:Pap1 protein, S pombe; C000612141:REG3A protein, human; C095409:sty1 protein, S pombe