Distinct signaling pathways respond to arsenite and reactive oxygen species in Schizosaccharomyces pombe.
Exposure to certain metal and metalloid species, such as arsenic, cadmium, chromium, and nickel, has been associated with an increased risk of cancer in humans. The biological effects of these metals are thought to result from induction of reactive oxygen species (ROS) and inhibition of DNA repair enzymes, although alterations in signal transduction pathways may also be involved in tumor development. To better understand metal toxicity and its connection to ROS, we have compared the effects of arsenite and hydrogen peroxide in wild-type and mutant strains of the fission yeast Schizosaccharomyces pombe. An atf1Delta pap1Delta strain, which is defective in two transcription factors that control stress responses, is extremely sensitive to hydrogen peroxide but not to arsenite. A strain that lacks the transcription factor Zip1 has the opposite relationship. Spc1 (Sty1) mitogen-activated protein kinase (MAPK), a homologue of mammalian p38 MAPK, and the upstream MAPK kinase (MAPKK) Wis1 are essential for survival of both arsenite and hydrogen peroxide. Inactivation of two MAPKK kinases, Win1 and Wis4, almost completely eliminates Spc1 activation by arsenite, yet these cells survive arsenite treatment. The two-component phosphorelay protein Mcs4, which acts upstream of Win1 and Wis4 and is required for Spc1 activation in response to oxidative stress, is not required for Spc1 activation in response to arsenite. We conclude that the toxic effects of arsenic are not strongly connected to oxidative stress and that although Spc1 is activated by arsenic exposure, the basal activity of Spc1 is largely sufficient for the survival of arsenic.
Rodríguez-Gabriel
Miguel A
MA
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Russell
Paul
P
D018053:Arsenites / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
D018053:Arsenites; D018797:Cell Cycle Proteins; C105788:Mcs4 protein, S pombe; D017382:Reactive Oxygen Species; D029702:Schizosaccharomyces pombe Proteins; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D020930:MAP Kinase Kinase Kinases; C109170:win1 protein, S pombe; D020929:Mitogen-Activated Protein Kinase Kinases; C072068:wis1 protein, S pombe; D017027:Protein Tyrosine Phosphatases; C097097:pyp1 protein, S pombe; C015001:arsenite