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Distinct signaling pathways respond to arsenite and reactive oxygen species in Schizosaccharomyces pombe
Miguel A Rodríguez-Gabriel1, Paul Russell
1Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Abstract:
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.
Insights
Arsenic toxicity in yeast is not strongly linked to oxidative stress. While Spc1 activation occurs with arsenic exposure, its basal activity is sufficient for survival.
Area of Science:
- Environmental toxicology
- Cellular stress responses
Background:
- Certain metals like arsenic are linked to cancer risk.
- Metal toxicity may involve reactive oxygen species (ROS) and DNA repair inhibition.
- Signal transduction pathways might play a role in metal-induced tumor development.
Purpose of the Study:
- To investigate the connection between metal toxicity and ROS.
- To compare the effects of arsenite and hydrogen peroxide in yeast.
- To elucidate the role of specific transcription factors and signaling pathways in metal stress response.
Main Methods:
- Utilized wild-type and mutant strains of Schizosaccharomyces pombe.
- Compared responses to arsenite and hydrogen peroxide exposure.
- Analyzed the involvement of transcription factors (Atf1, Pap1, Zip1) and the Spc1 MAPK pathway.
Main Results:
- An atf1Δ pap1Δ strain showed high sensitivity to hydrogen peroxide but not arsenite.
- A Zip1-deficient strain exhibited the opposite sensitivity pattern.
- Spc1 (Sty1) MAPK and Wis1 MAPKK were crucial for survival against both arsenite and hydrogen peroxide.
- Inactivation of Win1 and Wis4 reduced Spc1 activation by arsenite, but cells still survived.
- Mcs4 was not required for Spc1 activation by arsenite, unlike its role in oxidative stress.
Conclusions:
- Arsenic toxicity is not strongly associated with oxidative stress.
- Spc1 activation by arsenic occurs, but its basal activity is sufficient for arsenic survival.
- Distinct pathways mediate responses to arsenite and oxidative stress in yeast.
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