Regulation of the oxidative stress response through Slt2p-dependent destruction of cyclin C in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae C-type cyclin and its cyclin-dependent kinase (Cdk8p) repress the transcription of several stress response genes. To relieve this repression, cyclin C is destroyed in cells exposed to reactive oxygen species (ROS). This report describes the requirement of cyclin C destruction for the cellular response to ROS. Compared to wild type, deleting cyclin C makes cells more resistant to ROS while its stabilization reduces viability. The Slt2p MAP kinase cascade mediates cyclin C destruction in response to ROS treatment but not heat shock. This destruction pathway is important as deleting cyclin C suppresses the hypersensitivity of slt2 mutants to oxidative damage. The ROS hypersensitivity of an slt2 mutant correlates with elevated programmed cell death as determined by TUNEL assays. Consistent with the viability studies, the elevated TUNEL signal is reversed in cyclin C mutants. Finally, two results suggest that cyclin C regulates programmed cell death independently of its function as a transcriptional repressor. First, deleting its corepressor CDK8 does not suppress the slt2 hypersensitivity phenotype. Second, the human cyclin C, which does not repress transcription in yeast, does regulate ROS sensitivity. These findings demonstrate a new role for the Slt2p MAP kinase cascade in protecting the cell from programmed cell death through cyclin C destruction.
Krasley
Elizabeth
E
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Cooper
Katrina F
KF
Mallory
Michael J
MJ
Dunbrack
Roland
R
Strich
Randy
R
D019943:Amino Acid Substitution / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D056745:Cyclin C; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D017382:Reactive Oxygen Species / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D013489:Suppression, Genetic
C503674:CCNC protein, human; D056745:Cyclin C; D016213:Cyclins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; C490702:PKC1 protein, S cerevisiae; D011493:Protein Kinase C; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; C498309:SSN3 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae