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The cell wall integrity pathway regulates cyclin C-mediated cellular response to oxidative stress

Chunyan Jin
B.S., 2005
Nankai University, China

Thesis Advisor: Katrina Cooper, Ph.D.

Cell and Molecular Biology Program

Science Center, Room 290

Tuesday, April 23, 2013
12 pm


The Saccharomyces cerevisiae C-type cyclin and its cyclin-dependent kinase (Cdk8) repress the expression of several stress response genes. Following exposure to reactive oxygen species (ROS), this repression is relieved through cyclin C destruction that requires the cell wall integrity (CWI) MAP kinase pathway and the Ask10 associating factor. This report demonstrates that under low oxidative stress conditions, a combination of membrane sensors, Mtl1 and either Wsc1 or Mid2, are required jointly to transmit the oxidative stress signal to initiate cyclin C destruction. However, when exposed to elevated oxidative stress, additional pathways independent of these three sensor proteins are activated to destroy cyclin C. Combining constitutively active alleles at different stages in the CWI pathway with downstream mutations, two bifurcations in the signaling pathway were identified. First, activated Rho1 can trigger cyclin C destruction in the absence of stress even in a mutant strain lacking the MEK kinase Bck1. Second, activated Bck1 can induce cyclin C destruction in the absence of the MAP kinase Slt2/Mpk1. For this second branch, we identified the naturally inactive MAP kinase Kdx1 as an additional component functioning in the CWI-cyclin C destruction pathway. These results describe a highly branched CWI signal transduction pathway that responds to different levels of oxidative stress. Before cyclin C is destroyed, it is translocated from the nucleus into the cytoplasm where it initiates stress-induced mitochondrial fission and programmed cell death. The CWI pathway regulates the nuclear export of cyclin C in oxidative stress. We show here that the Slt2 MAP kinase and its pseudokinase paralog Kdx1 together mediate cyclin C translocation from the nucleus to the cytoplasm. Slt2 associates with cyclin C in both in vitro and in vivo. It phosphorylates cyclin C at Ser 266 in vitro kinase assay. A substitution mutation cyclin CS266A prevents its nuclear export. Kdx1 dose not associate with cyclin C, but it is required for cyclin C translocation and Ask10 phosphorylation that facilitates cyclin C destruction. Taken together, the highly branched CWI pathway regulates stress-induced cyclin C relocation and destruction by Slt2 phosphorylating cyclin C. Kdx1 facilitates cyclin C translocation and destruction by activating Ask10.

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